**2. Research advances in the pathogenesis of COPD**

Clinical guidelines issued by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) tend to simplify the definition of COPD. COPD is actually a heterogeneous and complex disease. Smoking is globally recognized as the most important risk factor for COPD. But data from population-based studies show that only half of COPD cases are caused by smoking. Reports from South Africa, China, and South Korea indicate that the proportion of non-smoking COPD in men and women was different, and the morbidity of non-smoking COPD in women was more than 50%, suggesting that it may be related to household smoke exposure. COPD caused by exposure to biomass fuels is quite different from smoking-induced COPD in terms of phenotype, morbidity, and disease progression. Tuberculosis infection, occupational exposure, and frequent infections in children are also considered as major risks for the development of COPD. Agriculture is also a risk factor for COPD, where pesticide exposure is associated with accelerated decline in lung function, with a reduction of 6.9 ml per year in forced expiratory volume in 1 second (FEV 1). In addition to environmental exposure, genetic risk factors are increasingly associated with the

*Exploration of Multi-Aspect Development of Chronic Obstructive Pulmonary Disease… DOI: http://dx.doi.org/10.5772/intechopen.106643*

development of nicotine addiction, chronic bronchitis, loss of lung function, and early lung development.

Unregulated inflammation, oxidative/antioxidant imbalance, proteolytic/ anti-proteolytic imbalance, and imbalance of cell damage/repair are recognized mechanisms. At the same time, microbiota bias, air-pollutant-related damage, and autoimmune processes in lung tissue are all underlying pathogenesis of COPD. Epigenetic regulation has also been implicated in the pathogenesis of COPD.

#### **2.1 Inflammatory mechanism**

The pathological changes of COPD are characterized by chronic inflammation of airway, lung parenchyma, and pulmonary vessels. When the body inhales harmful particles and gases, it can cause a variety of inflammatory cells to participate in the release of a variety of inflammatory mediators, leading to irreversible lung damage. Damage to airway epithelial cells triggers a nonspecific inflammatory response through the release of endogenous intracellular molecules or risk-associated molecular patterns. These signals are recognized by pattern recognition receptors such as Toll-like receptors 4 and 2 on epithelial cells, resulting in the release of cytokines, such as TNF-α, IL-1β, granulocyte-macrophage colony-stimulating factor (GM-CSF), transforming growth factor (TGF) -β1, MCP-1, LTB 4, and IL-8. Inflammatory cells such as macrophages, neutrophils, eosinophils, and dendritic cells are recruited to sites of inflammation to form innate immune responses, while Th1, Th17, and ILC3 lymphocytes constitute acquired immunity. At the same time, activated inflammatory cells release a variety of inflammatory mediators. The mediators act on airway epithelial cells, which in turn promote epithelial cell damage. In patients with COPD, tissue damage by inflammation is uninterrupted, and the inflammatory response persists even after smoking cessation. In the case of chronic bronchitis, prolonged exposure to risk factors leads to mucosal and glandular inflammation, increased mucus secretion and epithelial cell proliferation, and altered tissue repair of the small airways.

Circulating blood cells, including neutrophils, and inflammatory cells in the lungs have long been implicated as players in smoking-induced tissue damage. Neutrophils in the sputum and bronchoalveolar lavage fluid (BALF) of patients with COPD are found to rapidly appear at sites of inflammation in response to interleukin (IL) -8, and neutrophil numbers increase with interleukin (IL) -6. A variety of other chemokines can induce neutrophil migration, including chemokines CXC motif ligand 2 (CXCL2), leukotriene B4 (LTB4), and formyl-met-leuphe (fMLP), which are produced by the body's own immune cells and diseased tissue cells and are related to host-microbe interactions. Alpha-1-antitrypsin (AAT) is the major anti-protease, which is also a candidate chemokine for neutrophils. Neutrophils are major destroyers of the elastic matrix of the alveoli. By secreting proteases and small cationic peptides, neutrophils are able to attack invading bacteria, viruses, pollutants, and in some autoimmune situations, their own tissues. Under the influence of environmental pollution (including cigarette smoke), enzymes and peptides released by neutrophils are able to cut collagen into pieces, thereby activating inflammatory cells and driving further chronic inflammation.

