Preface

Chapter 7 **Treatment of Class II Malocclusion (Hypodivergent Face) with**

Chapter 9 **Assessment of All-Ceramic Dental Restorations Behavior by**

Liliana Porojan, Florin Topală and Sorin Porojan

**Section 4 Research Guidelines on Oral Health Promotion 193**

Chapter 10 **Oral Health Promotion: Evidences and Strategies 195**

**Development of Simulation-Based Experimental Methods 173**

Vikram R. Niranjan, Vikas Kathuria, Venkatraman J and Arpana

**MEAW Therapy 123**

**VI** Contents

Salve

Paulo Augusto de Sousa Beltrão

**Section 3 Innovations in Dental Restorations 143**

Chapter 8 **Functional Biomimetic Dental Restoration 145** Elham M. Senan and Ahmed A. Madfa

> Evidence-based dentistry is a concept held in high regard in the field of clinical dentistry for decades. The concept is based on the systematic approach of amalgamating establish‐ ed scientific and clinical evidence and relevant clinical application in everyday practice. An unbiased analytical approach of all relevant data should be undertaken in order to deliver the best care for the patient. This analysis involves the integration of the evidence into various aspects of clinical management and the oral status, as it relates to oral health and systemic risk factors.

> In *Insights into Various Aspects of Oral Health*, a comprehensive web-based resource, the aim is to combine the scientific literature with the clinical evidence. Here, there is evidenced lit‐ erature with clinical applications on systemic health, risk factors and periodontal disease, functional rehabilitation and innovative restorative material science. This web resource is a collaboration of numerous specialists and researchers from around the world showcasing varied topics from aspects of oral health status to clinical management. Due to the extensive nature of the areas presented in this resource, limitations are inevitable. An incorporation of review, research studies and clinical management of the following topics are covered:


The subject matter has relevance to a broad oral healthcommunity, including educators and dental students with interests in different subject areas of dentistry. The judicious integration of various topics is designed to give readers an insight into evidenced studies and review different aspects of the oral health status. This book has an international perspective, covering contemporary research on periodontal disease, functional occlusal rehabilitation, research on the biomimetic restorative materials and guidelines on oral health promotion strategies.

Information presented on periodontal status ranges from the diagnostics of specific disease or disorder causing desquamative gingivitis (DG) to the increase of oxidative stress seen in chronic inflammatory conditions and genetic risk factors associated with periodontitis. An investigative review is undertaken on the similarities in pathophysiology of both chronic obstructive pulmonary disease and chronic periodontitis, due to high levels of the pro-in‐ flammatory cytokines, such as CRP and TNF-α and proteases, associated with these chronic inflammatory conditions. Microbial interference therapy using different modalities in the treatment of advanced to aggressive periodontitis has been an ongoing treatment for years, but increasingly the side effects and transient nature of this approach have compromised the goal of the outcome. In this book, a review is presented on an alternative treatment involv‐ ing non-surgical treatment and probiotic intake. This can lead to host modulation and mi‐ crobial regulation and contribute to successful periodontal treatment outcomes.

Further, another aspect of oral health is the clinical management of cleft lip and palate (CLP) —the most common congenital deformity of the orofacial region. This chapter highlights the concepts and direction for treatment associated with clefts, with the aim of restoring aesthetics and functional impairments through various modalities. Also addressed is MEAW therapy in restoring aesthetics and occlusal function in the correction of class II deep bite malocclusion together with a hypo-divergent skeletal pattern. This is a difficult situation to treat due to insufficient vertical dimension, combined with steepness of the occlusal plane and strong muscle patterns present in these types of patients. The evidence-based patient cases presented here support MEAW therapy as an effective method of restoring this malocclusion.

In addition, an insight into bioinspired innovative restorative material, which has the ability to combine diverse material properties into a single structure of functionally graded materi‐ al (FGM), is presented here. The advantage of this system is the integration of dissimilar materials with minimal internal stress and reduced stress concentration at the interface re‐ sulting in a free surface intersection. The potential for delamination between layers is elimi‐ nated in the graded structure, unlike in traditional core-veneer fabrication, and has applications in implant dentistry, direct-filling tooth restoratives, crowns, dental prosthetics, dental posts, etc.

An analytical input of a digital simulation for providing a biomechanical explanation of the clinical behaviour of ceramic bilayer crowns is also presented here. Finite element analysis (FEA) is a powerful and flexible computational tool that models dental structures and devi‐ ces, simulates occlusal loading conditions and predicts stress and strain distribution. This can provide design guidelines for the development of complex structures and has the capa‐ bility to predict clinical survival of all-ceramic restorative prostheses, based on functional loading in the posterior region, hence predicting better crown outcomes.

Oral health promotion involves strategic planning, integrative activities, evidence-based concepts, evaluation, policy making and effective and sustainable intervention. In this en‐ deavour, along with the consideration of the above factors, contributing and limiting ele‐ ments such as fiscal limitations, regional factors and the comprehension of the population to create healthy living conditions are addressed here. The action programme is influenced by community empowerment, creating a sustainable supporting environment originating from local experiences and strengths. Oral health promotion has a wide scientific scope, with evi‐ dences and strategies varying in each region, so a platform to share an amalgamated global strategy is a challenging exercise and is the objective of this chapter.

**Jane Francis Manakil, BDS, MDS, PhD, GCHE, MRACDS (Periodontology)**

Senior Lecturer, School of Dentistry and Oral Health, Griffith University, Queensland, Australia **Relationship Between the Periodontal Diseases and the Systemic Health**

goal of the outcome. In this book, a review is presented on an alternative treatment involv‐ ing non-surgical treatment and probiotic intake. This can lead to host modulation and mi‐

Further, another aspect of oral health is the clinical management of cleft lip and palate (CLP) —the most common congenital deformity of the orofacial region. This chapter highlights the concepts and direction for treatment associated with clefts, with the aim of restoring aesthetics and functional impairments through various modalities. Also addressed is MEAW therapy in restoring aesthetics and occlusal function in the correction of class II deep bite malocclusion together with a hypo-divergent skeletal pattern. This is a difficult situation to treat due to insufficient vertical dimension, combined with steepness of the occlusal plane and strong muscle patterns present in these types of patients. The evidence-based patient cases presented

In addition, an insight into bioinspired innovative restorative material, which has the ability to combine diverse material properties into a single structure of functionally graded materi‐ al (FGM), is presented here. The advantage of this system is the integration of dissimilar materials with minimal internal stress and reduced stress concentration at the interface re‐ sulting in a free surface intersection. The potential for delamination between layers is elimi‐ nated in the graded structure, unlike in traditional core-veneer fabrication, and has applications in implant dentistry, direct-filling tooth restoratives, crowns, dental prosthetics,

An analytical input of a digital simulation for providing a biomechanical explanation of the clinical behaviour of ceramic bilayer crowns is also presented here. Finite element analysis (FEA) is a powerful and flexible computational tool that models dental structures and devi‐ ces, simulates occlusal loading conditions and predicts stress and strain distribution. This can provide design guidelines for the development of complex structures and has the capa‐ bility to predict clinical survival of all-ceramic restorative prostheses, based on functional

Oral health promotion involves strategic planning, integrative activities, evidence-based concepts, evaluation, policy making and effective and sustainable intervention. In this en‐ deavour, along with the consideration of the above factors, contributing and limiting ele‐ ments such as fiscal limitations, regional factors and the comprehension of the population to create healthy living conditions are addressed here. The action programme is influenced by community empowerment, creating a sustainable supporting environment originating from local experiences and strengths. Oral health promotion has a wide scientific scope, with evi‐ dences and strategies varying in each region, so a platform to share an amalgamated global

**Jane Francis Manakil, BDS, MDS, PhD, GCHE, MRACDS (Periodontology)**

Senior Lecturer, School of Dentistry and Oral Health,

Griffith University, Queensland,

Australia

loading in the posterior region, hence predicting better crown outcomes.

strategy is a challenging exercise and is the objective of this chapter.

crobial regulation and contribute to successful periodontal treatment outcomes.

here support MEAW therapy as an effective method of restoring this malocclusion.

dental posts, etc.

VIII Preface

**Chapter 1**

**Provisional chapter**

## **Desquamative Gingivitis**

**Desquamative Gingivitis**

Hiroyasu Endo, Terry D. Rees, Hideo Niwa, Kayo Kuyama, Morio Iijima, Ryuuichi Imamura, Takao Kato, Kenji Doi, Hirotsugu Yamamoto and Takanori Ito Kayo Kuyama, Morio Iijima, Ryuuichi Imamura, Takao Kato, Kenji Doi, Hirotsugu Yamamoto and Takanori Ito Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Hiroyasu Endo, Terry D. Rees, Hideo Niwa,

http://dx.doi.org/10.5772/intechopen.69268

#### **Abstract**

Desquamative gingivitis (DG) is characterized by erythematous, epithelial desquama‐ tion, erosion of the gingival epithelium, and blister formation on the gingiva. DG is a clinical feature of a variety of diseases or disorders. Most cases of DG are associated with mucocutaneous diseases, the most common ones being lichen planus, mucous membrane pemphigoid, and pemphigus vulgaris. Proper diagnosis of the underlying cause is important because the prognosis varies, depending on the disease. This chapter presents the underlying etiology that is most commonly associated with DG. The current literature on the diagnostic and management modalities of patients with DG is reviewed.

DOI: 10.5772/intechopen.69268

**Keywords:** gingival diseases/pemphigus/pemphigoid, benign mucous membrane/lichen planus, oral/hypersensitivity/autoimmune diseases

## **1. Introduction**

Manifestations of desquamative gingivitis (DG) include erythematous gingiva, epithelial des‐ quamation, and erosion of the gingival epithelium, as well as blister formation on the gingiva [1, 2] (**Figure 1**). The DG lesions may be localized or generalized and may extend into the alveolar mucosa. Similar lesions are often found on the buccal mucosa, tongue, and palate in the oral cavity. The signs of DG are clearly different from those of dental plaque‐induced gingivitis. Patients having DG may be asymptomatic or symptomatic [3]. Most symptomatic patients complain of mild or moderate oral discomfort, gingival soreness, or a burning sensa‐ tion [4, 5]. DG occurs more often in females than males; approximately 80% of the patients are female [4–8]. Most patients with DG are middle‐aged and older, although rare cases have

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**Figure 1.** Desquamative lesions on the attached gingiva. Gentle palpation with the periodontal probe elicited some desquamation of the gingival surface (positive Nikolsky's sign).

been observed in children [4, 6, 8, 9]. Early investigators believed that there was a single etiology for DG. However, it is apparent that the condition is a nonspecific manifestation of several diseases or disorders and therefore has multiple etiologies [1, 2]. Most cases of DG are associated with mucocutaneous diseases, the most common ones being lichen planus (LP), mucous membrane pemphigoid (MMP), and pemphigus vulgaris (PV) [1, 2, 4–8, 10, 11]. A variety of other potential causes, such as lupus erythematosus [12], mixed connective tissue disease [5, 10], graft versus host disease [13], erythema multiforme [14], epidermolysis bullosa [15, 16], epidermolysis bullosa acquisita [17], Kindler syndrome [18], chronic ulcerative sto‐ matitis [10, 19, 20], lichen planus pemphigoides [21, 22], plasmacytosis [23], plasma cell gingi‐ vitis [24], orofacial granulomatosis [25, 26], foreign body granulomas [27], candidal infection [28], and linear IgA disease [29, 30], may cause DG lesions. Factitious injury of the gingiva may also present with clinical features consistent with DG [31–34], which was suggestive of mucocutaneous diseases including MMP [32, 33] or PV [34]. Contact stomatitis due to den‐ tal hygiene products, dental materials, or food flavorings and preservatives may mimic DG [1, 11, 25, 35–39], while several systemic disorders, including Crohn's disease [40], psoriasis [41–43], sarcoidosis [44], and adverse drug reactions [38, 45], may possess some but usually not all of the clinical features of DG.

## **2. Diagnosis**

It is very important to accurately diagnose diseases or disorders causing DG because the prognosis varies widely, depending on the cause. Although PV rarely occurs, it is a poten‐ tially life‐threatening disease, so it is important to diagnose and treat it in its early stages. Airway obstruction due to laryngeal scarring and blindness due to conjunctival scarring would certainly deteriorate the quality of life for MMP patients. Early recognition and treat‐ ment of the lesions can prevent serious complications. Histopathological examination and direct immunofluorescence (DIF) testing of biopsied tissues are often required to deter‐ mine the underlying etiology of DG [6–8, 10]. For histopathological study, the biopsy site should be selected from an area of intact epithelium and include perilesional tissue. This may require two separate biopsies, one lesional and one non‐lesional. The perilesional tissue or non‐lesional biopsy site should show a nonspecific inflammatory response in suspected non‐autoimmune disorders such as LP, erythema multiforme, foreign body gingivitis, facti‐ tious disorder, and contact stomatitis [1, 7, 10]. In contrast, the DIF test should be performed on normal‐appearing tissue rather than perilesional sites in suspected autoimmune diseases such as MMP, PV, and chronic ulcerative stomatitis [1, 7, 10, 46, 47]. Since immune deposits in autoimmune bullous disease are present in all oral tissue, a positive result from DIF tests may be obtained from biopsies taken from distant normal mucosa [46]. The DIF test is consid‐ ered to be the best diagnostic evidence for MMP, PV, chronic ulcerative stomatitis, and other autoimmune disorders; therefore, DIF testing is often essential in obtaining a final diagnosis since clinical features may be so similar [6–8, 10, 47, 48]. On the other hand, DIF findings are supportive but not diagnostic for LP, psoriasis, lupus erythematosus, and mixed connective tissue disease because the DIF features of these diseases can also be found in other condi‐ tions [6, 10, 48]. A negative result from DIF tests should be anticipated in biopsies of contact stomatitis [1].

Biopsy sites appearing to have an intact epithelial surface should be selected. If lesions are present at several mucosal sites, including the gingiva, it is usually best not to use the gingiva for the biopsy [1, 49, 50]. However, in approximately half of DG cases, the gingiva was the only site of involvement [50, 51]. In these cases, the gingiva should be selected for the biopsy. Rees and Burkhart [1] described the six steps to be considered when a gingival biopsy is required in DG patients. They highlight the importance of careful site selection for gingival biopsies in order to obtain diagnostic tissue samples. An inadequate surgical site selection may easily lead to the loss of the gingival epithelium, since the biopsied gingival tissue is thin and tends to be fragile. The stab‐and‐roll biopsy technique is a procedure specially designed to prevent the epithelium from being removed from the biopsy specimen [1, 46, 52]. This biopsy technique prevents the occurrence of lateral shear forces. The operator applies gentle pressure on the gingiva with the tip of a #15 blade until the bone surface is reached and then the blade is rolled from the tip along the entire cutting edge. If a larger specimen is needed, the tip of the blade can be repositioned and the rolling stroke extended. The gingival epithe‐ lium was well maintained, and the relationship with the underlying connective tissue was diagnostic from the gingiva of DG patients using the stab‐and‐roll biopsy technique [1, 46, 52].

