**2.6 Conjunctivitis**

*Apolipoproteins, Triglycerides and Cholesterol*

exact effects of omega-3 PUFAs cannot be elucidated.

**2.5 Rheumatoid arthritis**

Smooth muscle cells, fibroblasts, and myofibroblasts play a key regulatory role in airway remodeling by generating different structural components, such as collagen and proteoglycans [54]. Although the mediators involved in structural remodeling of the bronchial wall remains unknown, chemokines, cytokines, and growth factors are thought to have a crucial role. Observational clinical studies suggest that n-3 PUFA levels in COPD are inversely related to systemic inflammation and directly related to clinical outcomes [55–57]. Interventional studies using n-3 PUFAs alone in COPD do not exist; however, many trials are currently underway, which may generate valuable data in the coming years [58–60]. An animal study in pneumonia model of mice, revealed RvE1 metabolite of n-3 PUFA decreased levels of several pro-inflammatory chemokines and cytokines in the lung, and improved survival [61]. However, currently, there is a paucity of data regarding the potential of n-3 PUFAs to be used therapeutically in COPD. Recent studies, conducted using omega-3 PUFAs in COPD has used nutrient combinations, in a manner that the

Rheumatoid arthritis (RA) is a low grade chronic inflammatory autoimmune disease affecting the joints and bones. RA and systemic lupus erythematosus (SLE) are multisystem autoimmune diseases featuring the production of a variety of autoantibodies, and resulting in higher immune-mediated inflammation. Prevalence of RA is known to affect 17.6 million people worldwide [7] with the huge economic burden to mankind. Pathogenesis of RA in early phase focused on auto-antibodies and immune complexes [62], however, the nature of T-cell mediated antigen-specific responses, T-cell-independent cytokine species, and aggressive tumor-like behavior of rheumatoid synovium have also been reported. Immune complex theory strongly suggests increased neutrophils accumulation in synovial fluid results in engulfment of immune complex and release proteolytic enzymes [62]. A better understanding of the intracellular targets that regulate cytokines in RA can potentially lead to new therapeutic interventions. For instance, studies reported activation of NF-κB in the synovium of RA patients [63] and mitogen-activated protein (MAP) kinases are identified as vital regulators of cytokine and metalloproteinase production. The mechanistic approach to currently available drugs is partially understood and mostly targeting the eicosanoid pathway, and reports are scarce about gene targets on CD28, AP-1, and MAP kinases. Investigators have examined the effect of dietary fatty acid supplementation in different autoimmune diseases, and the effects of both n-6 and n-3 PUFA on RA have been reported [64]. Resolvins derived from EPA and DHA are anti-inflammatory and resolve inflammation, serving as important mediators in regulating various homeostatic functions, including gastric mucosal integrity. Kremer and co-workers reported that a dose of 90 mg/kg/day EPA/DHA (3:2 ratio) showed a shorter period to respond than 45 mg/kg/day [65]. Clinical studies have ambiguity in results, few observed reductions in both tender joints by 36% and swollen joint to 38% in patients, whereas the placebo group showed no improvement in these parameters [66]. Fish oil supplementation in women patients showing a decrease in the production of serum nuclear factor-kappa B (Nf-kB) ligand/osteoprotegerin ratio [67]. Cell culture-based investigations have reported that EPA and DHA prevent the proliferation of human T cells and their generation of IL-2 [68]. Animal studies also reported a beneficial effect of marine n-3 PUFA in RA [69, 70]. Finally, supplementation with dietary n-3 PUFA and its ability to inhibit TNF-α and IL-1b synthesis is rational. Considering the emphasis on recommendations to increase dietary n-3 PUFA intake for health benefits, the possible therapeutic potential of fish oil/n-3 PUFA on autoimmune diseases need to be clearly defined.