Circulating progenitors of pulmonary macrophages are originated from mononuclear cells in peripheral blood. When local inflammation occurs in the airways, monocytes migrate from the circulatory system to the lung tissue and differentiate into interstitial and alveolar macrophages. Pulmonary macrophages coexist with emphysematous areas and increase in number in the airways, lung parenchyma, BALF, and

sputum of patients. The number of macrophages in the airways is positively correlated with the severity of COPD. Macrophages can be activated by cigarette smoke extracts to release inflammatory mediators including tumor necrosis factor (TNF) -a, interleukin-8, other chemokines such as CXCL9, CXCL10, and CXCL11, monocyte chemotactic peptide (MCP) -1, LTb4, and reactive oxygen species. In addition, alveolar macrophages also secrete elastase including MMP-2, MMP-9, MMP-12, cathepsins K, L, and S, and neutrophil elastase extracted from neutrophils. Inflammatory proteins that are upregulated in macrophages during acute exacerbations of COPD are regulated by transcription factors such as nuclear factor-κB (NF-κB), activator protein-1, and tyrosine kinase c-Src.

T lymphocytes are present in the entire human organism including the epithelial surface of lung and mediate host defense. Human lungs are rich in resident T cells (more than 10 billion). Th1-type cells are involved in a sustained autoimmune response with interferon gamma as the primary cytokine and lead to exaggerated pro-inflammatory responses that result in uncontrolled tissue damage. Emphysema is generally considered to be a Th1 disease. Studies have shown that the development of emphysema may be mediated by T lymphocytes, and all T cell phenotypes are increased in smokers with COPD. Although neutrophils are the predominant cells in the lung parenchyma of non-COPD smokers, there is an increase in T cells (CD3 and CD8), primarily CD8 cytotoxic T cells, with evidence of emphysema. Apoptosis may be one of the mechanisms of pulmonary emphysema. In emphysema, CD8 T-cell numbers are correlated with the severity of tissue destruction, and their accumulation continues even after smoking cessation. In addition, the number of T cells was correlated with smoking history. In conclusion, the different interrelationships between T cell subtypes in COPD may be important for the progression of inflammation.

Airway eosinophilia and Th2-type inflammation are associated with allergic airway diseases such as asthma. However, recent studies have reported that 20–40% of COPD patients exhibit stable sputum eosinophilia. The SPIROMICS (SubPopulations and InteRmediate Outcome Measures In COPD Study) cohort has found that stable sputum eosinophilia is related to an increased frequency of disease exacerbations. In the meantime, high blood eosinophil levels at steady state predict a better therapeutic response to inhaled corticosteroids, which may be used to guide treatment. Although stable sputum and blood eosinophilia would be regarded as biomarkers of disease and steroid responsiveness, further work is needed to assess the importance of increased Th2 inflammation during COPD exacerbations.

#### **2.2 Oxidative stress/antioxidant imbalance**

ROS are oxygen-rich unstable molecules that can be either donors or acceptors of free electrons. Intracellular ROS can induce functional and structural changes in cells. The intracellular redox state is determined by the oxidant load in the respirable air and the pooling capacity of the lung protective mechanisms to absorb oxidants. Alveolar lining fluid, alveolar epithelial cells, local macrophages, and lung fibroblasts are all major targets of ROS. They can also be a secondary source of ROS. It showed that most cell types induce ROS production, and all lung cells may be involved in the redox state transition of COPD. The body keeps a dynamic balance between oxidation and antioxidation in normal condition. However, under pathological conditions, the imbalance between oxidation and antioxidation leads to oxidative stress, lipid peroxidation, protein modification, DNA damage, and activation of pro-inflammatory factors such as transcription factors NF-κB, which initiate inflammatory response

#### *Exploration of Multi-Aspect Development of Chronic Obstructive Pulmonary Disease… DOI: http://dx.doi.org/10.5772/intechopen.106643*

and further promote oxidative stress. At the same time, the increase of oxidant can initiate the expression of antioxidant and anti-inflammatory genes through activation of nuclear factor E2-related factor (Nrf2). Therefore, antioxidant therapy may be effective in controlling and alleviating the symptoms and disease progression of COPD. Both outdoor environmental smoke and indoor airs are sources of environmental ROS. For example, laser printers can significantly increase indoor air pollution from ozone and volatile organic compounds (VOCs), and appropriate filters may reduce this pollution. In addition, office buildings are carpeted with pesticides, and the use of caustic cleaning products can produce large amounts of inhalable chemicals and particles. Aerosol spray products, air fresheners, chlorine bleaches, cleaners, dry cleaning chemicals, and furniture and floor polishes may release VOCs and other toxic substances. Therefore, it is necessary to install proper ventilation and ventilation devices.