#### **3. Oral mucosal diseases or disorders that are associated with DG**

#### **3.1. Lichen planus (LP)**

been observed in children [4, 6, 8, 9]. Early investigators believed that there was a single etiology for DG. However, it is apparent that the condition is a nonspecific manifestation of several diseases or disorders and therefore has multiple etiologies [1, 2]. Most cases of DG are associated with mucocutaneous diseases, the most common ones being lichen planus (LP), mucous membrane pemphigoid (MMP), and pemphigus vulgaris (PV) [1, 2, 4–8, 10, 11]. A variety of other potential causes, such as lupus erythematosus [12], mixed connective tissue disease [5, 10], graft versus host disease [13], erythema multiforme [14], epidermolysis bullosa [15, 16], epidermolysis bullosa acquisita [17], Kindler syndrome [18], chronic ulcerative sto‐ matitis [10, 19, 20], lichen planus pemphigoides [21, 22], plasmacytosis [23], plasma cell gingi‐ vitis [24], orofacial granulomatosis [25, 26], foreign body granulomas [27], candidal infection [28], and linear IgA disease [29, 30], may cause DG lesions. Factitious injury of the gingiva may also present with clinical features consistent with DG [31–34], which was suggestive of mucocutaneous diseases including MMP [32, 33] or PV [34]. Contact stomatitis due to den‐ tal hygiene products, dental materials, or food flavorings and preservatives may mimic DG [1, 11, 25, 35–39], while several systemic disorders, including Crohn's disease [40], psoriasis [41–43], sarcoidosis [44], and adverse drug reactions [38, 45], may possess some but usually

**Figure 1.** Desquamative lesions on the attached gingiva. Gentle palpation with the periodontal probe elicited some

It is very important to accurately diagnose diseases or disorders causing DG because the prognosis varies widely, depending on the cause. Although PV rarely occurs, it is a poten‐ tially life‐threatening disease, so it is important to diagnose and treat it in its early stages. Airway obstruction due to laryngeal scarring and blindness due to conjunctival scarring

not all of the clinical features of DG.

desquamation of the gingival surface (positive Nikolsky's sign).

4 Insights into Various Aspects of Oral Health

**2. Diagnosis**

LP is a relatively common, T‐cell‐mediated chronic inflammatory disease of unknown etiology. LP commonly occurs in middle‐aged and older people, and women are affected more frequently than men [53, 54]. The lesions are found in multiple regions including the skin, genitalia, or oral mucosa, although they are confined to the gingiva alone in some cases [53–56] (**Figures 2** and **3**). In many instances, atrophic, ulcerative, and bullous forms are combined as erosive LP. The reticular, popular, and plaque‐like forms of LP are often asymptomatic, whereas erosive forms may be quite painful when a patient is eating spicy foods or performing oral hygiene procedures [53–55, 57] (**Figures 4**–**6**). For these reasons, erosive LP usually requires treat‐ ment. Histopathologically, specimens may demonstrate hyperortho‐ or hyperparakeratosis, degenerative changes to the basal cells, and band‐like subepithelial infiltrate composed of lymphocytes [11] (**Figure 7**). When available, DIF testing is also valuable in establishing the diagnosis, although DIF findings are only suggestive, rather than diagnostic, of LP [6, 10, 48, 58]. Characteristic DIF findings in oral LP include a linear pattern of anti‐fibrin or anti‐fibrino‐ gen in the basement membrane zone and, to a lesser degree, the presence of IgM or IgG depos‐ its in cytoid bodies [6, 10, 48, 58] (**Figure 8**).

#### **3.2. Mucous membrane pemphigoid (MMP)**

MMP is an autoimmune, subepithelial blistering disease that affects mucous membranes. Most patients with MMP are between 60 and 80 years of age [59–61]. However, on relatively rare occasions, MMP has been reported in children [9]. Women are affected nearly two times more frequently than men [59–61]. MMP can involve any oral mucosal site, although the gingiva is affected far more often than other oral tissues [52, 59–62] (**Figures 9**–**13**). In more than half of early developing cases, the gingiva is the only site of lesions [61, 63]. Extraoral areas including the conjunctiva, skin, pharynx, nose, larynx, genitalia, anus, and esophagus may also be affected [52, 62, 64, 65]. Scarring of the mucous membranes is often considered the clinical hallmark of MMP, although scarring is rarely a feature of oral MMP [52, 64, 65].

**Figure 2.** Desquamative gingivitis associated with oral lichen planus. Erythematous lesions on the attached gingiva.

than men [53, 54]. The lesions are found in multiple regions including the skin, genitalia, or oral mucosa, although they are confined to the gingiva alone in some cases [53–56] (**Figures 2** and **3**). In many instances, atrophic, ulcerative, and bullous forms are combined as erosive LP. The reticular, popular, and plaque‐like forms of LP are often asymptomatic, whereas erosive forms may be quite painful when a patient is eating spicy foods or performing oral hygiene procedures [53–55, 57] (**Figures 4**–**6**). For these reasons, erosive LP usually requires treat‐ ment. Histopathologically, specimens may demonstrate hyperortho‐ or hyperparakeratosis, degenerative changes to the basal cells, and band‐like subepithelial infiltrate composed of lymphocytes [11] (**Figure 7**). When available, DIF testing is also valuable in establishing the diagnosis, although DIF findings are only suggestive, rather than diagnostic, of LP [6, 10, 48, 58]. Characteristic DIF findings in oral LP include a linear pattern of anti‐fibrin or anti‐fibrino‐ gen in the basement membrane zone and, to a lesser degree, the presence of IgM or IgG depos‐

MMP is an autoimmune, subepithelial blistering disease that affects mucous membranes. Most patients with MMP are between 60 and 80 years of age [59–61]. However, on relatively rare occasions, MMP has been reported in children [9]. Women are affected nearly two times more frequently than men [59–61]. MMP can involve any oral mucosal site, although the gingiva is affected far more often than other oral tissues [52, 59–62] (**Figures 9**–**13**). In more than half of early developing cases, the gingiva is the only site of lesions [61, 63]. Extraoral areas including the conjunctiva, skin, pharynx, nose, larynx, genitalia, anus, and esophagus may also be affected [52, 62, 64, 65]. Scarring of the mucous membranes is often considered the clinical hallmark of MMP, although scarring is rarely a feature of oral MMP [52, 64, 65].

**Figure 2.** Desquamative gingivitis associated with oral lichen planus. Erythematous lesions on the attached gingiva.

its in cytoid bodies [6, 10, 48, 58] (**Figure 8**).

6 Insights into Various Aspects of Oral Health

**3.2. Mucous membrane pemphigoid (MMP)**

**Figure 3.** Desquamative gingivitis associated with oral lichen planus. Patchy erythematous lesion was found on the palatal mucosa.

**Figure 4.** Desquamative gingivitis associated with oral lichen planus. Reticular lesions of buccal mucosa in addition to gingiva.

Multiple target antigens of MMP were identified in cell‐to‐basement membrane adhesion components by the presence of circulating autoantibodies in the patients' serum. These antigens include bullous pemphigoid antigens (BP180 and BP230), α6 β4 integrin, type VII collagen, and laminin 332 [62, 63, 66, 67]. The loss of cell‐to‐basement membrane adhesion

**Figure 5.** Extraoral lesion associated with oral lichen planus. The reticular lesion was observed on the lip.

**Figure 6.** Oral lichen planus patient. The examination revealed diffuse erythematous lesions on the gingiva (A and B). Lesions were also found on the buccal mucosa (C) and tongue (D).

caused by these antibodies may result in subepithelial blistering. Histopathologically, MMP is characterized by subepithelial bulla formation [11] (**Figure 14**). During DIF testing, the lin‐ ear deposition of complement component C3, IgG, or other immunoglobulin is observed in a linear pattern along the basement membrane zone [48, 62] (**Figure 15**).

**Figure 7.** Hematoxylin‐eosin‐stained section of oral lichen planus. The basal layer liquefaction and shortened rete ridges were found. A band‐like infiltration of lymphocytes in the lamina propria was also observed.

**Figure 8.** Direct immunofluorescence of oral lichen planus. A linear deposition of fibrinogen at the basement membrane zone was found.

#### **3.3. Pemphigus vulgaris (PV)**

caused by these antibodies may result in subepithelial blistering. Histopathologically, MMP is characterized by subepithelial bulla formation [11] (**Figure 14**). During DIF testing, the lin‐ ear deposition of complement component C3, IgG, or other immunoglobulin is observed in a

**Figure 6.** Oral lichen planus patient. The examination revealed diffuse erythematous lesions on the gingiva (A and B).

**Figure 5.** Extraoral lesion associated with oral lichen planus. The reticular lesion was observed on the lip.

linear pattern along the basement membrane zone [48, 62] (**Figure 15**).

Lesions were also found on the buccal mucosa (C) and tongue (D).

8 Insights into Various Aspects of Oral Health

PV is an autoimmune blistering disease characterized by acantholysis in the epithelium. Most patients with PV are middle‐aged and elderly [68–71]. The disease is equally common in men and women [71], and it is a potentially life‐threatening disease [72]. Characteristics

**Figure 9.** Desquamative gingivitis associated with mucous membrane pemphigoid. Ulcerated gingival surface was observed.

**Figure 10.** Desquamative gingivitis associated with mucous membrane pemphigoid. Ulceration of the palatal mucosa.

of the PV lesions are flaccid bulla formation, erosion, and ulceration in the skin or mucosa [1, 68] (**Figures 16**–**19**). PV frequently begins with oral lesions and later progresses to involve the skin [73, 74] (**Figure 20**). Oral lesions are the most common evidence and develop in almost all patients having PV [68, 71]. Lesions may affect the gingiva, and occasionally, the gingiva is the only site of involvement in early lesions [69, 73–75]. Circulating PV autoantibodies

**Figure 11.** Desquamative lesions featuring gingival erythema associated with mucous membrane pemphigoid.

**Figure 12.** Localized blister formation on the gingiva associated with mucous membrane pemphigoid.

of the PV lesions are flaccid bulla formation, erosion, and ulceration in the skin or mucosa [1, 68] (**Figures 16**–**19**). PV frequently begins with oral lesions and later progresses to involve the skin [73, 74] (**Figure 20**). Oral lesions are the most common evidence and develop in almost all patients having PV [68, 71]. Lesions may affect the gingiva, and occasionally, the gingiva is the only site of involvement in early lesions [69, 73–75]. Circulating PV autoantibodies

**Figure 10.** Desquamative gingivitis associated with mucous membrane pemphigoid. Ulceration of the palatal mucosa.

**Figure 9.** Desquamative gingivitis associated with mucous membrane pemphigoid. Ulcerated gingival surface was

observed.

10 Insights into Various Aspects of Oral Health

in the serum are pathogenic, and they can cause acantholysis in the epithelium [76]. More than 50 proteins have been reported to specifically react with pemphigus IgG autoantibodies [77], but it has been determined that the principal autoantigens in pemphigus patients are desmogleins, which are the components of desmosomes in the epidermis and mucous mem‐ branes [78, 79]. Almost all patients with PV lesions restricted to the oral mucosa have only anti‐desmoglein 3 antibody in the serum, whereas patients with advanced cases involving

**Figure 13.** Desquamative lesions on the attached gingiva associated with mucous membrane pemphigoid.

**Figure 14.** Hematoxylin‐eosin‐stained section of mucous membrane pemphigoid. A subepithelial blister formation was found.

the oral mucosa and skin may have both anti‐desmoglein 3 and anti‐desmoglein 1 antibodies [73, 74]. Histopathologically, PV is characterized by acantholysis and a suprabasilar split in the epithelium [11] (**Figure 21**). Tzanck cells are often found in intraepithelial clefts [80]. In the DIF examination of PV patients, the deposition of IgG and/or C3 is found in the intercel‐ lular spaces of the epithelium [48] (**Figure 22**).

**Figure 15.** Direct immunofluorescence of the mucous membrane pemphigoid. A linear deposition of IgG at the basement membrane zone was found.

**Figure 16.** Desquamative gingivitis associated with pemphigus vulgaris. Eroded gingival surface with ragged edges was observed.

#### **3.4. Contact hypersensitivity reactions as cause of DG**

the oral mucosa and skin may have both anti‐desmoglein 3 and anti‐desmoglein 1 antibodies [73, 74]. Histopathologically, PV is characterized by acantholysis and a suprabasilar split in the epithelium [11] (**Figure 21**). Tzanck cells are often found in intraepithelial clefts [80]. In the DIF examination of PV patients, the deposition of IgG and/or C3 is found in the intercel‐

**Figure 14.** Hematoxylin‐eosin‐stained section of mucous membrane pemphigoid. A subepithelial blister formation was

**Figure 13.** Desquamative lesions on the attached gingiva associated with mucous membrane pemphigoid.

lular spaces of the epithelium [48] (**Figure 22**).

12 Insights into Various Aspects of Oral Health

found.

Localized or generalized DG is sometimes elicited by contact hypersensitivity reactions to various foodstuffs, preservatives, oral hygiene products, and dental restorative materials [11, 25, 35–39, 81]. Toothpaste hypersensitivity reactions may occur in various oral or perioral

**Figure 17.** Desquamative gingivitis associated with pemphigus vulgaris. Localized erosions of the palatal mucosa.

**Figure 18.** Mild erythema and ulceration of gingiva associated with pemphigus vulgaris.

sites, but the gingiva was the most common site of onset [24, 35, 36, 39, 81] (**Figure 23**). Erythema has been expressed as a "velvet‐like appearance of the gingiva" or "fiery red gin‐ giva" [35]. Epithelial sloughing is the most common irritant effect associated with toothpastes and mouthwashes [1, 2, 35, 82] (**Figure 24**). Allergy to dental restorative materials usually causes localized DG in gingival or other mucosal tissues directly contacting the allergen [1, 11]. Gingival contact hypersensitivity lesions are usually not biopsied. However, if a biopsy

**Figure 19.** Pseudomembrane‐covered erosion of buccal mucosa associated with pemphigus vulgaris.

**Figure 20.** Skin involvement in a desquamative gingivitis associated with pemphigus vulgaris.

sites, but the gingiva was the most common site of onset [24, 35, 36, 39, 81] (**Figure 23**). Erythema has been expressed as a "velvet‐like appearance of the gingiva" or "fiery red gin‐ giva" [35]. Epithelial sloughing is the most common irritant effect associated with toothpastes and mouthwashes [1, 2, 35, 82] (**Figure 24**). Allergy to dental restorative materials usually causes localized DG in gingival or other mucosal tissues directly contacting the allergen [1, 11]. Gingival contact hypersensitivity lesions are usually not biopsied. However, if a biopsy

**Figure 18.** Mild erythema and ulceration of gingiva associated with pemphigus vulgaris.

**Figure 17.** Desquamative gingivitis associated with pemphigus vulgaris. Localized erosions of the palatal mucosa.

14 Insights into Various Aspects of Oral Health

is performed, these lesions present with non‐specific histopathologic findings with submuco‐ sal perivascular inflammatory cell infiltration [11, 35, 36]. The existence of focal granuloma‐ tous inflammation and/or multinucleated giant cells in the deep layer of the lamina propria was also described in some cases studying contact hypersensitivity stomatitis [25, 81]. DIF is not indicated because it is routinely negative [11]. To treat contact hypersensitivity reac‐ tions, the allergen should be identified and removed. To do so, patients should be questioned

**Figure 21.** Hematoxylin‐eosin‐stained section of pemphigus vulgaris. Acantholys was recognized.

**Figure 22.** Direct immunofluorescence of pemphigus vulgaris. An intercellular deposition of IgG was seen.

regarding the type(s) of oral hygiene products they use, and a 1–2‐week food diary may help identify causative agents [35]. Patch testing may be required to identify the allergen or to confirm a specific allergen in a dental hygiene product or in a dental restoration. Patients are considered to have allergic reactions to a relevant allergen if their patch test results are

**Figure 23.** Contact hypersensitivity reactions caused by toothpaste. Localized erythematous and edematous lesions were found on the gingiva.