**202**

Conjunctivitis is an ocular inflammatory condition of the membrane lining the eyelid, which provides a shelter to the open surface of the sclera [71]. It is said to be the most common cause of "red eye," and the infection, either acute or chronic can originate from three different sources, based on which it is commonly classified: viral, allergic, and bacterial conjunctivitis. The type of conjunctivitis may be determined by a diagnostic investigation which takes into account, the patient's age, time of the year, and physical examination findings [72]. Identification of the pathogen which elicits the inflammatory response is necessary to decide on the required treatment module, since some bacterial conjunctivitis forms are self-limiting, while those caused by *Chlamydia trachomatis* or *Neisseria gonorrhoeae* demand aggressive antibiotic therapy, and primarily good eyelid hygiene [71]. The visual symptoms of inflammation at the ocular surface, include, lid and conjunctival edema–redness, tearing, extreme itching, and photophobia during the acute phase cause immense discomfort, thereby necessitating treatment [73]. Effective pharmacological cure comprises antihistamines, mast cell stabilizers, and non-steroidal anti-inflammatory drugs [74]. The excess wateriness experienced during conjunctivitis and also early dry eye disease is because of enhanced goblet cell mucin secretion into tears, which otherwise produce a regulated amount of mucins only to protect the eye. This phenomenon is due to the action of inflammatory mediators, cysteinyl leukotrienes LTB4, LTC4, LTD4, and LTE4, and prostaglandin PGD2, which stimulate conjunctival goblet cell mucous secretion. Thus, mitigation of this LTD4 effect can aid in reducing mucin secretion, and this has been achieved previously by the action of Resolvins D1 (RvD1) and E1 (RvE1) [2]. The finding of Dartt and co-workers [2] indicates that lipids including fatty acids or lipid mediators play a role in suppression of systemic inflammation as well as local, such as in the case of inflammatory conjunctivitis. The connection between the quality of fat consumed and conjunctivitis was drawn from the results of a Japanese study, which states that meat intake is directly proportional to the prevalence of rhinoconjunctivitis in young adult Japanese women, while no correlation was seen between fish intake and rhinoconjunctivitis [75]. Though, there are not many reports from similar controlled clinical trials that specifically correlate meat intake with incidence of conjunctivitis, to ascertain such claims. The study does raise questions on the role of fats present in meat that possibly trigger the pathways in inflammation. The true potential of n-3 PUFA as an anti-inflammatory in managing conjunctivitis was elucidated through other detailed investigations of their actions and mechanisms at molecular levels. A primary mode of action is that of the resolvin mediated responses, as mentioned earlier. The process of resolution of inflammation is an active process facilitated by pro-resolution lipid mediators. Not only D-series resolvins RvD1, which are produced in the cornea but also aspirin-triggered RvD1 (ATRvD1) have exhibited regulation of inflammatory responses to histamine in allergic conjunctivitis. The effect is implemented by a cross-talk between two types of G protein-coupled receptors (GPCRs). When RvD1 interacts with its receptor GPR32, it prevents the histamine-stimulated H1 receptor-mediated rise in intracellular Ca2+, thereby blocking H1 receptor-mediated responses. Consequentially, this activates extracellularly regulated–protein kinase (ERK) 1/2 [76]. In addition to resolvins, another class of lipid mediators that can mimic these anti-inflammatory actions in conjunctivitis includes lipoxins, especially, lipoxin A4 that has benefits similar to that of ATRvDI and can activate ALX/FPR2 receptor to regulate conjunctival goblet cell secretion, which is particularly useful in maintaining ocular surface homeostasis, and managing the dry eye syndrome [77]. Another evidence of polyunsaturated fats aiding in the treatment of conjunctivitis emerged on evaluating the impact of the feeding of omega-3 and omega-6 PUFA on human leukocyte antigen-DR (HLA-DR) marker of conjunctival

inflammation in dry eye patients; it was observed that increased intake of both these fatty acids suppressed the expression of HLA-DR [78]. With this, it is evident that dietary supplementation of n-3 PUFA has a modulatory effect on conjunctivitis. Their efficacy has been tested in mammals such as dogs affected with keratoconjunctivitis sicca, where EPA + DHA + antioxidants in defined proportion was used as an adjuvant [79]. Furthermore, their use of topical treatment has also been suggested in the literature. Based on data from animal preliminary human studies, protectins (NPD1) and DHA turn out to be a safe, effective treatment for dry eye through a topical application [80]. Ultimately, investigators have also proposed formulations for active use in therapy, one such patented formulation by Aleo et al. [81], clearly provided the n-3 and n-6 PUFA proportion for creating an ophthalmic composition suitable for ocular inflammation.

