Current concepts on the role of inflammation in COPD and lung cancer

Abstract

Chronic obstructive pulmonary disease (COPD) and lung cancer are leading cause of death, and both are associated with cigarette smoke exposure. It has been shown that 50-70% of patients diagnosed with lung cancer suffer from COPD, and reduced lung function is an important event in lung cancer suggesting an association between COPD and lung cancer. However, a causal relationship between COPD and lung tumorigenesis is not yet fully understood. Recent studies have suggested a central role of chronic inflammation in the pathogenesis of both the diseases. For example, immune dysfunction, abnormal activation of NF-kappaB, epithelial-to-mesenchymal transition, altered adhesion signaling pathways, and extracellular matrix degradation/altered signaling are the key underlying mechanisms in both COPD and lung cancer. These parameters along with other processes, such as chromatin modifications/epigenetic changes, angiogenesis, and autophagy/apoptosis are altered by cigarette smoke, are crucial in the development of COPD and lung cancer. Understanding the cellular and molecular mechanisms underlying these processes will provide novel avenues for halting the chronic inflammation in COPD and devising therapeutic strategies against lung cancer.

Figure 1. Cells and mediators involved in the pathogenesis of COPD and lung cancer

Exposure to cigarette smoke or other pollutants/toxicants induces the release of chemokines from macrophages and epithelial cells which further attract other inflammatory and immune cells including neutrophils, T-cells, and B-cells into the lungs. As a result of influx of these inflammatory cells, proteases, perforin, and granzyme are released leading to alveolar wall destruction and mucus hypersecretion. Furthermore, activated B-cells produce autoantibodies against elastin, epithelium, and endothelium leading to autoimmune impairment in lungs. Epithelial cells and macrophages also release TGF-β leading to small airway remodeling through activation/differentiation of fibroblasts to myofibroblasts. Cigarette smoke is shown to induce the release of VEGF from epithelial cells leading to angiogenesis which plays an important role in progression, invasion, and metastasis of lung cancer. Interestingly, VEGF receptor 2 in endothelial cells is downregulated by cigarette smoke leading to endothelial dysfunction which occurs in emphysema.

Figure 2. Inflammation and its related pathways in COPD and lung cancer

Cigarette smoke is an important risk factor for COPD and lung cancer by inducing inflammation and oxidative stress in the lung. Furthermore, a number of proven and suspected carcinogens contained in cigarette smoke can induce gene mutations/epigenetic changes, ultimately leading to lung tumorigenesis. In addition, cigarette smoked-mediated processes, such as abnormal immunity, angiogenesis, cell proliferation/autophagy/apoptosis, and chromatin modifications, would differentiate and contribute to the development of COPD and lung cancer.