Airway Pathology in COPD
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Airway Pathology in COPD

Chronic obstructive pulmonary disease (COPD), a disease manifested by significantly impaired airflow, afflicts ~14.2 million cases in the United States alone with an estimated 63 million people world-wide. Although there are a number of causes, the predominant cause is excessive tobacco smoke. Other less frequent causes are associated with indirect cigarette smoke, air pollutants, biomass fuels, and genetic mutations. COPD is often associated with heart disease, lung cancer, osteoporosis and conditions can worsen in patients with sudden falls. COPD also affects both innate and adaptive immune processes. Cigarette smoke increases the expression of matrix metalloproteases and proinflammatory chemokines and increases lung titers of natural killer cells and neutrophils (Ref.1). COPD is a widespread chronic lung disorder which includes (a) chronic obstructive bronchitis with fibrosis and obstruction of small airways and (b)emphysema with enlargement of airspaces and destruction of lung parenchyma, loss of lung elasticity, and closure of small airways. The causes of COPD are not fully understood but the most important cause of chronic bronchitis and emphysema is cigarette smoking. Air pollution and occupational exposures may also play a role, especially when combined with cigarette smoking. Heredity also causes some emphysema cases, due to AAT (Alpha1-anti-trypsin) deficiency (Ref.3).

In bronchial biopsies, small airways, and lung parenchyma from patients with COPD, there are an infiltration of T cells (predominantly Th1 and type 1 cytotoxic T [Tc1] cells) and increased numbers of neutrophils and macrophages. Fibrosis around small airways is thought to be a major mechanism contributing to irreversible airway narrowing in individuals with COPD. The lungs are an important route of exposure to environmental pathogens and antigens. Specific and nonspecific defence mechanisms are involved in clearing these foreign substances from the lungs. In COPD, chronic inflammation leads to fixed narrowing of small airways and alveolar wall destruction (emphysema) in the lungs. This is characterized by increased numbers of alveolar macrophages, neutrophils, and cytotoxic T lymphocytes, and the release of multiple inflammatory mediators (lipids, chemokines, cytokines, growth factors). There is also a high level of oxidative stress, which may amplify this inflammation. Alveolar macrophages, neutrophils, and cytotoxic T lymphocytes accumulate in the lungs of smokers, leading to inflammation and the release of cellular products, such as enzymes that break down collagen and elastin in the lung and/or stimulate mucus production, resulting in emphysema and/or chronic bronchitis. Cigarette smoking increases the number of alveolar macrophages by several folds, and these cells express increased levels of lysosomal enzymes and secrete elastase (Ref.4). These enzymes might damage connective tissue and parenchymal cells of the lung, which contribute to the pathogenesis of COPD (for example, chronic bronchitis and emphysema). IL-8 is released from active monocytes and plays a primary role in the activation of both neutrophils and eosinophils in the airways of COPD patients and serves as a marker in evaluating the severity of airway inflammation (Ref.3). In addition, alveolar macrophages from smokers produce significantly higher levels of oxygen radicals and have higher myeloperoxidase activity; these are important mediators of the killing of intracellular pathogens. IFN-gamma is the predominant cytokines produced by Th1 and Tc1 cells and may play an important role in inflammation in individuals with COPD by inducing the release of chemokines. IFN-gamma activates T-bet via STAT1, resulting in expression of genes encoding Th1 cytokines and suppression of genes encoding Th2 cytokines. IFN-gammaalso orchestrates the infiltration of Th1 and Tc1 cells in the lungs of individuals with COPD through the upregulation of the chemokine receptor CXCR3 on these cells and the release of the CXCR3-activating chemokines CCL9 (also known as Mig), CCL10 (also known as IP-10), and CCL11 (also known as I-TAC).Consistent with this, there is an increase in the number of T cells secreting IFN-gamma in the airways of patients with COPD. IL-12 and IL-18 appear to have a synergistic effect on the induction of IFN-gamma release and the inhibition of IL-4–dependent IgE production and AHR. In individuals with COPD, IL-18 expression is increased in alveolar macrophages and CD8+ T cells in the airways and is correlated with disease severity (Ref.5).

Proinflammatory cytokines, such as TNF-Alpha, IL-1beta, and IL-6, are found in increased amounts in the sputum and BAL fluid in individuals with COPD and amplify inflammation, in part through the activation of NF-KappaB, which leads to the increased expression of multiple inflammatory genes. GM-CSF plays a role in the differentiation and survival of neutrophils, eosinophils, and macrophages and has been implicated in COPD. Its receptor comprises an Alpha-chain that is specific for the receptor for GM-CSF and a Beta-chain that is also part of the receptors for IL-3 and IL-5. TGF-beta is a family of pleiotropic cytokines that may play several roles in COPD. TGF-beta is a multifunctional growth factor that induces the proliferation of fibroblasts and airway smooth muscle cells, deposition of ECM, and epithelial repair. In COPD there is increased expression of TGF-beta by airway epithelial cells from small airways and macrophages. In the airways of individuals with COPD, there is increased expression of EGFR, EGF,and the related cytokine heregulin in airway epithelial cells (Ref.5).

COPD is an enormous cause of global morbidity and mortality that is becoming an even greater health problem with the growing use of cigarettes around the world. Pulmonary hypertension is a common complication of COPD. The increase in pulmonary artery pressures is often mild to moderate, but some patients may suffer from severe pulmonary hypertension, and present with a progressively downhill clinical course because of right-sided heart failure added to ventilatory handicap. The cause of pulmonary hypertension in COPD is generally assumed to be hypoxic pulmonary vasoconstriction leading to permanent medial hypertrophy. In addition to its adverse effects in cardiovascular disease, lung cancer and COPD, cigarette smoke suppresses the immune system. Female smokers have a greater propensity for miscarriages, low-birth weight babies, adverse menstrual symptoms, osteoporosis and transmission of HIV-1 from mother to child (Ref.6). COPD is more common in individuals of lower socio-economic status and has a poorer prognosis when associated with low body-mass index and with bronchial hyper-reactivity. There is also evidence that previous viral infections predispose smokers to COPD, and an increasing awareness that diet and factors involved during in utero and adolescent lung development may be important for the subsequent predisposition to obstructive lung disease. These other environmental factors are likely to be much less important than cigarette smoking, but they may interact with smoking to increase the risk of COPD (Ref.7). There are diverse medical and surgical treatments employed to alleviate and manage the symptoms of COPD. Some treatments include pulmonary rehabilitation, the use of supplemental oxygen, surgical removal of large air spaces in the lungs (bullectomy) and lung volume reduction surgery, lung transplantation and inhaled corticosteroids. Some of the more recent developments include HFCWO (High-Frequency Chest Wall Oscillation) therapy and the combining of spirometry and pulse oximetry.