**3. Forms of inflammation or damage**

**Neutrophilic inflammation** can be induced by cigarette smoke, fine dust, bacteria, and viruses, resulting in the release of neutrophilic mediators, including IL-8, which signal through its receptor on neutrophils. Macrophages are activated as well, and attract Th17 cells to release IL-17, which stimulates the release of IL-6 and IL-8 from epithelial cells. Neutrophils are maintained in the airway by TNF-α and GM-CSF (granulocyte-macrophage colony-stimulating factor) and release neutrophil elastase. Neutrophils also generate oxidative stress, which further activates inflammation and induces corticosteroid resistance. The neutrophilic inflammation in COPD is unresponsive to corticosteroids, even in high doses. Other therapies directed toward neutrophilic inflammation, including antibodies against TNF-α, have been largely clinically ineffective as well. A CXCR2 (chemokine receptor-2) antagonist, which blocks the chemotactic effect of IL-8 and related chemokines, is at least able to reduce the neutrophils in the sputum of COPD patients but has no clinical benefit on lung function, symptoms, or exacerbations. Neutrophil elastase is a major proteinase in primary granules in neutrophils that participates in the microbicidal activity. It induces airway remodeling with increased mucin secretion and impaired ciliary motility, it interrupts epithelial repair by promoting cellular apoptosis, and it activates inflammation by increasing cytokine expression [1, 4–8, 14].

**Eosinophilic inflammation** is well-known in patients with bronchial asthma. Some people have clinical features from both diseases, bronchial asthma and COPD. In case of such overlap, airway epithelial cells can release the upstream cytokines TSLP and IL-33 in response to cigarette smoke and virus infection, which recruit Th2 and type 2 innate lymphoid cells, which secrete IL-5, resulting in eosinophilic inflammation. Eosinophils may be attracted into the lungs by CCL5 (chemokine (C-C motif) ligand) and maintained in the lungs by IL-5 and GM-CSF. Patients with so-called eosinophilic COPD may have a better response to corticosteroid therapy and more reversibility to bronchodilators, and these patients show an increase in sputum eosinophils and an increased FeNO, which are characteristic features of asthma [1, 5–7, 14].

#### *COPD and Inflammation DOI: http://dx.doi.org/10.5772/intechopen.107863*

**Protease-antiprotease imbalance** means that inhaled pollutants, such as cigarette smoke and fine dust, activate immune cells like macrophages and T-helper cells, which release inflammatory messengers. These signals cause neutrophilic granulocytes to migrate into the bronchial mucosa. Together with the macrophages, they release cell-damaging proteases. And at the same time, protective antiprotease is disabled. According to current knowledge, this imbalance of proteases and antiproteases favors the formation of pulmonary emphysema. Various proteases produced by inflammatory cells and epithelial cells are elevated in many people with COPD [3, 19].

**Oxidant-antioxidant imbalance** leads to inflammatory reactions due to oxidative stress. As a result, pulmonary cells are damaged, and inflammation is further promoted. This accelerates the development of COPD or emphysema. Oxidative stress also increases mucus production, the formation of proteases, and the migration of neutrophilic granulocytes into the bronchial mucosa. An oxidant-antioxidant imbalance also occurs in other lung diseases, such as pulmonary fibrosis or bronchial asthma [3, 5, 15, 19].

**Apoptosis** is critical for the maintenance of normal tissue homeostasis and is in equilibrium with proliferation and differentiation. There is increasing evidence that disturbance of the balance between apoptosis and proliferation in lung tissue contributes to the pathogenesis of COPD. Several experimental studies in animal models of COPD provide more insight into the association between cigarette smoking, apoptosis, and the development of emphysema. Epithelial cells in the small airways express TGF-β, which then induces local fibrosis. VEGF (vascular endothelial growth factor) appears to be necessary to maintain alveolar cell integrity, and blockade of VEGF receptors in rats induces apoptosis of alveolar cells and an emphysema-like pathology [19].
