Pathophysiological Aspects in COPD

Several pathogenic processes are thought to be involved in COPD development and progression, including local and systemic oxidative stress (i.e., oxidants in excess compared with antioxidant capacity) and inflammation (neutrophils, macrophages, eosinophils, cytokines, chemokines, eicosanoids, Toll-like receptors, acute phase proteins), Pro catabolic status, protease/antiprotease imbalance, alteration of immune responses and cell proliferation, apoptosis, and cellular senescence, and remodeling of the small-airway compartment and loss of elastic recoil by emphysematous destruction of parenchyma [2]. Oxidative stress may directly cause lung damage through modification of DNA, lipids or proteins, as well as initiate cellular responses that can drive the inflammatory response within the lung, leading to lung tissue degradation (emphysema). Molecular switches triggering inflammatory responses in COPD involve the activation of redox-sensitive transcription factors (e.g., nuclear factor (NF)-κB), induction of autophagy, and unfolded protein response [24]. In particular, NF-κB plays a crucial role in the chronic inflammatory responses found in COPD, regulating the expression of genes for pro-inflammatory mediators (e.g., IL-1, IL-6, IL-8, MCP-1, TNF-α) and chemotactic factors (e.g., IL-17A and MIP-1a) involved in triggering lung infiltration by inflammatory cells, thus amplifying oxidative stress and inflammation, as well as causing emphysema, fibrosis of small airways and remodeling of airway walls, ultimately impairing lung function. Indeed, the number of NF-κB-positive epithelial cells and macrophages increased in smokers and COPD patients and correlated with the degree of airflow limitation [25].
Although primarily affecting the lungs, COPD is associated with extra-pulmonary (systemic) manifestations such as weight loss, malnutrition, and skeletal muscle dysfunction, which contribute to the morbidity, reduced quality of life, and, possibly, mortality of this disease. Furthermore, other chronic diseases (also called co-morbidities), including CVD and especially coronary artery disease (CAD), osteoporosis, metabolic syndrome, depression, and lung cancer, among others, are highly prevalent in patients with COPD, can be considered part of the Non pulmonary sequelae of the disease, with the low-grade systemic inflammation playing a decisive role in their pathogenesis, and importantly contribute to worsening health status and vital prognosis of COPD patients. In particular, CV-related co-morbidities are the leading cause of morbidity and mortality in patients with COPD, sharing various risk factors and pathophysiological aspects (inflammation-associated oxidative stress) [26]. Reduced lung function is a marker for all-cause, respiratory- and CV-related mortality [27], thus representing a clinically relevant therapeutic target for preventing the development of COPD and its life-threatening complications.

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