#### **2.3 Imbalance of protease and anti-protease**

Proteolytic enzymes have damaging and destructive effects on tissues, while anti-protease inhibits the activity of elastase. Imbalanced proteolysis is a plausible mechanism to explain the long-term persistence of emphysema. This theory partly explains the development of COPD. Proteolytic enzymes in healthy human lungs are resisted by anti-proteases. When exposed to cigarette smoke, this balance is broken and tends to proteolysis. Cigarette smoke or irritants derived from polluted air recruit inflammatory cells to produce protease 3, cathepsins L and S, MMP-2, MMP-9, and MMP-12, which are secreted primarily by neutrophils and macrophages. The anti-proteolytic barrier is composed of AAT, secretory leukocyte protease inhibitor, and tissue inhibitors of MMPs (TIMPs). Various modified forms of AAT (oxidized, aggregated, cleaved, nitrated, and citrullinated) have been implicated in inflammatory lung tissue destruction, of which proteolysis and ROS attack are major processes. Deficiency of α1-antiprotease causes an imbalance between protease and anti-protease, resulting in emphysema. In addition to proteolytic enzymes and inhibitory substances secreted by host inflammatory cells, bacterial enzymes and inhibitors should also be considered. In lung fibroblasts, elastase released by *Pseudomonas aeruginosa* activates the epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (ERK) signaling pathway to promote IL-8 production by upregulating NF-κB. Besides proteases from neutrophils and macrophages, matrix metalloproteinases (MMPs) secreted by structural cells also play important roles in the pathogenesis of COPD. A number of MMPs members have been found to be involved in the process of COPD. Among them, MMP-1 is usually produced by fibroblasts, and MMP-8 is mainly expressed by neutrophils, both of which have collagenase activity and destroy the normal structure of alveolar septa. MMP-9 is produced by macrophages, neutrophils, and epithelial cells, not only to degrade ECM, but also to activate the immune response through the production of N-acetylproline-glycine-proline chemokines. MMPs can degrade almost all components of the extracellular matrix (ECM). ECM is hydrolyzed into peptide fragments that can promote local inflammation, which play a chemotactic role. For example, after MMP-12 degrades elastin, the peptide fragments have chemotactic effects on monocytes and fibroblasts, promote inflammatory responses, and accelerate lung tissue damage. Proteolytic products of ECM may perpetuate inflammation even after smoking cessation. Therefore, the level of elastin degradation products can be used as a good indicator of lung injury. As in COPD patients with α1 antitrypsin deficiency, a known genetic background (endotype)

with distinct clinical manifestations (phenotype) of emphysema leads to targeted therapeutic intervention (enhancing α1 antitrypsin). Major advances in lung imaging have paved the way to a new concept of COPD diversity. We need a more detailed understanding of the risk factors that contribute to these different endotypes and phenotypes to better describe therapeutic interventions.

## **2.4 Cell senescence and apoptosis**

Cell senescence is an irreversible cell cycle arrest, which is a normal physiological phenomenon. Normal aging and emphysema share common pathophysiological features including the enlargement of alveolar space and the loss of elastic recoil. The accumulation of senescent cells in the body with aging leading to a senescence-associated secretion phenotype (senescence-related secretory phenotype, SASP) induces a pro-inflammatory state, which plays an important role in various age-related diseases. At present, the mechanisms of cell aging involved in COPD include oxidative stress, telomere shortening, mitochondrial dysfunction, activation of mTOR signal transduction, reduction of antiaging molecules, stem cell failure, and DNA damage repair defects. Cell senescence usually results in reduced proliferation with unchanged metabolic activity. This leads to increase inflammation and reduce cell regeneration, a process that is further accelerated by smoking and oxidative stress. Aging affects lung structures and inflammatory cells, fibroblasts, and progenitor cells, resulting in insufficient repair and regeneration. Defective clearance of apoptotic cells in patients with emphysema contributes to the persistence of pulmonary inflammation and increases the risk of acute exacerbation. It is also one of the important reasons leading to the progressive decline of lung function in patients. Autophagy dysregulation is present in cells from COPD patients as well. Insufficient autophagy results in the accumulation of the contents of damaged cells, causing senescence. In the normal lung, autophagy maintains a balance between organelle and protein production, degradation, and recycling. In COPD lung, chronic imbalance in autophagy leads to increased tissue senescence and insufficient repair.