**Figure 24.** Contact hypersensitivity reactions caused by mouth rinse. Epithelial sloughing was noted.

regarding the type(s) of oral hygiene products they use, and a 1–2‐week food diary may help identify causative agents [35]. Patch testing may be required to identify the allergen or to confirm a specific allergen in a dental hygiene product or in a dental restoration. Patients are considered to have allergic reactions to a relevant allergen if their patch test results are

**Figure 22.** Direct immunofluorescence of pemphigus vulgaris. An intercellular deposition of IgG was seen.

**Figure 21.** Hematoxylin‐eosin‐stained section of pemphigus vulgaris. Acantholys was recognized.

16 Insights into Various Aspects of Oral Health

positive [35, 81]. However, diagnosis of contact hypersensitivity reactions may be confirmed simply by the discontinuation of the causative agent(s) resulting in the remission of clinical signs and symptoms [35, 36, 81].

**Figure 25.** Desquamative gingivitis associated with mucous membrane pemphigoid. The initial examination revealed moderate erythema and swelling of the gingiva with plaque and calculus deposits (A). Treatment response. The condition of the gingiva improved due to a topical corticosteroid therapy combined with effective plaque control (B).

## **4. Managing DG patients**

The specific disease or disorder causing DG, the severity of the gingival lesions, the pres‐ ence or absence of extraoral involvements, and the medical history of the patient are the key factors in determining the selection of a topical or systemic immunosuppressive ther‐ apy [1, 2, 69, 83]. The patients diagnosed as having an autoimmune disease should be closely followed because they may require immediate referral to other health care experts especially if they develop extraoral lesions. After MMP is diagnosed from DG or con‐ comitant lesions, patients should undergo examination by medical specialists including an ophthalmologist and an otolaryngologist, and the presence or absence of extraoral lesions should be determined. PV patients with exclusively oral lesions should be fol‐ lowed closely and referred to other experts immediately if they develop lesions elsewhere on the body. Management of the specific disease or disorder causing DG may best be provided by a specialist in oral medicine, oral pathology, periodontics, or oral surgery, but the dentist may still be responsible for maintaining the dental and periodontal health of the patient. This is important because periodontal and dental considerations are often observed in DG patients, but the literature contains minimal information regarding the periodontal and dental management of these individuals. Plaque‐induced gingivitis is almost universal in patients with symptomatic DG, and an effective therapeutic protocol should include non‐surgical periodontal therapy consisting of oral hygiene instruction, scaling, and root planting [2, 84–89] (**Figure 25**). We believe that excessively vigorous scaling and root planting can be unnecessarily damaging to DG‐affected lesions, and we prefer a sequential gingival management approach that features gentle supragingival and slight subgingival debridement which can be repeated at two‐week intervals resulting in gradual improvement in periodontal status until an acceptable level of periodontal health has been achieved. The relationship between the existence of DG lesions and the progression of periodontal diseases is inconclusive, although some but not all studies demonstrated a correlation between compromised periodontal status and autoimmune bullous diseases affecting the mouth [90–96]. There are several reports on periodontal surgery or dental implant therapy performed on patients having DG [15–17, 73, 97–100]. Tissue sloughing and a lack of tissue elasticity caused by active autoimmune bullous disease can disturb the manipulation of the mucosal flap. Strict mucosal disease control prior to surgery may reduce the surgical complications [101]. Implant therapy is likely to enhance the quality of life in patients with systemic diseases and may help them maintain long‐term masticatory function. Patients with DG are often unable to wear tissue‐borne prostheses because of discomfort. This tissue irritation and oral pain can be increased if the appliances are ill fitting or damaged. A dental implant‐supported prosthesis improves the stabilization of the prosthesis, resulting in a higher degree of comfort. Published case reports indicated that DG patients can be successfully managed with dental implants. These reports suggest that the degree of disease control may be more important than the nature of the disease itself in regard to the effects on osseointegration. Penarrocha et al. [98] reported that implants can be successfully placed and used to support den‐ tal prostheses in patients with recessive dystrophic epidermolysis bullosa. A total of 38 implants were placed in six totally edentulous patients. Only one implant failed to achieve osseointegration. The average follow‐up from implant placement was 5.5 years. The implant‐supported prostheses were associated with improvements in the patients' comfort and function, esthetics and appearance, taste, speech, and self‐esteem. Altin et al. [99] presented a case of PV rehabilitation using a successful implant‐supported pros‐ thesis with a 32‐month follow‐up. They concluded that the implant treatment may be considered as a good alternative to a tissue‐borne prosthesis in PV patients. Esposito et al. [100] reported implant retained overdentures for two patients with severe oral LP. The patients were often unable to wear tissue‐borne prostheses because of the discomfort. There was good integration of the implants with no clinical or radiographic evidence of bone loss, and the soft‐tissue/implant response was excellent. Lesions occasionally flared‐ up but were successfully treated with topical steroids. There was no evidence of potential implant failure as a result of these flare‐ups. Although these descriptions of successful management using dental implants for patients with DG are promising, further studies are needed since these were individual case reports.

## **5. Conclusion**

**4. Managing DG patients**

18 Insights into Various Aspects of Oral Health

control (B).

The specific disease or disorder causing DG, the severity of the gingival lesions, the pres‐ ence or absence of extraoral involvements, and the medical history of the patient are the key factors in determining the selection of a topical or systemic immunosuppressive ther‐ apy [1, 2, 69, 83]. The patients diagnosed as having an autoimmune disease should be closely followed because they may require immediate referral to other health care experts especially if they develop extraoral lesions. After MMP is diagnosed from DG or con‐ comitant lesions, patients should undergo examination by medical specialists including an ophthalmologist and an otolaryngologist, and the presence or absence of extraoral lesions should be determined. PV patients with exclusively oral lesions should be fol‐ lowed closely and referred to other experts immediately if they develop lesions elsewhere on the body. Management of the specific disease or disorder causing DG may best be provided by a specialist in oral medicine, oral pathology, periodontics, or oral surgery, but the dentist may still be responsible for maintaining the dental and periodontal health of the patient. This is important because periodontal and dental considerations are often observed in DG patients, but the literature contains minimal information regarding the periodontal and dental management of these individuals. Plaque‐induced gingivitis is almost universal in patients with symptomatic DG, and an effective therapeutic protocol should include non‐surgical periodontal therapy consisting of oral hygiene instruction, scaling, and root planting [2, 84–89] (**Figure 25**). We believe that excessively vigorous scaling and root planting can be unnecessarily damaging to DG‐affected lesions, and we prefer a sequential gingival management approach that features gentle supragingival and slight subgingival debridement which can be repeated at two‐week intervals resulting in gradual improvement in periodontal status until an acceptable level of periodontal health has been achieved. The relationship between the existence of DG lesions and the progression of periodontal diseases is inconclusive, although some but not all studies

**Figure 25.** Desquamative gingivitis associated with mucous membrane pemphigoid. The initial examination revealed moderate erythema and swelling of the gingiva with plaque and calculus deposits (A). Treatment response. The condition of the gingiva improved due to a topical corticosteroid therapy combined with effective plaque

> DG is a clinical manifestation that is common to several diseases or disorders. It is important to diagnose the diseases causing DG because the prognosis varies, depending on the dis‐ ease. Histopathological examination and DIF testing are often required to establish the final diagnosis. The patients diagnosed with autoimmune diseases such as MMP or PV should be closely followed because they must be immediately referred to other experts when they develop lesions on parts of their body other than the oral cavity.

## **Abbreviations**


## **Author details**

Hiroyasu Endo1 \*, Terry D. Rees2 , Hideo Niwa3 , Kayo Kuyama4 , Morio Iijima5 , Ryuuichi Imamura6 , Takao Kato7 , Kenji Doi1 , Hirotsugu Yamamoto4 and Takanori Ito1

\*Address all correspondence to: endo.hiroyasu@nihon‐u.ac.jp

1 Department of Oral Diagnosis, School of Dentistry at Matsudo, Nihon University, Matsudo, Japan

2 Department of Periodontics, Texas A&M College of Dentistry, Dallas, Texas, USA

3 Department of Head and Neck Surgery, School of Dentistry at Matsudo, Nihon University, Matsudo, Japan

4 Department of Oral Pathology, School of Dentistry at Matsudo, Nihon University, Matsudo, Japan

5 Department of Removable Prosthodontics, School of Dentistry at Matsudo, Nihon University, Matsudo, Japan

6 Department of Maxillofacial Orthodontics, School of Dentistry at Matsudo, Nihon University, Matsudo, Japan

7 Department of Oral Implantology, School of Dentistry at Matsudo, Nihon University, Matsudo, Japan

## **References**


com/articles/show/title/diagnosis‐and‐management‐of‐desquamative‐gingivitis [Accessed: February 9, 2017]

[3] Nisengard RJ, Levine RA. Diagnosis and management of desquamative gingivitis. Periodontal Insights. 1995;**2**:4‐10

**Abbreviations**

20 Insights into Various Aspects of Oral Health

**Author details**

Hiroyasu Endo1

Matsudo, Japan

Matsudo, Japan

**References**

University, Matsudo, Japan

University, Matsudo, Japan

February 9, 2017]

, Takao Kato7

Imamura6

Japan

Japan

\*, Terry D. Rees2

DG Desquamative gingivitis

MMP Mucous membrane pemphigoid

DIF Direct immunofluorescence

LP Lichen planus

PV Pemphigus vulgaris

, Kenji Doi1

\*Address all correspondence to: endo.hiroyasu@nihon‐u.ac.jp

, Hideo Niwa3

2 Department of Periodontics, Texas A&M College of Dentistry, Dallas, Texas, USA

, Hirotsugu Yamamoto4

1 Department of Oral Diagnosis, School of Dentistry at Matsudo, Nihon University, Matsudo,

3 Department of Head and Neck Surgery, School of Dentistry at Matsudo, Nihon University,

4 Department of Oral Pathology, School of Dentistry at Matsudo, Nihon University, Matsudo,

5 Department of Removable Prosthodontics, School of Dentistry at Matsudo, Nihon

6 Department of Maxillofacial Orthodontics, School of Dentistry at Matsudo, Nihon

7 Department of Oral Implantology, School of Dentistry at Matsudo, Nihon University,

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**Provisional chapter**

## **Periodontal Disease and Nuclear and Oxidative DNA Damage Periodontal Disease and Nuclear and Oxidative DNA Damage**

DOI: 10.5772/intechopen.68446

Ana L. Zamora-Perez, Guillermo M. Zúñiga-González, Belinda C. Gómez-Meda, Blanca P. Lazalde-Ramos, Yveth M. Ortiz-García, Gabriela Morales-Velazquez, Celia Guerrero Velázquez and María G. Sánchez-Parada Ana L. Zamora-Perez, Guillermo M. Zúñiga-González, Belinda C. Gómez-Meda, Blanca P. Lazalde-Ramos, Yveth M. Ortiz-García, Gabriela Morales-Velazquez, Celia Guerrero Velázquez and María G. Sánchez-Parada

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.68446

#### **Abstract**

Oral health is an important aspect of the overall health status of an individual. DNA damage has been associated with oral health and dental factors due to the increased of oxidative stress (OxS). DNA damage can produce a wide range of effects on human health. These effects could appear immediately, but others do not become evident much later. Chronic diseases have been study to understand their mechanisms, clinical implications, and the development of secondary disease such as cancer. Periodontitis is one of the most common oral diseases. It is an inflammatory chronic infectious disease, which is characterized by the loss of supporting tissues and tooth loss caused by periodontopathogens and long-term release of reactive oxygen species (ROS); thus, oxidative stress is increased during periodontitis. Oxidative stress can produce DNA damage, including the oxidation of nucleosides, which could cause DNA strand break. This oxidative damage leads the formation of micronuclei (MN) a marker of nuclear damage. Also, oxidative stress increased 8-hydroxy-2′-deoxyguanosine levels which are the most common stable product of oxidative DNA damage.

**Keywords:** periodontal disease, buccal mucosa, DNA damage, oxidative stress, saliva.

## **1. Introduction**

DNA damage can generate many effects on human health and is the prime mechanism during carcinogenesis. Many of these effects could emerge directly, but others do not become

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

evident until much later. Chronic diseases have been studied to understand their mechanisms of perpetuation of clinical complications and the development of secondary diseases such as cancer [1]. Oxidative stress (OxS) and, therefore, DNA damage has an important impact on the pathogenesis of chronic disease [2]. Periodontal diseases are inflammatory disorders characterized by gingival inflammation in which periodontopathic bacteria generate immunological inflammatory responses [3]. The OxS plays an important role in the pathogenesis of periodontitis, which can lead damage to genetic material [4]. Since periodontal disease is an example of the excess effects locally and systemically of OxS over production, the effect of periodontal disease over oxidative and nuclear DNA damage is the topic attended in this chapter.

## **2. Periodontitis**

Moreover, dental caries, periodontal disease is one of the most prevalent oral diseases in the world and includes the major conditions gingivitis and periodontitis, which is a group of conditions affecting the supporting tissues of the teeth—the gingiva, periodontal ligament, cementum, and alveolar bone [1]. The reversible form of the disease, gingivitis, comprises inflammation of the gingival tissue without loss of alveolar bone. It is plaque induced and can be reversed with improved oral hygiene. In disease-susceptible individuals, gingivitis may develop into periodontitis, which is a chronic inflammatory condition of the gingiva causing destruction of connective tissue as well as of alveolar bone resulting in reduced support for the teeth and, ultimately, tooth loss (**Figure 1**) [5].

Periodontitis initiated by the complex interaction between the presence of periodontal pathogens (e.g., *Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia*, and *Fusobacterium nucleatum*) and host response [6]. Besides, the presence of periodontal pathogens associated with the progressive form of the disease, microbial by-products, the host immune response, environmental and behavior factors, and genetics may contribute the risk for developing periodontal disease [7].

Two main forms of periodontitis have been identified, chronic or aggressive, and are characterized by gingival inflammation and bleeding, periodontal pocket formation, destruction of

**Figure 1.** Characteristics of periodontitis. Healthy periodontal tissue (right) and periodontitis (left). Periodontitis is characterized by progressive and irreversible alveolar bone loss, and, ultimately, loosening and loss of teeth.

connected tissues attachment, and alveolar bone loss. But, loss of connective tissue attachment is faster in aggressive periodontitis than in chronic periodontitis [8].

Moreover, the pathogenesis of periodontal diseases is mediated by the inflammatory response to bacteria in the dental biofilm. The inflammatory reaction that characterizes periodontitis is the complex interaction between periodontopathic bacteria and the host defense system, and its purpose is to protect the tissues from bacterial attack [6]. In periodontitis, neutrophil plays an important role in the initial host inflammation. Exaggerated neutrophil activity is the biological features characteristic of the periodontitis phenotype in agreement with a hyperinflammatory host response. Thus, reactive oxygen species (ROS) produced from neutrophil are implicated in the destruction of periodontal tissue; therefore, oxidative stress (OxS) is enhanced during periodontitis [9].