### **2.7 Hepatitis**

Hepatitis is the inflammation of the liver with symptoms that generally include right upper abdominal pain, headache, fatigue and malaise, myalgia, altered sense of smell or taste, nausea and vomiting, coryza, photophobia, diarrhea (may have pale stools and dark urine) [5]. Hepatitis treatment can be managed better without any inconveniences, with the help of dietary interventions, which not only limit the progression of hepatitis but can also be used as a novel therapy. Considering the abundant evidence of n-3 PUFA and their anti-inflammatory effect in most liver maladies, including fatty liver disease, cirrhosis, and acute liver failure, their role in immunemediated liver diseases is not fully exploited. Fatty acids belonging to the n-3 family have been shown to suppress hepatitis via an autophagy-dependent mechanism and are particularly helpful for therapy in autoimmune hepatitis [82]. In this regard, the n-3 PUFA mediators resolvin D1 and E1 can be particularly useful, as they inhibit concanavalin A-induced liver injury and restricting the progression of hepatitis to liver cancer in mice through suppression of NF-kβ/AP-1 activity [83]. The actions of n-3 PUFA were evaluated in a macrophage-dependent acute D-galactosamine/lipopolysaccharide (D-GalN/LPS) hepatitis model in the transgenic fat-1 mice. The findings clearly stated that the n-3 PUFA supplementation dampened the severity of the inflammatory liver injury and histological liver damage in fat-1 mice. The balance in n-6/n-3 PUFA ratio was improved, and levels of serum alanine aminotransferase and TNF-α and IL-1β cytokine production were lowered. The effect was confirmed through the lowered hepatic gene expression of all the pro-inflammatory cytokines, thus proving their anti-inflammatory benefits in the framework of liver inflammation [84]. The most striking feature of n-3 PUFA therapy in HCV was discovered when the efficacy of EPA was evaluated against ribavirin (RBV) associated hemolytic anemia. When EPA was supplemented with the standard combination therapy of peginterferon (PEG-IFN) and ribavirin (RBV), patients receiving EPA, required reduced RBV doses compared to the non-EPA group, and also showed decreased RBV-induced hemolysis, although rates of virological response are yet to be elucidated [85]. Therefore, it is encouraging that EPA can lower dependency on drugs in even such morbid disorders. Some of the other adverse effects of RBV treatment which have been effectively countered by n-3 PUFA include lowering of the impairment of the filterability of erythrocytes of chronic HCV patients in whom erythrocyte filterability was caused due to oxidative membrane damage induced by RBV which led to hemolytic anemia [86]. This finding further ensures the maintenance of the lymphocyte levels and improvement in hemoglobin levels in the patients of PEG-IFN and RBV treatment [87]. Thus, n-3 PUFA and their mediators can be recommended for concurrent administration with the recommended standard interferon and antibiotic therapy, to facilitate recovery, ameliorate adverse effects, and prevent mortalities in chronic cases.

**205**

productivity at work.

**3. Summary and conclusion**

Taken together, findings from in-vitro and in-vivo studies of inflammatory diseases suggest that n-3 PUFA could be potential therapeutic molecules to combat

*Modulatory Potentials of n-3 Polyunsaturated Fatty Acids in Inflammatory Diseases*

Allergic rhinitis (AR) is a highly prevalent heterogeneous disorder, caused by pollens, molds, dust mites, and animal dander, but often goes undiagnosed as a condition of rhinitis. The symptoms of AR, which include sneezing, itching, nasal congestion, and rhinorrhea are mostly IgE mediated and triggered through mucosal infiltration and action on eosinophils, plasma cells, and mast cells, [7]. Some other discomforts experienced by the patients in chronic rhinitis include sinusitis, eustachian-tube dysfunction, sleep disturbances, and forces the patient to breathe through the mouth. AR may not appear as a serious ailment but is clinically relevant as it triggers numerous complications, is a potential risk factor for asthma, deteriorates the quality of life and efficiency at work. The range of pharmaceutical options available to manage a rhinitis episode includes intranasal corticosteroids, which are effective and safe. The most common drug type is that of first-generation antihistamines, but they are well-known to cause sedation, psychomotor retardation, and decreased academic performance. AR is tackled most effectively from its natural history, using immunotherapy by targeting allergens singly [88]. Various dietary factors have been associated with allergic rhinitis, such as dietary antioxidants in vegetables may reduce wheezing symptoms, but fats such as butter and margarine tend to aggravate the symptoms [89]. The exact mechanism by which saturated fats alter airway inflammation has neither been fully understood nor has it received much attention. Yet, reports suggest that accumulation of saturated fatty acids is associated with changes in levels of serum cholesterol and arachidonic acid content in the cell membranes, which together modify the lymphocyte function. These observations and other epidemiological data led to the conclusion that saturated fats aggravate rhinitis, asthma and related conditions [90]. Since saturated fats were implicated in worsening rhinitis, the effect of unsaturated fats on allergic sensitization and allergic rhinitis was also investigated by many researchers. It was found that the presence of unsaturated fatty acids in membranes of red blood cells (RBC) in the form of EPA and the diet as ALA, lower sensitivity and incidence of rhinitis [8, 91]. Fish consumption during pregnancy as well as childhood was associated with a lowered risk of any respiratory illnesses—allergic rhinitis, wheezing or asthma in childhood and later, and long chain n-3 PUFA supplementation was also not related to the risk of postpartum hemorrhages in mothers as well [92, 93]. An insight into the mechanism by which this effect is achieved suggests that n-3 PUFA supplementation during pregnancy boosts levels of placental DHA and specialized pro-resolving lipid mediators (SPM) precursors without aggravating inflammatory gene expression [94]. Also, adjunctive supplementation of fish quickens the effects of routine pharmacotherapy in AR subjects by lowering AR related symptoms and serum levels of Ig E, which is crucial since IL-5 and Ig E are found in higher concentrations in nasal secretion and sputum of AR patients [95]. With such abundant information pointing towards the preventive and prophylactic effects of polyunsaturated fatty acids on the rhinitis, the dietary incorporation of n-3 PUFA, as well as their use as adjuvant therapy for lowering the incidence and severity of a rhinitis episode, can be strongly recommended. These fatty acids have also demonstrated a potential to slow down the progression of chronic rhinitis, thereby improving quality of life and