## **2.5 Pathogenesis of COPD acute exacerbation**

The common symptom of AECOPD is transient dyspnea, sputum suppuration, and increased sputum volume. Mild symptoms also occur, such as nasal obstruction, wheezing, sore throat, cough, fever, chest tightness, fatigue, insomnia, or physical activity limitation. In most cases, exacerbation in inflammatory airway is triggered by infection. Respiratory virus (rhinovirus, influenza virus, RSV, parainfluenza virus, human metapneumovirus, coronavirus, and adenovirus) infection is the main cause. Bacterial infection and environmental factors such as air pollution and ambient temperature also trigger or aggravate acute events. Meanwhile, heart failure, pneumothorax, pulmonary embolism, and anxiety cause acute exacerbation. Rhinoviruses account for 60% of exacerbations, which is the most prevalent predisposing factor. At present, it is believed that the antiviral immunity of COPD patients is impaired after respiratory viral infection, but the specific mechanism of aggravation of the disease is not fully understood. Bacteria are also extremely important in the pathogenesis of COPD exacerbations. Common species include the nontypeable *Haemophilus influenzae*, *Moraxella catarrhalis*, *Streptococcus pneumoniae*, and *Pseudomonas aeruginosa*, with *Mycoplasma pneumoniae* and *Chlamydia pneumoniae* occasionally present. The

#### *Exploration of Multi-Aspect Development of Chronic Obstructive Pulmonary Disease… DOI: http://dx.doi.org/10.5772/intechopen.106643*

application of microbiome technology has led to a new understanding of the interaction between the host and millions of microorganisms. 16S ribosomal RNA sequencing reveals that the lungs of healthy people and patients with COPD are colonized by rich, complex bacterial flora. The acute exacerbation is caused by the dysbiosis of preexisting bacteria in the lungs, rather than by the elimination of old species or emergence of new species [3].

AECOPD is also characterized by abnormal airway inflammation. Traditionally, airway eosinophilia and Th2-type inflammation have been associated with allergic airway diseases such as asthma. Recent studies have found that 20–40% of patients with COPD exhibit sputum eosinophilia. The SPIROMICS (SubPopulations and InteRmediate Outcome Measures In COPD Study) cohort has found that sputum eosinophilia in stable state is associated with an increased frequency of COPD exacerbations and deteriorations. In addition, the high level of eosinophil in blood indicates a better therapeutic response to inhaled corticosteroids, which may be used to guide treatment [4]. Although stable sputum and blood eosinophilia are considered as biomarkers of disease outcome and steroid responsiveness, further work is needed to assess the importance of increased Th2 inflammation during COPD exacerbations. In contrast to non-bacterial attacks, bacterial-associated COPD exacerbations result in airway neutrophilia and release of inflammatory mediators including IL-8, leukotriene B4, and TNF-α. Macrophages and T lymphocytes are also involved in the pathogenesis of COPD exacerbation.

These mechanisms mentioned above work together to produce two major pathologies: small airway pressure elevation and emphysema, which cause persistent irreversible airflow limitation. COPD is a chronic disease with high morbidity and mortality, which is a serious threat to human health. Because of its complex etiology and pathogenesis, at present, there are still no effective targeted drugs and treatments. We should further study the cellular and molecular mechanisms in the pathogenesis of COPD in order to detect the disease early and delay disease progression.

### **2.6 Epigenetic changes in the development of COPD**

The imbalanced proteolysis theory is also supported by data from genome-wide association studies (GWAS) and gene expression studies. Recent COPD GWAS studies identified the following genome-wide locus that is strongly associated with the risk and development of COPD, including FAM13a at 4q22, the upstream enhancer of HHIP at 4q31, IREB2 and nicotinic acetylcholine receptors (CHRNA3 and CHRNA5) o at 15q25, the 19q13 locus with RAB4B, EGLN2, and CYP2A6, RIN3 at 14q32, MMP12 at 11q22, and TGFB2 at 1q41 [5–8]. Epigenetic changes includes, but are not limited to, posttranslational modifications of histones, DNA methylation, and RNA modification, which regulate gene expression without altering the gene sequence. Screening of miRNA and mRNA profiles in lung samples from smokers with or without COPD revealed that 70 miRNAs and 2667 mRNA differentially expressed. Several miRNAs, including members of the miR15/107 family, were found to regulate TGF-β signaling in COPD [9]. DNA methylation is an important regulator of gene expression, which is strongly regulated by environmental factors. DNA methylation analysis of small airway epithelia from COPD subjects found 1120 differentially methylated genes, mostly hypermethylated, which showed enrichment for three pathways: G-proteincoupled receptor signaling, arene receptor signaling, and cAMP-mediated signaling. The methylation status of 144 genes was negatively correlated with gene expression,

which involved in phosphatase and tensin homolog (PTEN) signaling, the nuclear factor erythroid-derived 2-related factor 2 (also known as Nrf2) oxidative stress response, and the effect of IL-17F on allergic inflammatory diseases [10]. The emerging role of epigenetics in the development of COPD will make it possible to reprogram, minimize risk, explain causes, and create new treatments for COPD.