## **3. Free radicals (FR) and oxidative stress**

evident until much later. Chronic diseases have been studied to understand their mechanisms of perpetuation of clinical complications and the development of secondary diseases such as cancer [1]. Oxidative stress (OxS) and, therefore, DNA damage has an important impact on the pathogenesis of chronic disease [2]. Periodontal diseases are inflammatory disorders characterized by gingival inflammation in which periodontopathic bacteria generate immunological inflammatory responses [3]. The OxS plays an important role in the pathogenesis of periodontitis, which can lead damage to genetic material [4]. Since periodontal disease is an example of the excess effects locally and systemically of OxS over production, the effect of periodontal

disease over oxidative and nuclear DNA damage is the topic attended in this chapter.

Moreover, dental caries, periodontal disease is one of the most prevalent oral diseases in the world and includes the major conditions gingivitis and periodontitis, which is a group of conditions affecting the supporting tissues of the teeth—the gingiva, periodontal ligament, cementum, and alveolar bone [1]. The reversible form of the disease, gingivitis, comprises inflammation of the gingival tissue without loss of alveolar bone. It is plaque induced and can be reversed with improved oral hygiene. In disease-susceptible individuals, gingivitis may develop into periodontitis, which is a chronic inflammatory condition of the gingiva causing destruction of connective tissue as well as of alveolar bone resulting in reduced support for

Periodontitis initiated by the complex interaction between the presence of periodontal pathogens (e.g., *Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia*, and *Fusobacterium nucleatum*) and host response [6]. Besides, the presence of periodontal pathogens associated with the progressive form of the disease, microbial by-products, the host immune response, environmental and behavior factors, and genetics may contribute

Two main forms of periodontitis have been identified, chronic or aggressive, and are characterized by gingival inflammation and bleeding, periodontal pocket formation, destruction of

**Figure 1.** Characteristics of periodontitis. Healthy periodontal tissue (right) and periodontitis (left). Periodontitis is

characterized by progressive and irreversible alveolar bone loss, and, ultimately, loosening and loss of teeth.

**2. Periodontitis**

30 Insights into Various Aspects of Oral Health

the teeth and, ultimately, tooth loss (**Figure 1**) [5].

the risk for developing periodontal disease [7].

A free radical (FR) is any molecular species that contains at least one unpaired electron. The unpaired electron increased the chemical reactivity of an atom or molecule that generates a high instability. Due to the increase in FR, oxidative stress (OxS) arises. The OxS has been defined as a disturbance in the balance between the production of reactive oxygen/ nitrogen species (ROS/RNS; FR) and the antioxidant defense system capacity to counteract their action [10]. The OxS occurs from an improved ROS/RNS generation or from a deterioration of the antioxidant protective ability. This process leads to the oxidation of biomolecules with consequent loss of its biological functions, whose manifestation is the potential oxidative damage to cells and tissues. Accumulation of ROS/RNS can result in several adverse effects such as lipid peroxidation, protein oxidation, and DNA damage (**Figure 2**) [11].

**Figure 2.** Sources of free radicals that arise oxidative stress.

## **4. Nuclear and oxidative DNA damage**

DNA is chemically unstable and vulnerable to oxidation, due to its susceptibility to endogenous and exogenous damage. The endogenous genotoxic agents are mainly produced by cellular metabolism and composed of ROS and RNS, estrogen metabolites, and aldehydes produced by lipid peroxidation [12, 13]. The OxS leads to different lesions in DNA, including direct modification of nucleotide bases, training sites a purinic/a pyrimidinic, single strand break, the oxidation of nucleosides, which could cause DNA strand breaks; this type of damage could have teratogenic or carcinogenic consequences [14].

One method for measuring DNA nuclear damage is the micronuclei (MN) assay [15–17]. MN are extranuclear bodies originated from chromosome fragments or whole chromosome that spontaneously or because of clastogenic (agents who broke chromosome) or aneuploidogenic (disrupted the spindle apparatus) agents that were not incorporated into the nucleus after cell division (**Figure 3**) [18]. The MN formation leads to cell death, genomic instability, or cancer development. Therefore, the increased in MN frequency is linking to environmental and occupational exposure to genotoxic agents, lifestyle, genetic profile cancer, and occurrence of other diseases, and MN screening is considered as a biomarker of DNA nuclear damage [19].

On the other hand, different markers of oxidative DNA damage have been identified. The most popular markers were designed for lipid peroxidation, such as malondialdehye (MDA), oxidized low-density lipoprotein (LDL), MDA-modified LDL, among other. In recent years, 8-hydroxy-2′-deoxyguanosine (8-OHdG or 8-oxodG) has appeared as a marker of oxidative stress in body fluids [20]. The 8-OHdG is the most common stable product of oxidative DNA damage caused by ROS. Among all purine and pyridine bases, guanine is most susceptible to oxidation. Hydroxyl radical addition to the eighth position of the molecule leads to the formation of guanine-modified product 8-OHdG (**Figure 4**) [21]. Oxidative-modified DNA in the form of 8-OHdG can be quantified to indicate the extent damage to genetic material is the most frequent and most mutagenic lesion in nuclear DNA and is important in mutagenesis and carcinogenesis processes [22].

**Figure 3.** MN in buccal mucosa cells (oil-immersion objective 60x, acridine orange stain).

Periodontal Disease and Nuclear and Oxidative DNA Damage http://dx.doi.org/10.5772/intechopen.68446 33

**Figure 4.** 8-OHdG formation by oxygen radicals.

**4. Nuclear and oxidative DNA damage**

32 Insights into Various Aspects of Oral Health

and carcinogenesis processes [22].

age could have teratogenic or carcinogenic consequences [14].

**Figure 3.** MN in buccal mucosa cells (oil-immersion objective 60x, acridine orange stain).

DNA is chemically unstable and vulnerable to oxidation, due to its susceptibility to endogenous and exogenous damage. The endogenous genotoxic agents are mainly produced by cellular metabolism and composed of ROS and RNS, estrogen metabolites, and aldehydes produced by lipid peroxidation [12, 13]. The OxS leads to different lesions in DNA, including direct modification of nucleotide bases, training sites a purinic/a pyrimidinic, single strand break, the oxidation of nucleosides, which could cause DNA strand breaks; this type of dam-

One method for measuring DNA nuclear damage is the micronuclei (MN) assay [15–17]. MN are extranuclear bodies originated from chromosome fragments or whole chromosome that spontaneously or because of clastogenic (agents who broke chromosome) or aneuploidogenic (disrupted the spindle apparatus) agents that were not incorporated into the nucleus after cell division (**Figure 3**) [18]. The MN formation leads to cell death, genomic instability, or cancer development. Therefore, the increased in MN frequency is linking to environmental and occupational exposure to genotoxic agents, lifestyle, genetic profile cancer, and occurrence of other diseases, and MN screening is considered as a biomarker of DNA nuclear damage [19]. On the other hand, different markers of oxidative DNA damage have been identified. The most popular markers were designed for lipid peroxidation, such as malondialdehye (MDA), oxidized low-density lipoprotein (LDL), MDA-modified LDL, among other. In recent years, 8-hydroxy-2′-deoxyguanosine (8-OHdG or 8-oxodG) has appeared as a marker of oxidative stress in body fluids [20]. The 8-OHdG is the most common stable product of oxidative DNA damage caused by ROS. Among all purine and pyridine bases, guanine is most susceptible to oxidation. Hydroxyl radical addition to the eighth position of the molecule leads to the formation of guanine-modified product 8-OHdG (**Figure 4**) [21]. Oxidative-modified DNA in the form of 8-OHdG can be quantified to indicate the extent damage to genetic material is the most frequent and most mutagenic lesion in nuclear DNA and is important in mutagenesis

## **5. Periodontitis and OxS: nuclear and oxidative DNA damage**

The OxS plays an important role in the pathology of several diseases, including arthritis, Alzheimer's disease, diabetes, Parkinson's disease, and more recently periodontitis. The OxS is a phenomenon that occurs within the periodontal disease and has been linked with both onset of periodontal tissue destruction [23] and systemic inflammation [24]. Inflammatory periodontal disease resulting in tissue damage is mediated by ROS which are formed during the phagocytosis of periodontopathic bacteria by polymorphonuclear leukocytes. ROS generation can occur through different mechanisms such as protein disruption, lipid peroxidation, induction of proinflammatory cytokines, and DNA damage [22]. Therefore, periodontitis is associated with OxS which in turn can lead to nuclear and oxidative DNA damage and thus the formation of MN and 8-OHdG [25].

Some authors have been demonstrated that individual with periodontal disease exhibited an increase in the frequency of MN, which is directly related to DNA damage [25–27]. Similarly, elevated MN frequency has been reported in patients with cancer [28], rheumatoid arthritis [29], autoimmune diseases [30], and premature aging syndrome [31]. The presence of MN in a cell is an indicator of DNA damage and genetic instability, and it could be associated with the collateral complications in these patients and with future risk of cancer development in humans.

On the other hand, 8-OHdG level has been studies in oral pathologies, including periodontal disease [25, 32–35] and oral cancer [36]. As described above, in periodontitis OxS because of the formation of ROS, which is stimulated by neutrophils, produce damage of the bonesupporting tissues. The exceeds of ROS levels, the reduction of antioxidant enzyme activity, and defects in DNA reparation mechanism led to increased oxidative DNA damage [35].

8-OHdG is used as a standard biomarker of oxidative-induced DNA damage mainly because of its reliable detectability. Elevated levels of 8-OHdG from cancer patients compared with healthy subjects have been observed in lung cancer [37], basal cell carcinoma [38], colorectal cancer [39], bladder cancer [40], and renal cell carcinoma [41]. With respect to periodontitis, published data on oxidative damage to DNA have been reported by many authors around the world who investigated 8-OHdG levels in the saliva of periodontitis patients [4, 25, 33, 34]. These studies demonstrated that salivary levels of 8-OHdG in samples from periodontitis patients were significantly higher than those from periodontally healthy controls and indicated that salivary 8-OHdG levels may be a useful marker for disease activity and may be indirectly reflect disease severity parameters [4, 25, 33, 34].

Also, a study report significant positive correlation between MN frequency (a marker of nuclear damage) and 8-OHdG enzyme levels in subjects with periodontitis. This finding could suggest that these variables are associated and can be hypothesized that they could be linked in the development of periodontal disease [25]. The augmented 8-OHdG levels might indicate early oxidative mitochondrial DNA damage [33], and mitochondrial DNA undertakes OxS early than nuclear DNA [42].

## **6. Conclusion**

Periodontal diseases are prevalent in human populations and represent a significant public health problem [43], and oxidative damage plays an important function in the pathogeny of the disease [9]. Nuclear and oxidative DNA damage area increased in subjects with periodontal disease, and genetic damage is a critical event not only in the initiation phase but also in the promotion and progression phases, which could be related to carcinogenesis events. Moreover, recent studies have associated periodontitis with some cancer including head and neck cancer [44], pancreatic cancer [45], colon cancer [46], and orodigestive cancers [47], which are relevant to the control of this disease and to promote the importance of good oral health.

## **Author details**

Ana L. Zamora-Perez<sup>1</sup> \*, Guillermo M. Zúñiga-González2 , Belinda C. Gómez-Meda<sup>3</sup> , Blanca P. Lazalde-Ramos<sup>4</sup> , Yveth M. Ortiz-García<sup>1</sup> , Gabriela Morales-Velazquez<sup>1</sup> , Celia Guerrero Velázquez<sup>1</sup> and María G. Sánchez-Parada<sup>5</sup>

\*Address all correspondence to: anazamora@gmail.com

1 Institute of Dentistry Research, University Center for Health Science, University of Guadalajara, Guadalajara, Jalisco, Mexico

2 Mutagenesis Laboratory, Western Biomedical Research Center, Mexican Institute of Social Security, Guadalajara, Jalisco, Mexico

3 Department of Molecular Biology and Genomics, Institute of Molecular Biology in Medicine and Gene Therapy, University Center of Health Sciences, University of Guadalajara, Guadalajara, Jalisco, Mexico

4 Academic Unit of Chemical Sciences, Autonomous University of Zacatecas, Zacatecas, Mexico

5 Health Science Department, University Center of Tonalá, Tonalá, Jalisco, Mexico

## **References**

the world who investigated 8-OHdG levels in the saliva of periodontitis patients [4, 25, 33, 34]. These studies demonstrated that salivary levels of 8-OHdG in samples from periodontitis patients were significantly higher than those from periodontally healthy controls and indicated that salivary 8-OHdG levels may be a useful marker for disease activity and may be

Also, a study report significant positive correlation between MN frequency (a marker of nuclear damage) and 8-OHdG enzyme levels in subjects with periodontitis. This finding could suggest that these variables are associated and can be hypothesized that they could be linked in the development of periodontal disease [25]. The augmented 8-OHdG levels might indicate early oxidative mitochondrial DNA damage [33], and mitochondrial DNA undertakes OxS early

Periodontal diseases are prevalent in human populations and represent a significant public health problem [43], and oxidative damage plays an important function in the pathogeny of the disease [9]. Nuclear and oxidative DNA damage area increased in subjects with periodontal disease, and genetic damage is a critical event not only in the initiation phase but also in the promotion and progression phases, which could be related to carcinogenesis events. Moreover, recent studies have associated periodontitis with some cancer including head and neck cancer [44], pancreatic cancer [45], colon cancer [46], and orodigestive cancers [47], which are relevant to the control of this disease and to promote the importance of good oral health.

\*, Guillermo M. Zúñiga-González2

1 Institute of Dentistry Research, University Center for Health Science, University of Guada-

2 Mutagenesis Laboratory, Western Biomedical Research Center, Mexican Institute of Social

3 Department of Molecular Biology and Genomics, Institute of Molecular Biology in Medicine and Gene Therapy, University Center of Health Sciences, University of Guadalajara,

4 Academic Unit of Chemical Sciences, Autonomous University of Zacatecas, Zacatecas, Mexico

5 Health Science Department, University Center of Tonalá, Tonalá, Jalisco, Mexico

, Yveth M. Ortiz-García<sup>1</sup>

and María G. Sánchez-Parada<sup>5</sup>

\*Address all correspondence to: anazamora@gmail.com

, Belinda C. Gómez-Meda<sup>3</sup>

, Gabriela Morales-Velazquez<sup>1</sup>

, Blanca P.

, Celia Guerrero

indirectly reflect disease severity parameters [4, 25, 33, 34].

than nuclear DNA [42].

34 Insights into Various Aspects of Oral Health

**6. Conclusion**

**Author details**

Lazalde-Ramos<sup>4</sup>

Velázquez<sup>1</sup>

Ana L. Zamora-Perez<sup>1</sup>

lajara, Guadalajara, Jalisco, Mexico

Security, Guadalajara, Jalisco, Mexico

Guadalajara, Jalisco, Mexico


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1600-0757.2006.00178.x


**Provisional chapter**

## **Oral and Periodontal Diseases in Consanguineous Marriages Marriages**

**Oral and Periodontal Diseases in Consanguineous** 

DOI: 10.5772/intechopen.68801

#### Metin Çalisir Additional information is available at the end of the chapter

Metin Çalisir

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38 Insights into Various Aspects of Oral Health

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.68801

#### **Abstract**

Periodontitis is defined as an inflammatory disease of supporting tissues of teeth characterized by progressive destruction of the periodontal ligament and alveolar bone. Periodontal manifestations of these genetic disorders or syndromes, such as familial and cyclic neutropenias, granulomatous disease, agranulocytosis, Langerhans' cell disease, glycogen storage disease, hypophosphatasia, leucocyte adhesion deficiency, and Papillon‐Lefèvre, Chédiak‐Higashi, Cohen, Ehlers‐Danlos, Marfan, Down, Haim‐Munk, and Kindlers syndromes, imitate some types of periodontal diseases. Most of these syndromes have autosomal‐recessive characterization and can be seen commonly in consanguineous marriages. Therefore, consanguineous marriages have generally been accepted as having important detrimental effects on offspring. There is a lot of genetic research about consanguineous marriage and its detrimental effects on offspring. Although consanguineous marriages are common in the world, the relationship with oral and periodontal diseases has not been thoroughly investigated. We do not have enough of an understanding of the effects of consanguineous marriage on oral and periodontal diseases. In this chapter, previous studies in the literature related to this subject will be investigated and evaluated, and then this research will be related to oral and periodontal diseases. Therefore, this chapter will guide further research. The aim of this chapter is to show the relation between consanguineous marriages and oral‐periodontal diseases.