*DOI: http://dx.doi.org/10.5772/intechopen.88394*

**2.8 Rhinitis**

*Modulatory Potentials of n-3 Polyunsaturated Fatty Acids in Inflammatory Diseases DOI: http://dx.doi.org/10.5772/intechopen.88394*

#### **2.8 Rhinitis**

*Apolipoproteins, Triglycerides and Cholesterol*

ocular inflammation.

**2.7 Hepatitis**

inflammation in dry eye patients; it was observed that increased intake of both these fatty acids suppressed the expression of HLA-DR [78]. With this, it is evident that dietary supplementation of n-3 PUFA has a modulatory effect on conjunctivitis. Their efficacy has been tested in mammals such as dogs affected with keratoconjunctivitis sicca, where EPA + DHA + antioxidants in defined proportion was used as an adjuvant [79]. Furthermore, their use of topical treatment has also been suggested in the literature. Based on data from animal preliminary human studies, protectins (NPD1) and DHA turn out to be a safe, effective treatment for dry eye through a topical application [80]. Ultimately, investigators have also proposed formulations for active use in therapy, one such patented formulation by Aleo et al. [81], clearly provided the n-3 and n-6 PUFA proportion for creating an ophthalmic composition suitable for

Hepatitis is the inflammation of the liver with symptoms that generally include right upper abdominal pain, headache, fatigue and malaise, myalgia, altered sense of smell or taste, nausea and vomiting, coryza, photophobia, diarrhea (may have pale stools and dark urine) [5]. Hepatitis treatment can be managed better without any inconveniences, with the help of dietary interventions, which not only limit the progression of hepatitis but can also be used as a novel therapy. Considering the abundant evidence of n-3 PUFA and their anti-inflammatory effect in most liver maladies, including fatty liver disease, cirrhosis, and acute liver failure, their role in immunemediated liver diseases is not fully exploited. Fatty acids belonging to the n-3 family have been shown to suppress hepatitis via an autophagy-dependent mechanism and are particularly helpful for therapy in autoimmune hepatitis [82]. In this regard, the n-3 PUFA mediators resolvin D1 and E1 can be particularly useful, as they inhibit concanavalin A-induced liver injury and restricting the progression of hepatitis to liver cancer in mice through suppression of NF-kβ/AP-1 activity [83]. The actions of n-3 PUFA were evaluated in a macrophage-dependent acute D-galactosamine/lipopolysaccharide (D-GalN/LPS) hepatitis model in the transgenic fat-1 mice. The findings clearly stated that the n-3 PUFA supplementation dampened the severity of the inflammatory liver injury and histological liver damage in fat-1 mice. The balance in n-6/n-3 PUFA ratio was improved, and levels of serum alanine aminotransferase and TNF-α and IL-1β cytokine production were lowered. The effect was confirmed through the lowered hepatic gene expression of all the pro-inflammatory cytokines, thus proving their anti-inflammatory benefits in the framework of liver inflammation [84]. The most striking feature of n-3 PUFA therapy in HCV was discovered when the efficacy of EPA was evaluated against ribavirin (RBV) associated hemolytic anemia. When EPA was supplemented with the standard combination therapy of peginterferon (PEG-IFN) and ribavirin (RBV), patients receiving EPA, required reduced RBV doses compared to the non-EPA group, and also showed decreased RBV-induced hemolysis, although rates of virological response are yet to be elucidated [85]. Therefore, it is encouraging that EPA can lower dependency on drugs in even such morbid disorders. Some of the other adverse effects of RBV treatment which have been effectively countered by n-3 PUFA include lowering of the impairment of the filterability of erythrocytes of chronic HCV patients in whom erythrocyte filterability was caused due to oxidative membrane damage induced by RBV which led to hemolytic anemia [86]. This finding further ensures the maintenance of the lymphocyte levels and improvement in hemoglobin levels in the patients of PEG-IFN and RBV treatment [87]. Thus, n-3 PUFA and their mediators can be recommended for concurrent administration with the recommended standard interferon and antibiotic therapy, to facilitate recovery, ameliorate adverse

**204**

effects, and prevent mortalities in chronic cases.