**Keywords:** periodontal diseases, genetic disorders related with periodontitis, consanguinity

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

## **1. Introduction**

#### **1.1. Oral and periodontal health**

Etymologically, the word "health" was reproduced from the Old English "hale" and means wholesome, sound, or well‐being [1]. Although there is significant improvement in oral health in developed countries, oral disease still persists as a global problem, especially among underprivileged groups in both developing and developed countries [2]. The global public health problems associated with oral disease are a serious burden on governments [3]. In the Preamble to the Constitution of the World Health Organization (WHO) [4, 5], health was described as "a state of complete physical, mental and social well‐being and not merely the absence of disease or infirmity." Moreover, the Preamble proposes: "The enjoyment of the highest attainable standard of health is one of the fundamental rights of every human being without distinction of race, religion, political belief, economic or social condition." Therefore, the WHO suggests that complete health should be an endpoint that people and society should struggle to achieve. At the Ottawa Charter for Health Promotion (1986), the WHO added that "health is a resource for everyday life, not the objective of living." This means that health is a necessity for people's daily lives. "Health promotion is the process of enabling people to increase control over, and to improve, their health." For this purpose, government and health care workers have important duties to extend health services for people. What is "complete physical and mental health" and "absence of disease or infirmity"? Unfortunately, these questions have not been—and probably never will be answered satisfactorily [1].

Tooth caries, periodontal diseases, loss of teeth, oral mucosal lesions, and cancers are some of the major oral health problems that the public face. Pain and trouble with eating, chewing, smiling, speaking, and communication due to discolored, rotten, or missing teeth are factors that adversely affect people's everyday lives [6]. Periodontal diseases have historically been considered one of the most important global oral health burdens for governments [7, 8].

Periodontal health means the absence of any clinical signs and symptoms of current or past periodontal disease [1]. For many patients, healthy periodontium is comfortable and free of functional and aesthetic problems [9]. The American Academy of Periodontology (AAP) has defined health as "the condition of a patient when there is function without evidence of disease or abnormality" (AAP 2001). It could be said one has periodontal health if there are no disease signs and symptoms of periodontal tissues. The diagnosis of periodontal disease is usually documented by the presence of bleeding on probing (BOP), probing pocket depth (PPD), and clinical attachment level (CAL) loss. However, other symptoms of periodontal disease include the results of chronic gingival inflammation and the destruction of tooth‐supporting tissues, such as redness, bleeding on brushing, loosening of affected teeth, and persistent bad breath [10]. These symptoms affect the quality of daily life of people.

## **2. Classification system for periodontal diseases and conditions**

The most commonly accepted systems of classification of periodontal disease have been offered by the American Academy of Periodontology (AAP). (*International Workshop for Classification of Periodontal Diseases in 1999*) [11].

Partial list of periodontal disease which may be associated with genetic conditions has been given below [11].

#### (1) **Gingival lesions of genetic origin**


**1. Introduction**

**1.1. Oral and periodontal health**

40 Insights into Various Aspects of Oral Health

answered satisfactorily [1].

ments [7, 8].

daily life of people.

Etymologically, the word "health" was reproduced from the Old English "hale" and means wholesome, sound, or well‐being [1]. Although there is significant improvement in oral health in developed countries, oral disease still persists as a global problem, especially among underprivileged groups in both developing and developed countries [2]. The global public health problems associated with oral disease are a serious burden on governments [3]. In the Preamble to the Constitution of the World Health Organization (WHO) [4, 5], health was described as "a state of complete physical, mental and social well‐being and not merely the absence of disease or infirmity." Moreover, the Preamble proposes: "The enjoyment of the highest attainable standard of health is one of the fundamental rights of every human being without distinction of race, religion, political belief, economic or social condition." Therefore, the WHO suggests that complete health should be an endpoint that people and society should struggle to achieve. At the Ottawa Charter for Health Promotion (1986), the WHO added that "health is a resource for everyday life, not the objective of living." This means that health is a necessity for people's daily lives. "Health promotion is the process of enabling people to increase control over, and to improve, their health." For this purpose, government and health care workers have important duties to extend health services for people. What is "complete physical and mental health" and "absence of disease or infirmity"? Unfortunately, these questions have not been—and probably never will be—

Tooth caries, periodontal diseases, loss of teeth, oral mucosal lesions, and cancers are some of the major oral health problems that the public face. Pain and trouble with eating, chewing, smiling, speaking, and communication due to discolored, rotten, or missing teeth are factors that adversely affect people's everyday lives [6]. Periodontal diseases have historically been considered one of the most important global oral health burdens for govern-

Periodontal health means the absence of any clinical signs and symptoms of current or past periodontal disease [1]. For many patients, healthy periodontium is comfortable and free of functional and aesthetic problems [9]. The American Academy of Periodontology (AAP) has defined health as "the condition of a patient when there is function without evidence of disease or abnormality" (AAP 2001). It could be said one has periodontal health if there are no disease signs and symptoms of periodontal tissues. The diagnosis of periodontal disease is usually documented by the presence of bleeding on probing (BOP), probing pocket depth (PPD), and clinical attachment level (CAL) loss. However, other symptoms of periodontal disease include the results of chronic gingival inflammation and the destruction of tooth‐supporting tissues, such as redness, bleeding on brushing, loosening of affected teeth, and persistent bad breath [10]. These symptoms affect the quality of

#### (2) **Chronic periodontitis**


#### (3) **Aggressive periodontitis**


#### (4) **Periodontitis as a manifestation of systemic diseases**

#### (a) **Associated with hematologic disorders**


#### (b) **Associated with genetic disorders**


#### **2.1. Periodontitis**

Periodontal diseases are major global oral health problems that occur on teeth and tissues around the teeth. One of the most common periodontal disease is periodontitis. Periodontitis starts first on gingiva and progresses to periodontal ligament and alveolar bone, which causes the degradation of supporting tissues of teeth and eventually leads to loss of teeth [12]. Periodontitis is primarily caused by pathogenic microorganisms in the biofilm. The other predisposing factors are genetic and environmental factors [13].

The shifting of the nucleotides in the genes can lead to periodontitis. Susceptibility to periodontitis among patients is different [14]. The correlation between genetic composition and periodontal diseases is complex and not clearly explained [11]. Only a special gene is not correlated with the all mechanisms of the disease [14]. Family history is a criterion for periodontal diseases that must be taken into consideration [11]. Although the family aggregation may be affected by both genetic and environmental factors, studies on twins reared apart have shown that genetic factors are effective parameters for diseases [15].

According to the studies on monozygotic and dizygotic twins, 50% of variance in periodontal disease has been associated with genetic factors [16]. Also, genetic factors have an important role on the balance between protective and destructive chemical mediators [17, 18]. Genetic components may determine the roles of the immune system, host response, and cytokines in periodontal disease [19]. Researchers who have investigated the genetic effect on periodontal diseases have focused on familial aggregation and genetic components of aggressive periodontitis (AP) [20], periodontitis associated with Mendelian‐inherited diseases [20], twin research [15, 21], and segregation analysis and linkage studies [22, 23].

#### *2.1.1. Genetic studies on chronic periodontitis and aggressive periodontitis*

• Langerhans cell disease (histiocytosis syndromes)

• Ehlers‐Danlos syndrome (types IV and VIII)

• Crohn disease (inflammatory bowel disease)

predisposing factors are genetic and environmental factors [13].

shown that genetic factors are effective parameters for diseases [15].

research [15, 21], and segregation analysis and linkage studies [22, 23].

Periodontal diseases are major global oral health problems that occur on teeth and tissues around the teeth. One of the most common periodontal disease is periodontitis. Periodontitis starts first on gingiva and progresses to periodontal ligament and alveolar bone, which causes the degradation of supporting tissues of teeth and eventually leads to loss of teeth [12]. Periodontitis is primarily caused by pathogenic microorganisms in the biofilm. The other

The shifting of the nucleotides in the genes can lead to periodontitis. Susceptibility to periodontitis among patients is different [14]. The correlation between genetic composition and periodontal diseases is complex and not clearly explained [11]. Only a special gene is not correlated with the all mechanisms of the disease [14]. Family history is a criterion for periodontal diseases that must be taken into consideration [11]. Although the family aggregation may be affected by both genetic and environmental factors, studies on twins reared apart have

According to the studies on monozygotic and dizygotic twins, 50% of variance in periodontal disease has been associated with genetic factors [16]. Also, genetic factors have an important role on the balance between protective and destructive chemical mediators [17, 18]. Genetic components may determine the roles of the immune system, host response, and cytokines in periodontal disease [19]. Researchers who have investigated the genetic effect on periodontal diseases have focused on familial aggregation and genetic components of aggressive periodontitis (AP) [20], periodontitis associated with Mendelian‐inherited diseases [20], twin

• Glycogen storage disease

• Cohen syndrome

42 Insights into Various Aspects of Oral Health

• Hypophosphatasia

• Marfan syndrome

(c) **Not otherwise specified (NOS)**

• Other

**2.1. Periodontitis**

• Chronic granulomatous disease

• Infantile genetic agranulocytosis

Chronic periodontitis (CP) is the most common type of periodontitis and shows a slow rate of progression. It can begin in adolescence but usually does not become clinically significant until 35 years of age [24, 25]. There is no proven genetic determinant for patients with chronic periodontitis in any research. To determine the role of genetic factors in chronic periodontitis, twin and family studies are the optimal methods [26].

In a study, chronic periodontitis was shown to be 50% of heritable [16]. Chronic periodontitis has shown familial heredity in a Dutch population epidemiological study [27]. Also, there is some evidence that shows a correlation between IL‐1, IL‐6, IL‐10, VDR, and CD14 genes and chronic periodontitis susceptibility [26]. IL‐1 polymorphisms have been associated with severity of periodontitis [28, 29].

Aggressive periodontitis (AP) is a type of periodontitis that is characterized by destruction of periodontal tissues and alveolar bone, despite the presence of a small amount of dental plaque. It occurs in systemically healthy individuals who are generally younger in age, but patients may be older [11]. There are two types of aggressive periodontitis. Generalized and localized forms of aggressive periodontitis are rare types of periodontal disease that first occur with rapid attachment and bone loss and tend to appear in the families [30]. The prevalence of localized aggressive periodontitis (LAP) is less than 1% and that of generalized aggressive periodontitis (GAP) is 0.13%. Black populations are at higher risk than whites; male population is at higher risk of GAP than females [31].

Both genetic and environmental factors have crucial roles in the occurrence of these diseases. Chronic periodontitis and aggressive periodontitis are also affected by the combined effects of environmental and genetic factors [32, 33].

Although the familial aggregation of aggressive periodontitis is known, the mode of inheritance is still unclear. Family linkage studies have informed different modes of inheritance such as X‐linked‐dominant [34], autosomal‐dominant [23], autosomal‐recessive [22], or both X‐linked‐dominant and autosomal‐dominant [35].

Polymorphisms in the cytokine genes, such as interleukin‐1 receptor antagonist (*IL‐1RN*) and interleukin‐4 (*IL‐4*), have been found to be positively correlated with aggressive periodontitis [36, 37]. A combination of two alleles of interleukin, *IL‐1A*−889 and *IL‐1B*<sup>+</sup>3954, have been found associated with aggressive periodontitis [38–40]. *IL‐4‐590* T/T, *IL‐4‐34* T/T genotype, *IL‐6‐174*G allele, and *IL‐6‐572* C/G polymorphism are associated with aggressive periodontitis [41, 42]. A relationship between *IL‐6‐1363,‐1480* polymorphism and LAP susceptibility has been found [43].

IL‐10 promoter polymorphisms at positions −1082 G‐A, −819C‐T, and −590C‐A [44] and FPR348 T‐C gene polymorphism in African‐American people [45] are potential risk indicators for GAP. It is said that Fc gamma RIIIb‐NA2 allele and Fc gamma RIIIb‐NA2/NA2 genotype, composite genotype FcaRIIIb‐NA2/NA2, FCgammaRIIIa‐H/H131 [46], and FCgamma polymorphisms [47] may lead to aggressive periodontitis. IL‐1 (IL‐1α and IL‐1β) genes genotype‐positive individuals have higher levels of virulent bacterial complexes. The number of virulent bacterial species in deep pockets is seen at higher levels in IL‐1 genes genotype‐positive people than genotype‐negative people [48].

Angiotensinogen, cathepsin C, E‐selectin, formyl peptide receptor, NADPH oxidase, plasminogen activator inhibitor 1, calprotectin, tissue inhibitor of matrix metalloproteinase 2, and tissue plasminogen activator have been correlated with aggressive periodontitis [49]. TLR‐4 399 Ile polymorphism has shown a protective effect against aggressive periodontitis in contrast to chronic periodontitis [50]. HLA‐DR4 gene polymorphism is found in higher frequency in rapidly progressive periodontitis patients, and HLA‐A9, B‐15 gene polymorphisms are found to be significantly elevated [51, 52]. HLA‐DQB1 plays a crucial role in pathogenesis of aggressive periodontitis [53].

#### *2.1.2. Role of genetic factors in periodontitis as a manifestation of systemic diseases*

Periodontal diseases include a wider spectrum of diseases than just periodontitis. Some periodontal diseases are affected by genetic variations. Thus, it could be said that genetic factors play a crucial role in periodontal health and disease (**Table 1**) [16, 54].


**Table 1.** Some syndromes with clinical manifestations of severe periodontitis.

## **3. Consanguineous marriages**

individuals have higher levels of virulent bacterial complexes. The number of virulent bacterial species in deep pockets is seen at higher levels in IL‐1 genes genotype‐positive people

Angiotensinogen, cathepsin C, E‐selectin, formyl peptide receptor, NADPH oxidase, plasminogen activator inhibitor 1, calprotectin, tissue inhibitor of matrix metalloproteinase 2, and tissue plasminogen activator have been correlated with aggressive periodontitis [49]. TLR‐4 399 Ile polymorphism has shown a protective effect against aggressive periodontitis in contrast to chronic periodontitis [50]. HLA‐DR4 gene polymorphism is found in higher frequency in rapidly progressive periodontitis patients, and HLA‐A9, B‐15 gene polymorphisms are found to be significantly elevated [51, 52]. HLA‐DQB1 plays a crucial role in pathogenesis of

Periodontal diseases include a wider spectrum of diseases than just periodontitis. Some periodontal diseases are affected by genetic variations. Thus, it could be said that genetic factors

**Syndrome Mutated gene Chromosome region**

collagen alpha‐2(V) gene (COL5A2)

Cathepsin C (CTSC gene) (dipeptidyl

abnormal transport of vesicles to and from neutrophil lysozyme caused by mutations in lysosomal trafficking regulator gene (LYST)

GDP‐fucose transporter‐1 11p11.2

Type III collagen for EDS type IV, unknown for

9q34, 2q31

11q14.1–q14.3

1q42.1–q42.2

Trisomy 21

*2.1.2. Role of genetic factors in periodontitis as a manifestation of systemic diseases*

play a crucial role in periodontal health and disease (**Table 1**) [16, 54].

Ehlers‐Danlos syndrome Collagen alpha‐1(V) gene (COL5A1) or the

Chediak‐Higashi syndrome Lysosomal trafficking regulator CHS1/LYST,

Down syndrome Multiple, vertical trisomic regions at least 5Mb (megabase) long

**Table 1.** Some syndromes with clinical manifestations of severe periodontitis.

EDS type VIII

aminopeptidase)

Hypophosphatasia ALPL, tissue non‐specific alkaline phosphatase 1p36.12

Leukocyte adhesion deficiency type I Beta‐2 integrin chain 21q22.3

Congenital and cyclic neutropenia ELANE 19p13.3 Glycogen storage disease SLC37A4 11q23.3

than genotype‐negative people [48].

44 Insights into Various Aspects of Oral Health

aggressive periodontitis [53].

Papillon‐Lefévre syndrome and Haim‐Munk syndrome

Leukocyte adhesion deficiency type

II

Linguistically, the word "consanguinity" is reproduced from two Latin words: "con" meaning common or shared and "sanguineus" meaning blood. The meaning of consanguineous marriage is a relationship between biologically related individuals. As a clinical genetic term, "a consanguineous marriage" is a union between couples who are related as second cousins or closer [55–57]. The terms of inbreeding and consanguinity are used to define relations between couples who have at least one common ancestor [58, 59]. It is estimated that more than one billion of the global population who live in different communities and countries prefer consanguineous marriage [56, 60]. At present, this rate corresponds about 20% of world populations [56]. Categories of consanguineous marriages are different (**Figure 1**).

Consanguinity rates differ in communities depending on religion, culture, and geography. The prevalence is high among Middle Eastern and Arab citizens [61]. The highest rates of consanguineous marriages in the world are seen in many Arab countries where 20–50% of all marriages include consanguineous marriages, especially first cousin marriages [62]. In developed countries, the rate of consanguineous marriage has decreased to a low level but includes different ethnic groups, some of which continue to practice their traditional cultural habits [63]. It is commonly accepted that consanguinity is more prevalent among underprivileged persons in poor communities [64–66]. Education level and socio‐economic status of the persons may have a potential effect on consanguinity [67].

**Figure 1.** Categories of consanguineous marriages.

Studies of consanguineous marriage and genetic disorders have yielded conflicting results [68, 69]. The correlation between relationship and proportion of genes is as follows [70] (**Table 2**).

Research on the association between consanguinity and the different parameters of oral and periodontal health is limited, both in quantity and in quality [71].

Consanguineous marriage leads to increased genetic homogeneity of inbred individuals. Inbred individuals have similar paternal and maternal genetic materials. The detrimental effects of inbreeding are the result of homozygosity of harmful genes [58].

Consanguineous marriages have generally been accepted as having important detrimental effects on offspring [72, 73]. Some of the rare autosomal‐recessive diseases can commonly be seen in consanguineous marriages. Health workers should be aware of these conditions and should inform patients about possible syndromes [73, 74].

The high consanguinity rates in communities could induce the expression of autosomal‐recessive diseases. These include very rare or new syndromes. Therefore, health workers must be aware of the risks associated with consanguineous marriages. Currently, many young consanguineous couples planning to have children are afraid of the consequences of consanguinity for their offspring [74].

If there is a closer biological relationship between parents, identical copies of one or more detrimental recessive gene will be transferred to their offspring [73]. If one of the parents is affected, in general, consanguineous marriage does not increase the risk for autosomal‐dominant conditions in offspring [75].

If parents are not related, their offspring have a 2–3% possibility of inheriting detrimental genes. If parents are first cousins, their offspring have up to 5–6% possibility of inheriting detrimental genes because they will both transport the same autosomal‐recessive mutation. If parents are consanguineous, no increased rate is observed for X‐linked or autosomal‐dominant genes [70].

Although consanguineous marriages are common in the world, the effects on oral diseases have not been thoroughly investigated. We do not have enough of an understanding of the effects of consanguineous marriage on oral and periodontal diseases.


**Table 2.** Proportion of genes among the relatives [70].

## **4. Genetic disorders with periodontal manifestations and consanguinity**

Studies of consanguineous marriage and genetic disorders have yielded conflicting results [68, 69]. The correlation between relationship and proportion of genes is as follows [70] (**Table 2**).

Research on the association between consanguinity and the different parameters of oral and

Consanguineous marriage leads to increased genetic homogeneity of inbred individuals. Inbred individuals have similar paternal and maternal genetic materials. The detrimental

Consanguineous marriages have generally been accepted as having important detrimental effects on offspring [72, 73]. Some of the rare autosomal‐recessive diseases can commonly be seen in consanguineous marriages. Health workers should be aware of these conditions and

The high consanguinity rates in communities could induce the expression of autosomal‐recessive diseases. These include very rare or new syndromes. Therefore, health workers must be aware of the risks associated with consanguineous marriages. Currently, many young consanguineous couples planning to have children are afraid of the consequences of consanguinity for their

If there is a closer biological relationship between parents, identical copies of one or more detrimental recessive gene will be transferred to their offspring [73]. If one of the parents is affected, in general, consanguineous marriage does not increase the risk for autosomal‐dominant

If parents are not related, their offspring have a 2–3% possibility of inheriting detrimental genes. If parents are first cousins, their offspring have up to 5–6% possibility of inheriting detrimental genes because they will both transport the same autosomal‐recessive mutation. If parents are consanguineous, no increased rate is observed for X‐linked or autosomal‐dominant

Although consanguineous marriages are common in the world, the effects on oral diseases have not been thoroughly investigated. We do not have enough of an understanding of the

First degree (1°) ½, 50%

Second degree (2°) ¼, 25%

Third degree (3°) 1/8, 12.5%

**Relationship Relationship degree Proportion of genes**

effects of consanguineous marriage on oral and periodontal diseases.

Brothers and sisters, non‐identical (dizygotic) twins, parents

Uncles and aunts, nephews and nieces, grandparents and

First cousins, half‐uncles and aunts and half‐nephews and

**Table 2.** Proportion of genes among the relatives [70].

Identical (monozygotic) twins 100%

periodontal health is limited, both in quantity and in quality [71].

should inform patients about possible syndromes [73, 74].

offspring [74].

genes [70].

and children

nieces

half‐brothers and half‐sisters

conditions in offspring [75].

46 Insights into Various Aspects of Oral Health

effects of inbreeding are the result of homozygosity of harmful genes [58].

Genetic disorders with periodontal manifestations are as follows: familial and cyclic neutropenias (CyN); Crohn disease; chronic granulomatous disease (CGD); agranulocytosis; Langerhans' cell disease; glycogen storage disease; hypophosphatasia; and leucocyte adhesion deficiency, Papillon‐Lefèvre, Chédiak‐Higashi, Cohen, Ehlers‐Danlos (types 4 and 8), Marfan, Down, Haim‐Munk, and Kindlers syndromes [13].

Familial gingival fibromatosis is a rare hereditary condition that causes aesthetic, functional, psychological, and masticatory problems for patients [76]. It may manifest as an autosomal‐ dominant and autosomal‐recessive mode of inheritance [77, 78]. Consanguinity has been observed in the recessive mode of familial gingival fibromatosis [79, 80].

Leukocyte adhesion deficiency (LAD) type I is caused by the combined loss of expression on the surface of leukocytes of the leukocyte integrins LFA‐1, Mac‐1, and pl50, 95. It is a rare, inherited, autosomal‐recessive, immunodeficiency disease [81]. Leukocyte adhesion deficiency type II is a disease with impaired fucosylation leading to an abnormal sialyl‐lewis X (CD15). It is characterized by recurrent infections, persistent leukocytosis, and severe mental and growth retardation [82]. Leukocyte adhesion deficiency II was first described in two nonrelated children who have consanguineous parents [83, 84]. In a study, consanguinity has been found as a major factor for the distribution of LAD [85].

Langerhans‐cell histiocytosis (LCH), once known as histiocytosis X, is considered a rare and non‐hereditary disorder that includes a variety of diseases characterized by the dysregulated proliferation of Langerhans cells and infiltration of organs by pathological Langerhans cells [86]. Research on the relationship between periodontitis and consanguineous marriage is limited [87].

Glycogen storage disease type 1 (GSD‐1) is a autosomal‐recessive disorder that is caused by a deficiency in microsomal glucose‐6‐phosphatase activity [88]. Because of neutrophil dysfunction and neutropenia, there is an increased susceptibility to bacterial infection. This leads to symptoms of periodontitis [89, 90]. In a linkage analysis, consanguineous marriages and glycogen storage disease type 1 have been found to be related to each other [88].

Chronic granulomatous disease (CGD) is a rare inherited disease of the innate immune system that is characterized by impaired phagocyte microbicidal activity. It is caused by genetic defects in the superoxide‐generating NADPH oxidase of phagocytes [91]. In a retrospective study, 14 patients with CGD were investigated. According to results of this study, a high consanguinity rate (75%) was observed [92].

Infantile genetic agranulocytosis is rare, inherited as an autosomal‐recessive pattern, and characterized by severe neutropenia [93]. Patients may suffer from recurrent gingivitis and even severe periodontitis [94]. To have a family history of consanguineous parenthood may be a predisposing factor for infantile genetic agranulocytosis [95].

Some rare syndromes affecting phagocytes, epithelia, connective tissue, and teeth may cause severe periodontal conditions. Some genes that were responsible for these syndromes were identified. Haim‐Munk and Papillon‐Lefèvre syndromes (PLS) are rare autosomal‐recessive disorders associated with periodontitis onset at early stage of the life. At childhood, both deciduous and permanent teeth are lost early. Mutations in the cathepsin gene (CTSC) on chromosome 11q 14–21 are the cause of PLS [96–98]. Papillon‐Lefèvre syndrome is an autosomal‐recessive disorder, and consanguinity in 20–40% of patients has been demonstrated in some studies [99, 100]. Consanguineously married parents may have offspring with PLS [101, 102]. In patients with PLS, deciduous teeth are lost early, but gingiva remains healthy. When permanent teeth erupt, gingivitis and periodontitis occur and all permanent teeth except the third molars are lost in a short time [103].

Ehler‐Danlos syndrome is a group of autosomal‐recessive disorders that affect the connective tissues such as skin, blood vessels, joints, etc. [104, 105]. In a case study, a patient with third‐degree consanguineous parents has been described as having the appearance of old age, hypermobile joints, and skin laxity [106].

Once a patient's host response or immune system is impaired, severe periodontal disease and loss of periodontal tissues are often seen. Various systemic diseases such as leukemia, thrombocytopenia, and leucocyte disorders, such as agranulocytosis, cyclic neutropenia, and leucocyte adhesion deficiency, could result in increased severity of periodontal disease [13].

Cyclic neutropenia (CyN) is defined as an absolute neutrophil count (ANC) less than 0.5 × 109/L for at least 3–5 days per approximately 21‐day cycles [107]. Neutrophil elastase (NE) gene (ELANE, formerly known as ELA2) located on chromosome 19p13.3 is the suspected gene that is the only known genetic defect in patients with CyN. This condition shows an autosomal‐dominant transmission [108, 109]. Alangari et al. [110] have investigated both cyclic neutropenia and severe congenital neutropenia (SCN) phenotypes in an extended consanguineous multiplex family. According to results of this study, they have shown for the first time that a G6PC3 homozygous mutation resulted in a phenotype that is compatible with CyN in addition to the classical phenotype of SCN. They have reported that mutations in that gene could be said to have an autosomal‐recessive pattern of inheritance in patients with CyN.

Chediak‐Higashi syndrome (CHS) is a severe autosomal‐recessive disease. It is characterized by partial oculocutaneous albinism, a predisposition to infections, the presence of abnormally large granules in many different cell types, and insufficient natural killer cell activity [111– 113]. In consanguineous families, patients with Chediak‐Higashi syndrome were found to have homozygous for the haplotype defined by the markers DlS235 and DlS2649 [111].

Cohen syndrome is a rare autosomal‐recessive syndrome [114]. Diagnosis of Cohen syndrome is determined as the presence of at least seven of the following clinical symptoms as originally reported by Cohen et al. [114] and further described by Norio et al. [115]: mental retardation, microcephaly, characteristic facial appearance, slim tapering extremities with relative truncal obesity, hypotonia, joint hyperextensibility, benign neutropenia, and ophthalmic abnormalities such as myopia and retinal dystrophy. Cohen syndrome has been shown to be related with consanguinity [116].

Down syndrome is one of the most common human chromosomal disorders. Incidence of Down syndrome is quite high about 1 in 700 live births [117]. It is a result of an extra copy of the human chromosome 21 (trisomy 21) [118], and it is the most frequent genetic cause of mental retardation [117]. Studies investigating the relationship between Down syndrome and consanguineous marriage are contradictory [119–121].

Marfan syndrome is an autosomal‐dominant disorder and a heritable disorder of fibrous connective tissue. The main symptoms occur in three systems: skeletal, ocular, and cardiovascular [122]. It appears to be due to heterozygous mutation in the fibrillin‐1 gene on chromosome 15q21. De Vries et al. [123] described Marfan syndrome in two cousins from a consanguineous Turkish family.

Inflammatory bowel diseases (IBD) in the form of Crohn disease and ulcerative colitis result from a dysregulated immune response to environmental factors in genetically susceptible people [124]. In a study, Crohn disease was found to be related with consanguinity [125].

Kindler syndrome, a rare subtype of inherited epidermolysis bullosa, shows oral symptoms such as gingivitis, periodontitis, and loss of teeth. Kindler syndrome is reported more frequently in populations with high rates of consanguinity [126].

## **5. Conclusion**

disorders associated with periodontitis onset at early stage of the life. At childhood, both deciduous and permanent teeth are lost early. Mutations in the cathepsin gene (CTSC) on chromosome 11q 14–21 are the cause of PLS [96–98]. Papillon‐Lefèvre syndrome is an autosomal‐recessive disorder, and consanguinity in 20–40% of patients has been demonstrated in some studies [99, 100]. Consanguineously married parents may have offspring with PLS [101, 102]. In patients with PLS, deciduous teeth are lost early, but gingiva remains healthy. When permanent teeth erupt, gingivitis and periodontitis occur and all permanent teeth except the

Ehler‐Danlos syndrome is a group of autosomal‐recessive disorders that affect the connective tissues such as skin, blood vessels, joints, etc. [104, 105]. In a case study, a patient with third‐degree consanguineous parents has been described as having the appearance of old age,

Once a patient's host response or immune system is impaired, severe periodontal disease and loss of periodontal tissues are often seen. Various systemic diseases such as leukemia, thrombocytopenia, and leucocyte disorders, such as agranulocytosis, cyclic neutropenia, and leucocyte adhesion deficiency, could result in increased severity of periodontal disease [13]. Cyclic neutropenia (CyN) is defined as an absolute neutrophil count (ANC) less than 0.5 × 109/L for at least 3–5 days per approximately 21‐day cycles [107]. Neutrophil elastase (NE) gene (ELANE, formerly known as ELA2) located on chromosome 19p13.3 is the suspected gene that is the only known genetic defect in patients with CyN. This condition shows an autosomal‐dominant transmission [108, 109]. Alangari et al. [110] have investigated both cyclic neutropenia and severe congenital neutropenia (SCN) phenotypes in an extended consanguineous multiplex family. According to results of this study, they have shown for the first time that a G6PC3 homozygous mutation resulted in a phenotype that is compatible with CyN in addition to the classical phenotype of SCN. They have reported that mutations in that gene could be said to have an autosomal‐recessive pattern of inheritance in patients with CyN. Chediak‐Higashi syndrome (CHS) is a severe autosomal‐recessive disease. It is characterized by partial oculocutaneous albinism, a predisposition to infections, the presence of abnormally large granules in many different cell types, and insufficient natural killer cell activity [111– 113]. In consanguineous families, patients with Chediak‐Higashi syndrome were found to have homozygous for the haplotype defined by the markers DlS235 and DlS2649 [111].