Allergic rhinitis (AR) is a highly prevalent heterogeneous disorder, caused by pollens, molds, dust mites, and animal dander, but often goes undiagnosed as a condition of rhinitis. The symptoms of AR, which include sneezing, itching, nasal congestion, and rhinorrhea are mostly IgE mediated and triggered through mucosal infiltration and action on eosinophils, plasma cells, and mast cells, [7]. Some other discomforts experienced by the patients in chronic rhinitis include sinusitis, eustachian-tube dysfunction, sleep disturbances, and forces the patient to breathe through the mouth. AR may not appear as a serious ailment but is clinically relevant as it triggers numerous complications, is a potential risk factor for asthma, deteriorates the quality of life and efficiency at work. The range of pharmaceutical options available to manage a rhinitis episode includes intranasal corticosteroids, which are effective and safe. The most common drug type is that of first-generation antihistamines, but they are well-known to cause sedation, psychomotor retardation, and decreased academic performance. AR is tackled most effectively from its natural history, using immunotherapy by targeting allergens singly [88]. Various dietary factors have been associated with allergic rhinitis, such as dietary antioxidants in vegetables may reduce wheezing symptoms, but fats such as butter and margarine tend to aggravate the symptoms [89]. The exact mechanism by which saturated fats alter airway inflammation has neither been fully understood nor has it received much attention. Yet, reports suggest that accumulation of saturated fatty acids is associated with changes in levels of serum cholesterol and arachidonic acid content in the cell membranes, which together modify the lymphocyte function. These observations and other epidemiological data led to the conclusion that saturated fats aggravate rhinitis, asthma and related conditions [90]. Since saturated fats were implicated in worsening rhinitis, the effect of unsaturated fats on allergic sensitization and allergic rhinitis was also investigated by many researchers. It was found that the presence of unsaturated fatty acids in membranes of red blood cells (RBC) in the form of EPA and the diet as ALA, lower sensitivity and incidence of rhinitis [8, 91]. Fish consumption during pregnancy as well as childhood was associated with a lowered risk of any respiratory illnesses—allergic rhinitis, wheezing or asthma in childhood and later, and long chain n-3 PUFA supplementation was also not related to the risk of postpartum hemorrhages in mothers as well [92, 93]. An insight into the mechanism by which this effect is achieved suggests that n-3 PUFA supplementation during pregnancy boosts levels of placental DHA and specialized pro-resolving lipid mediators (SPM) precursors without aggravating inflammatory gene expression [94]. Also, adjunctive supplementation of fish quickens the effects of routine pharmacotherapy in AR subjects by lowering AR related symptoms and serum levels of Ig E, which is crucial since IL-5 and Ig E are found in higher concentrations in nasal secretion and sputum of AR patients [95]. With such abundant information pointing towards the preventive and prophylactic effects of polyunsaturated fatty acids on the rhinitis, the dietary incorporation of n-3 PUFA, as well as their use as adjuvant therapy for lowering the incidence and severity of a rhinitis episode, can be strongly recommended. These fatty acids have also demonstrated a potential to slow down the progression of chronic rhinitis, thereby improving quality of life and productivity at work.

### **3. Summary and conclusion**

Taken together, findings from in-vitro and in-vivo studies of inflammatory diseases suggest that n-3 PUFA could be potential therapeutic molecules to combat inflammatory diseases as described in this chapter. The results from mechanistic studies reveal the effects of LC-PUFAs (n-6 and n-3) on human health are highly favorable. However, the relation between the two families of LC-PUFAs on the mechanisms of action needs to be further understood as the presence of these two fatty acids in the diet play a significant effect on the metabolism of other. The inflammatory mechanism involved in the pathogenesis provides novel candidature targets for cost-effective pharmacological and nutraceutical drugs. Despite a better understanding of the beneficial effects of LC-PUFAs, there is a lack of data on attempts to replace or supplement with currently available drugs. Investigating the synergistic potential of various food bioactive molecules with existing clinically proven drugs could be the most effective therapy to ameliorate many of these inflammatory diseases.