Cohen syndrome is a rare autosomal‐recessive syndrome [114]. Diagnosis of Cohen syndrome is determined as the presence of at least seven of the following clinical symptoms as originally reported by Cohen et al. [114] and further described by Norio et al. [115]: mental retardation, microcephaly, characteristic facial appearance, slim tapering extremities with relative truncal obesity, hypotonia, joint hyperextensibility, benign neutropenia, and ophthalmic abnormalities such as myopia and retinal dystrophy. Cohen syndrome has been shown to be related

Down syndrome is one of the most common human chromosomal disorders. Incidence of Down syndrome is quite high about 1 in 700 live births [117]. It is a result of an extra copy of the human chromosome 21 (trisomy 21) [118], and it is the most frequent genetic cause of

third molars are lost in a short time [103].

48 Insights into Various Aspects of Oral Health

hypermobile joints, and skin laxity [106].

with consanguinity [116].

There does not seem to exist sufficient research on periodontal diseases related to the genetic disorders. Moreover, further research is needed on periodontal diseases in relation to consanguineous marriages.

## **Author details**

#### Metin Çalisir

Address all correspondence to: metincalisir@adiyaman.edu.tr

Department of Periodontology, Faculty of Dentistry, Adiyaman University, Adiyaman, Turkey

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**Provisional chapter**

## **Periodontitis and Chronic Obstructive Pulmonary Disease Disease**

**Periodontitis and Chronic Obstructive Pulmonary** 

DOI: 10.5772/intechopen.69957

Agathi Spiropoulou, Olga Lagiou,

Agathi Spiropoulou, Olga Lagiou, Dimosthenis Lykouras, Kiriakos Karkoulias and Kostas Spiropoulos Dimosthenis Lykouras, Kiriakos Karkoulias and Kostas Spiropoulos Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.69957

#### **Abstract**

Chronic periodontitis and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases in which neutrophilic inflammation plays a major role. There are a few studies showing that these two entities share various predisposing factors and pathogenetic mechanisms; however, a direct connection between them has not yet been achieved. Epidemiology data may also show a connection between the two conditions. Neutrophilic inflammation in periodontitis and COPD is orchestrated by CD8+ lympho‐ cytes and macrophages, leading to the aggregation of neutrophils and causing an imbal‐ ance to the proteases and antiproteases equilibrium. Finally, further research is needed to clarify the common pathogenesis of the two diseases to optimize their therapeutic management.

**Keywords:** chronic inflammation, neutrophils, oral hygiene

## **1. Introduction**

Periodontitis is a chronic inflammatory disease of the oral cavity, affecting the structures that support the teeth. Almost half of the adult population has a great inflammation of the gums that causes loss of optimal contact between the teeth and periodontal tissues [1]. About 11% of adults develop clinical periodontitis. The dental plaque is caused by the development of anaerobic bacteria that cause accumulation and activation of neutrophils, which is orchestrated by various mediators and enzymes that destroy the connective tissue [2, 3]. Untreated periodontitis ultimately leads to loss of support of the teeth, and atrophy of the alveolar process, causing loss of the teeth.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder of the air‐ ways, largely caused by smoking, and it is characterized by progressive and partially reversible airflow limitation [4]. The airflow obstruction and consequently the disease are confirmed by the presence of a postbronchodilator FEV1/FVC < 0.70 [5]. The disease con‐ stitutes one of the leading causes of morbidity and mortality in the industrialized world, affecting approximately 210 million people worldwide. In 2004, COPD was the fourth most common cause of death and it is expected to be the third cause of mortality by 2030 [6, 7].

COPD is a combination of chronic bronchitis and emphysema, and as a result, it constitutes a heterogeneous disease. The most common symptoms in patients suffering from COPD are dyspnea, cough, and production of sputum, which are chronic and progressive [8].

The lesions present in COPD and periodontitis are linked to various immunologic mecha‐ nisms, in which T‐lymphocytes, macrophages, and neutrophils have a major role. Our chap‐ ter attempts to analyze the similarities in pathophysiology of COPD and chronic periodontitis and to elucidate the common pathogenetic mechanisms.

## **2. The role of chronic inflammation**

COPD and chronic periodontitis are characterized by chronic neutrophilic inflammation, which mainly stems from the activity of enzymes released from granules of neutrophils. It is known that the development of COPD depends on the variable exposure to harmful factors, such as cigarette smoking, as well as on the susceptibility of the individual [9]. It is estimated that only a percentage of smokers (5–20%) develop COPD. Moreover, some patients develop mild disease, others moderate, and others serious disease. Among COPD patients, 80–90% have been current or ex‐smokers. Air pollution and occupational exposure have also been responsible for some COPD cases at a lower rate.

On the other hand, in periodontitis, there is an interaction between environmental and genetic factors, which eventually leads to the development of the disease. In both COPD and periodontitis, the pathophysiological mechanisms include the accumulation and activation of neutrophils. Factors secreted by neutrophil granules cause damage to the connective tissue [10].

It is believed that COPD is a condition of chronic systemic inflammation, characterized by elevated C‐reactive protein (CRP), interleukin‐8 (IL‐8), and tumor necrosis factor‐α (TNF‐α), whose levels determine the severity of disease, which is in line with the degree of muscle atrophy and dysfunction. These cytokines are also related to the development of coronary artery disease and diabetes [11]. Morbidity and mortality also depend on social and economic factors [12].

Inflammatory responses taking place in periodontitis are usually caused by the presence of anaerobic microbes. Thus, the levels of pro‐inflammatory cytokines, such as CRP and TNF‐α, are remarkably elevated. In both COPD and periodontitis, there is an increased incidence of heart attack, osteoporosis, diabetes mellitus and rheumatoid arthritis as a result of chronic inflammation [13].

## **3. Epidemiology of COPD and periodontitis**

Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder of the air‐ ways, largely caused by smoking, and it is characterized by progressive and partially reversible airflow limitation [4]. The airflow obstruction and consequently the disease are confirmed by the presence of a postbronchodilator FEV1/FVC < 0.70 [5]. The disease con‐ stitutes one of the leading causes of morbidity and mortality in the industrialized world, affecting approximately 210 million people worldwide. In 2004, COPD was the fourth most common cause of death and it is expected to be the third cause of mortality by 2030

COPD is a combination of chronic bronchitis and emphysema, and as a result, it constitutes a heterogeneous disease. The most common symptoms in patients suffering from COPD are

The lesions present in COPD and periodontitis are linked to various immunologic mecha‐ nisms, in which T‐lymphocytes, macrophages, and neutrophils have a major role. Our chap‐ ter attempts to analyze the similarities in pathophysiology of COPD and chronic periodontitis

COPD and chronic periodontitis are characterized by chronic neutrophilic inflammation, which mainly stems from the activity of enzymes released from granules of neutrophils. It is known that the development of COPD depends on the variable exposure to harmful factors, such as cigarette smoking, as well as on the susceptibility of the individual [9]. It is estimated that only a percentage of smokers (5–20%) develop COPD. Moreover, some patients develop mild disease, others moderate, and others serious disease. Among COPD patients, 80–90% have been current or ex‐smokers. Air pollution and occupational exposure have also been

On the other hand, in periodontitis, there is an interaction between environmental and genetic factors, which eventually leads to the development of the disease. In both COPD and periodontitis, the pathophysiological mechanisms include the accumulation and activation of neutrophils. Factors secreted by neutrophil granules cause damage to the connective tissue

It is believed that COPD is a condition of chronic systemic inflammation, characterized by elevated C‐reactive protein (CRP), interleukin‐8 (IL‐8), and tumor necrosis factor‐α (TNF‐α), whose levels determine the severity of disease, which is in line with the degree of muscle atrophy and dysfunction. These cytokines are also related to the development of coronary artery disease and diabetes [11]. Morbidity and mortality also depend on social and economic

Inflammatory responses taking place in periodontitis are usually caused by the presence of anaerobic microbes. Thus, the levels of pro‐inflammatory cytokines, such as CRP and TNF‐α,

dyspnea, cough, and production of sputum, which are chronic and progressive [8].

and to elucidate the common pathogenetic mechanisms.

**2. The role of chronic inflammation**

responsible for some COPD cases at a lower rate.

[6, 7].

62 Insights into Various Aspects of Oral Health

[10].

factors [12].

A variety of stimuli can induce the development of COPD, including heritable genes in con‐ junction with environmental risk factors. Air pollutants, cold temperature, lack of compliance with respiratory medication, and other noninfectious causes, as well as infections, are the usual triggers of acute exacerbations of COPD. Infections, which are the most frequent cause of exacerbations, could be of either bacterial or viral etiology [14]. It is known that almost half of the infections are caused by bacteria, while viruses are responsible for almost the rest of the infections. Moreover, coinfection with bacteria and viruses is identified in patients with severe COPD.

Smoking is an important predisposing factor both in COPD and in periodontitis. Almost 80% of COPD patients are current or ex‐smokers. COPD is also associated with age, impaired lung function, and gender. Initially, it was believed that the impact was greater in men, but more recent data exhibit equal or greater sensitivity of women smokers to develop COPD [15].

A working environment involving exposure to dust and harmful gases increases the risk of developing the disease. When smoking coexists, there is a sixfold risk. Exposure to inhaled gases from burning biomass increases the risk. There are not causative microbes causing COPD to develop. However, several viruses and bacteria are responsible for COPD disease exacerbations that lead to impaired lung function and quality of life deterioration [16].

Smoking is also a risk factor for the development of periodontitis, and the severity of the disease depends on the density of smoking habit [17]. Men and elderly people are more susceptible for COPD and periodontitis. Other predisposing factors include diabetes and poor socioeconomic conditions. Since 1990, there has been an increasing interest in the possible links between COPD and periodontitis. There is a correlation between poor oral hygiene and COPD [18].

In a study of military veterans, a diagnosis of COPD was made in subjects with an FEV1/FVC ratio < 70% and a history of smoking. The existence of periodontitis was documented by X‐ray results which show the loss of the alveolar bone. It was observed that a loss of 20% of the alveolar bone leads to an increased risk for development of COPD by 60%. However, it should be noted that the reduction of FEV1 is related not only to the existence of COPD but also to other respiratory diseases [19].

Other notable studies attempt to correlate COPD severity with the existence of periodontitis using more comprehensive definitions for the existence of COPD. In a study of 600 people with COPD was shown that the risk of developing COPD was associated directly with the quality of oral hygiene [20]. More specifically, patients with COPD had a higher dental plaque index, and an insufficient support of the tooth from the surrounding tissues. Moreover, the same patients had an unsatisfactory behavior regarding their oral hygiene, as measured by the frequency of toothbrushing, the use of dental yarns, and the frequency of visits to the dentist [21]. In another study, a direct correlation between COPD severity and poor hygiene was found in general. Therefore, this observation implies that the possibility of poor oral hygiene and the unfavorable course of COPD may be linked to nonhealthy lifestyle and poor socioeconomic conditions [22].

It is known that the pathogenesis of COPD is directly associated with the pathological relation‐ ship of proteases/antiproteases in the lung. The same theory has been suggested in periodon‐ titis. Past studies have shown that in patients suffering from mild COPD and periodontitis the levels of metalloproteinase‐8 (MMP‐8) are elevated in saliva and serum. MMP‐8 is a product of the secretion of neutrophils. However, levels of MMP‐8 in saliva showed no statistically sig‐ nificant difference in patients with mild COPD who had no periodontitis compared to those that did not suffer from COPD. Some other studies demonstrate a poor correlation between COPD and periodontitis [23].

To sum up, several meta‐analyses have shown that periodontitis increases the risk of develop‐ ing COPD; however, the exact mechanism is still not fully understood. Future studies should focus on the elucidation of such pathogenetic mechanisms.

## **4. Pathophysiology of COPD and periodontitis**

COPD is characterized by limitation of airflow which is partially reversible. Progressive decline of FEV1, inadequate lung emptying on expiration, and static and dynamic hyperinfla‐ tion are the results of remodeling of the small‐airway compartment and loss of elastic recoil by emphysematous destruction of parenchyma [24]. Exposure to smoke leads to infiltration of the mucosa, submucosa, and glandular tissue by inflammation cells. Increased mucus con‐ tent, epithelial‐cell hyperplasia, and disturbed tissue repair with wall thickening in the small conducting airways are the main features of COPD [25].

Smoking can cause injury of airway epithelial cells, and as a result, endogenous signals are released and recognized by receptors such as Toll‐like receptors 4 and 2 on epithelial cells. This recognition leads to a nonspecific inflammatory response which involves the release of early cytokines, macrophages, neutrophils, and dendritic cells and the transportation of these features to the site of inflammation [26]. Self‐antigens released from damaged tissue as well as foreign antigens from incoming pathogens are presented to naïve T‐cells by dendritic cells. The T‐cells are activated into T‐helper‐1 cells, and these specific CD4 and CD8 cells as well as B‐cells which produce antibodies are transferred to the lungs so as to neutralize the antigens [27].

Alveolar macrophages and other immune cells produce proteinases that destroy the basal mem‐ brane and also cause damage to the collagen and elastic fibers of the connective tissue, leading to the development of emphysema [28]. Moreover, they secrete IL‐4 and IL‐3 that cause edema and increased production of mucus, which are both associated with airway hyperresponsive‐ ness. These responses take place at the respiratory lobule of second order that is located after the terminal bronchiole. It consists of 3–5 generations of respiratory bronchioles that contain alveoli. This is the structure that is responsible for the exchange of respiratory gases, and its destruction may cause impaired gas exchange and respiratory failure [29]. Moreover, apart from the lack of α‐1 antitrypsin, other genetic factors involved in the pathogenesis of the dis‐ ease include interleukins and cysteine proteinases and elastases, which orchestrate an immune response which can lead to the destruction of the pulmonary parenchyma. Mast cells play an important role as antigen‐presenting cells in the lung as well, and they have been shown to be valuable both in COPD and in periodontitis.

had an unsatisfactory behavior regarding their oral hygiene, as measured by the frequency of toothbrushing, the use of dental yarns, and the frequency of visits to the dentist [21]. In another study, a direct correlation between COPD severity and poor hygiene was found in general. Therefore, this observation implies that the possibility of poor oral hygiene and the unfavorable course of COPD may be linked to nonhealthy lifestyle and poor socioeconomic conditions [22]. It is known that the pathogenesis of COPD is directly associated with the pathological relation‐ ship of proteases/antiproteases in the lung. The same theory has been suggested in periodon‐ titis. Past studies have shown that in patients suffering from mild COPD and periodontitis the levels of metalloproteinase‐8 (MMP‐8) are elevated in saliva and serum. MMP‐8 is a product of the secretion of neutrophils. However, levels of MMP‐8 in saliva showed no statistically sig‐ nificant difference in patients with mild COPD who had no periodontitis compared to those that did not suffer from COPD. Some other studies demonstrate a poor correlation between

To sum up, several meta‐analyses have shown that periodontitis increases the risk of develop‐ ing COPD; however, the exact mechanism is still not fully understood. Future studies should

COPD is characterized by limitation of airflow which is partially reversible. Progressive decline of FEV1, inadequate lung emptying on expiration, and static and dynamic hyperinfla‐ tion are the results of remodeling of the small‐airway compartment and loss of elastic recoil by emphysematous destruction of parenchyma [24]. Exposure to smoke leads to infiltration of the mucosa, submucosa, and glandular tissue by inflammation cells. Increased mucus con‐ tent, epithelial‐cell hyperplasia, and disturbed tissue repair with wall thickening in the small

Smoking can cause injury of airway epithelial cells, and as a result, endogenous signals are released and recognized by receptors such as Toll‐like receptors 4 and 2 on epithelial cells. This recognition leads to a nonspecific inflammatory response which involves the release of early cytokines, macrophages, neutrophils, and dendritic cells and the transportation of these features to the site of inflammation [26]. Self‐antigens released from damaged tissue as well as foreign antigens from incoming pathogens are presented to naïve T‐cells by dendritic cells. The T‐cells are activated into T‐helper‐1 cells, and these specific CD4 and CD8 cells as well as B‐cells which produce antibodies are transferred to the lungs so as to neutralize the antigens [27].

Alveolar macrophages and other immune cells produce proteinases that destroy the basal mem‐ brane and also cause damage to the collagen and elastic fibers of the connective tissue, leading to the development of emphysema [28]. Moreover, they secrete IL‐4 and IL‐3 that cause edema and increased production of mucus, which are both associated with airway hyperresponsive‐ ness. These responses take place at the respiratory lobule of second order that is located after the terminal bronchiole. It consists of 3–5 generations of respiratory bronchioles that contain

COPD and periodontitis [23].

64 Insights into Various Aspects of Oral Health

focus on the elucidation of such pathogenetic mechanisms.

**4. Pathophysiology of COPD and periodontitis**

conducting airways are the main features of COPD [25].

Smoking is the main factor that initiates immune system reaction in chronic inflammatory diseases as the chronic obstructive pulmonary disease and periodontitis [30]. In response to smoking, neutrophils accumulate rapidly in the lung, because the macrophages and epithelial cells of the lung are activated. They secrete neutrophil‐attracting factors such as IL‐8, C5a, and LTB4. The stimulation of neutrophils causes oxidative damage to the lung due to oxygen radi‐ cals produced by activated neutrophils. Moreover, free oxygen radicals cause oxidative injury to the lung [31]. Oxygen radicals play a role in premature cellular death, but also act on the epithelial and mesenchymal cells. The destruction of the cellular matrix causes a destruction of the supporting connective tissue. Some of these polypeptides as laminin and fibronectin have chemotactic effect and attract neutrophils, playing a key role in the sequence of events of the destruction of lung parenchyma due to smoking. Neutrophils contain proteinases stored in their granules, which are released and destroy the parenchyma. There are metalloproteinase‐9 (MMP‐9) and serine proteinases, which are released and destroy elastin. Elastin is the charac‐ teristic component of elastic fibers, which determine the elastic properties of the lung paren‐ chyma. The destruction of the elastic fibers causes an increased lung compliance and reduction of elasticity, which are characteristic changes in pulmonary emphysema [32]. Elastin segments act as chemotactic agents for macrophages. The aggregated macrophages secrete metallopro‐ teinases in turn and participate in the destruction of lung parenchyma. Macrophages secrete chemokines, which maintain the chronic inflammation that characterizes COPD (**Figure 1**) [33].

**Figure 1.** Pathogenetic mechanisms of lung destruction in COPD.

Apart from neutrophils and macrophages, there are also increased numbers of CD4+ T lym‐ phocytes and CD8+ T lymphocytes in bronchioles and alveoli of COPD patients. Epithelial cells of smokers with COPD show an increased expression of CXC40 factor, which is a structural element of the agent of T‐cell, CXRCR3 [34]. Although the precise role of T cells is not fully understood, it seems that they produce metalloproteinases, which have profound destructive effects on pulmonary parenchyma. The cytotoxic T‐cells are also likely to affect epithelial cells, leading to premature cellular death. Other cells, such as dendritic cells and eosinophils, have also been reported to be increased in COPD. But their exact role is still unknown.

Cigarette smoking, as previously explained, is the main factor to initiate chronic inflammation. However, a few other factors cause inflammation to perpetuate, even years after smoking ces‐ sation. Indeed, in histological lung preparations derived from pneumonectomy, inflammation cells, such as macrophages, T‐cells, neutrophils, and eosinophils are observed, even 9 years after the end of smoking habit [35]. The exact mechanism of persistent inflammation is not known, but it seems that the impaired mobility of the cilia of epithelial cells of the respiratory mucosa predisposes to the colonization of airways with bacteria, which in turn predisposes to viral infections, especially adenovirus infections, which trigger the inflammatory processes. Despite the controversial pathogenesis, numerous inflammatory cells participate in COPD pathogenesis and cause inflammation that proceeds even when the original trigger of cigarette smoke is absent.

These pathogenetic mechanisms have not yet been confirmed in the case of periodonti‐ tis. It is known that neutrophils are the inflammatory cells that predominate in cases of gingivitis [36] and their role in the pathogenesis of chronic periodontitis has been inves‐ tigated. But, it is not yet fully understood whether the neutrophils have the same charac‐ teristics and the same role in both periodontitis and COPD. Further research is needed in the field. However, it is known that in both COPD and periodontitis, activated neu‐ trophils secrete inflammatory mediators, such as proteinases and oxygen radicals, which are involved in tissue damage and in chronic inflammation. This is an important feature of both conditions. Moreover, increased free radicals are produced when cells are exog‐ enously stimulated by the means of *Fusobacterium nucleatum*, a bacterium that frequently causes periodontitis [37].

It should be noted that adverse effects are also caused when local levels of antioxidant factors in interstitial fluid gum are disrupted. At this point, we should remark that if the hypothesis of diffuse inflammation is adopted, we can assume that successful treatment of one disease (periodontitis) could improve the other (COPD) and conversely. It is known that there is a positive correlation between poor oral hygiene and the frequency of COPD exacerbations [38]. In a recent study, patients with COPD and concomitant periodontitis were tested. Half of them (20 patients) received proper treatment for periodontitis, while the rest 20 patients did not receive any treatment at all. They were all observed for 12 months, and it was reported that in the first group a lower frequency of COPD exacerbations was documented. Although this is a significant finding, the study had some methodological problems such as the fact that the selection of patients was not randomized and the sample size was small. Nevertheless, the findings of this study should be carefully considered in order to carry out further investigation in the field.

## **5. Antibiotic treatment in chronic periodontitis and COPD**

Apart from neutrophils and macrophages, there are also increased numbers of CD4+ T lym‐ phocytes and CD8+ T lymphocytes in bronchioles and alveoli of COPD patients. Epithelial cells of smokers with COPD show an increased expression of CXC40 factor, which is a structural element of the agent of T‐cell, CXRCR3 [34]. Although the precise role of T cells is not fully understood, it seems that they produce metalloproteinases, which have profound destructive effects on pulmonary parenchyma. The cytotoxic T‐cells are also likely to affect epithelial cells, leading to premature cellular death. Other cells, such as dendritic cells and eosinophils, have also been reported to be increased in COPD. But their exact role is still unknown.

Cigarette smoking, as previously explained, is the main factor to initiate chronic inflammation. However, a few other factors cause inflammation to perpetuate, even years after smoking ces‐ sation. Indeed, in histological lung preparations derived from pneumonectomy, inflammation cells, such as macrophages, T‐cells, neutrophils, and eosinophils are observed, even 9 years after the end of smoking habit [35]. The exact mechanism of persistent inflammation is not known, but it seems that the impaired mobility of the cilia of epithelial cells of the respiratory mucosa predisposes to the colonization of airways with bacteria, which in turn predisposes to viral infections, especially adenovirus infections, which trigger the inflammatory processes. Despite the controversial pathogenesis, numerous inflammatory cells participate in COPD pathogenesis and cause inflammation that proceeds even when the original trigger of cigarette

These pathogenetic mechanisms have not yet been confirmed in the case of periodonti‐ tis. It is known that neutrophils are the inflammatory cells that predominate in cases of gingivitis [36] and their role in the pathogenesis of chronic periodontitis has been inves‐ tigated. But, it is not yet fully understood whether the neutrophils have the same charac‐ teristics and the same role in both periodontitis and COPD. Further research is needed in the field. However, it is known that in both COPD and periodontitis, activated neu‐ trophils secrete inflammatory mediators, such as proteinases and oxygen radicals, which are involved in tissue damage and in chronic inflammation. This is an important feature of both conditions. Moreover, increased free radicals are produced when cells are exog‐ enously stimulated by the means of *Fusobacterium nucleatum*, a bacterium that frequently

It should be noted that adverse effects are also caused when local levels of antioxidant factors in interstitial fluid gum are disrupted. At this point, we should remark that if the hypothesis of diffuse inflammation is adopted, we can assume that successful treatment of one disease (periodontitis) could improve the other (COPD) and conversely. It is known that there is a positive correlation between poor oral hygiene and the frequency of COPD exacerbations [38]. In a recent study, patients with COPD and concomitant periodontitis were tested. Half of them (20 patients) received proper treatment for periodontitis, while the rest 20 patients did not receive any treatment at all. They were all observed for 12 months, and it was reported that in the first group a lower frequency of COPD exacerbations was documented. Although this is a significant finding, the study had some methodological problems such as the fact that the selection of patients was not randomized and the sample size was small.

smoke is absent.

66 Insights into Various Aspects of Oral Health

causes periodontitis [37].

Exacerbations are short periods in the course of COPD characterized by increased cough, dyspnea, and production of sputum that can become purulent. They can lead to accelerated lung function impairment, worse quality of life, and increased mortality [39]. Except from the severity, the frequency of the exacerbations, also, plays an important role in the management of the exacerbations. Depending on the severity of the exacerbation, different therapeutic strategies could be used. Therefore, increased doses of bronchodilators are required for mild exacerbations, systemic corticosteroids, and antibiotics can be used for moderate exacerba‐ tions, whereas severe exacerbations often require admission to hospital [40]. However, the most frequent causes of exacerbations are bacterial or viral infections, which are responsible for 60–80% of all exacerbations. These infectious exacerbations are more severe than the non‐ infectious exacerbations.

There are some articles concerning the possible relationship between chronic inflammatory diseases and their comorbidities. Both chronic periodontitis and COPD are neutrophilic, inflammatory conditions characterized by loss of local connective tissue. It is possible that there is an association and perhaps a casual link between the two diseases. It has been reported that respiratory pathogens such as *Pseudomonas aeruginosa* might adhere better to oral epithe‐ lial cells obtained from patients colonized by respiratory pathogens than to cells harvested from noncolonized patients. Trypsin treatment of epithelial cells from noncolonized patients in vitro resulted in increased adhesion of respiratory pathogens [41]. This suggests that muco‐ sal alteration promoted enhanced bacterial adhesion of these bacteria. This alteration is per‐ haps the loss of fibronectin (by exposure to proteases) from the epithelial cell surface, which may unmask mucosal surface receptors for respiratory pathogen adhesions.

Subjects with poor hygiene may have elevated levels of hydrolytic enzymes in their saliva. These enzymes may process mucins to reduce their ability to bind to and clear pathogens such as *Haemophilus influenzae*. Conversely, the enzymes may process the respiratory epithe‐ lium to modulate the adhesion of such pathogens to the mucosal surface. Mannino et al. [42] postulated that oral pathogens continuously stimulate the cells of the periodontium (epithe‐ lial cells) to release a wide variety of cytokines and other biologically active molecules such as IL‐1a, IL‐1b, IL‐6, IL‐8, and TNF‐a. Oral bacteria in secretions may adhere to the mucosal surface and stimulate the epithelial cells of the respiratory epithelium to secrete cytokines. These stimulated cells may then release other cytokines that recruit inflammatory cells to the site. These inflammatory cells release hydrolytic enzymes resulting in damaged epithelium that may be more susceptible to colonization by respiratory pathogens. It is possible that the poor oral health might work in concert with other factors (smoking, environmental pollution, viral infections, and genetic factors) to promote the progression and exacerbation of pulmo‐ nary disease.

## **6. Conclusions**

The associations demonstrated between periodontitis and COPD suggest a basis for test‐ ing the effects of treatment for one condition upon the severity of the other. Improving oral hygiene might reduce the risk of respiratory infection among subjects who are at risk.

Our article describes similarities in epidemiology and pathogenetic mechanisms of COPD and periodontitis and proposes that improvement of one condition is linked to the treatment of the other. Future research is needed to clarify the existing pathogenetic mechanisms and extend possible therapeutic options.

## **Authors' contributions**

Agathi Spiropoulou and Dimosthenis Lykouras have worked on manuscript concept, lit‐ erature review, and manuscript preparation. Olga Lagiou worked on literature review and manuscript preparation. Kiriakos Karkoulias worked on manuscript preparation. Kostas Spiropoulos worked on revision of manuscript for important intellectual content.

## **Abbreviations**


#### **Author details**

Agathi Spiropoulou, Olga Lagiou, Dimosthenis Lykouras, Kiriakos Karkoulias and Kostas Spiropoulos\*

\*Address all correspondence to: spircos@upatras.gr

Department of Pulmonary Medicine, University Hospital of Patras, Rio, Patras, Greece

## **References**

**6. Conclusions**

68 Insights into Various Aspects of Oral Health

extend possible therapeutic options.

**Authors' contributions**

**Abbreviations**

**Author details**

Spiropoulos\*

The associations demonstrated between periodontitis and COPD suggest a basis for test‐ ing the effects of treatment for one condition upon the severity of the other. Improving oral

Our article describes similarities in epidemiology and pathogenetic mechanisms of COPD and periodontitis and proposes that improvement of one condition is linked to the treatment of the other. Future research is needed to clarify the existing pathogenetic mechanisms and

Agathi Spiropoulou and Dimosthenis Lykouras have worked on manuscript concept, lit‐ erature review, and manuscript preparation. Olga Lagiou worked on literature review and manuscript preparation. Kiriakos Karkoulias worked on manuscript preparation. Kostas

(FEV1/FVC) ratio The ratio of the forced expiratory volume in the first one second to the forced vital capacity of the lungs

Agathi Spiropoulou, Olga Lagiou, Dimosthenis Lykouras, Kiriakos Karkoulias and Kostas

Department of Pulmonary Medicine, University Hospital of Patras, Rio, Patras, Greece

Spiropoulos worked on revision of manuscript for important intellectual content.

COPD Chronic obstructive pulmonary disease

CD Cluster of differentiation

CRP C‐reactive protein MMP Metalloproteinase

TNF Tumor necrosis factor

C5a Complement component 5a

\*Address all correspondence to: spircos@upatras.gr

IL Interleukin

LTB4 Leukotriene B4

hygiene might reduce the risk of respiratory infection among subjects who are at risk.


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**Provisional chapter**
