Current concepts on the role of inflammation in COPD and lung cancer
Introduction
Both chronic obstructive pulmonary disease (COPD) and lung cancer are associated with cigarette smoking and/or various environmental pollutants exposure. They represent the fourth-leading and second-leading causes of death in USA and worldwide, respectively. COPD is shown to increase the risk for developing lung cancer [1]. Hence, there are shared mechanisms (e.g. chronic inflammation) in both COPD and lung cancer, or in the progression of COPD which increase the susceptibility for lung tumorigenesis up to 4.5-fold (Figure 1). This review focuses on current knowledge of specific processes/molecules that drive chronic inflammation which are important in the pathogenesis of both COPD and lung cancer, and identify the potential therapeutic targets for these chronic diseases (Figure 2).
Section snippets
Chronic inflammation in COPD and lung cancer
Cigarette smoke contains more than 1014 oxidants/free radicals and 4700 reactive chemical compounds including aldehydes, quinones, semiquinones, nitrosamines, benzo(a)pyrene, and other carcinogens, and it is a risk factor in the development of COPD/emphysema and lung cancer by inducing chronic inflammation. Macrophages, neutrophils, and lymphocytes, the main orchestrators and amplifiers in the progression of COPD, are thought to fight against cancers by eradicating dysplastic and neoplastic
NF-κB pathway in COPD and lung cancer
It is well known that canonical and noncanonical NF-κB pathways play crucial role in the pathogenesis/development of COPD by increasing the release of proinflammatory mediators leading to chronic inflammation in the lung. Indeed, NF-κB-regulated genes including cytokines, adhesion molecules, angiogenic factors, antiapoptotic factors, and matrix metalloproteinases (MMPs) that all have shown to be associated with tumor progression and metastasis. Furthermore, NF-κB in lung epithelium functions as
Adaptive immune response and immunosculpting in COPD and lung cancer
Chronic inflammation of COPD is characterized by the accumulation of neutrophils, macrophages, B cells, CD4+-T, CD8+-T cells, dendritic cells, and eosinophils, particularly in the smaller airways, and the severity of COPD is associated with the infiltration of these inflammatory immune cells. The role of inflammatory cells in COPD has focused on oxidants, proteinases, perforin, and granzymes released from these cells leading to alveolar wall destruction and mucus hypersecretion. Recently, it
Adhesion molecules: integrins and TGF-β pathways in COPD and lung cancer
Integrins are heterodimeric transmembrane receptors, and are involved in a variety of cellular functions as well as in lung inflammation. Integrin αvβ6 is one of the integrins which is located in epithelial cells, and its expression is increased during lung inflammation or injury. Interestingly, integrin αvβ6 plays an important role in maintaining normal lung homeostasis and preventing lung destruction since ablation of integrin αvβ6 leads to airspace enlargement in mice by regulating
Hypoxia/angiogenesis in COPD and lung cancer
Hypoxia is shown to induce pulmonary inflammation by inducing the activation of transcription factor and triggering the expression of proinflammatory genes. In COPD, progressive airflow limitation and destruction of the alveolar capillary may lead to decreased oxygen transport and alveolar hypoxia. In this context, hypoxia-inducible factor (HIF) is activated leading to the enhancement of VEGF transcription and increased angiogenesis. Interestingly, the levels of VEGF and its receptors are
MMPs in COPD and lung cancer
Emphysema is a consequence of an imbalance between antiproteinases and proteinases (balance shifted toward proteinases) including elastase and MMPs from activated inflammatory cells and epithelial cells in lungs. Lungs structural cell death occurs when they lose the attachment because of ECM degradation by MMPs as well as by defective tissue repair. Furthermore, ECM fragments have chemotactic activity to attract inflammatory cells into the lung which aggravates the progression of emphysema in
Cell cycle regulator in COPD and lung cancer
Cigarette smoke is a potent genotoxic stimulus of DNA damage through oxidant stress/carcinogens, thereby arrests cell cycle. It has been shown that the expression of p21CIP1/WAF1/SDI1 (p21), a cyclin-dependent kinase (CDK) inhibitor, is increased in alveolar epithelial cells exposed to cigarette smoke extract, and in alveolar macrophages and biopsies isolated from smokers [28, 29]. Furthermore, the antiapoptotic protein Bcl-XL is increased in alveolar macrophages from smokers suggesting that
Autophagy/apoptosis in COPD and lung cancer
Autophagy is a dynamic process responsible for the turnover of cellular organelles and proteins, which are essential for maintaining cell homeostasis and conferring adaption to adverse environmental stimuli. However, excessive autophagy will lead to cell death. Recently, it has been shown that autophagy regulated the inflammatory immune response via controlling inflammasome activation [35]. Interestingly, increased autophagy and apoptosis of epithelial/endothelial cells are shown to occur in
Chromatin remodeling/epigenetics in COPD and lung cancer
Chromatin remodeling includes post-translational modifications of core histone proteins and DNA methylation which is shown to regulate proinflammatory gene expression during the development of COPD and lung carcinogenesis. Increased histone acetylation is observed on the promoters of proinflammatory genes in airway epithelial cells and alveolar macrophages in patients with COPD, and the degree of acetylation is positively correlated with disease severity [42•]. The mechanism that underlies
SIRT1 in COPD and lung cancer
SIRT1, a class III HDAC, is shown to regulate inflammation, senescence, autophagy/apoptosis, and aging by deacetylating histones/nonhistone proteins including transcription factors, coactivators, and other signaling molecules, such as NF-κB, FOXO, HIF-2α, and p53. Anti-inflammatory property of SIRT1 is associated with decreased NF-κB transcriptional activity by deacetylating RelA/p65 at lys310 residue [48]. Given that a significant reduction of SIRT1 in rodent lungs exposed to cigarette smoke
Conclusions and future directions
Both COPD and lung cancer are tobacco smoking-associated chronic diseases that cluster in families and aggravate with age, and 50–70% of patients diagnosed with lung cancer have declined spirometric evidence of COPD. Furthermore, reduced lung function (FEV1) is the important event for lung cancer indicating an association between COPD and lung cancer. Nevertheless, a causal relationship between COPD and lung tumorigenesis is not yet known. It is generally accepted that chronic inflammation
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This study was supported by the NIH R01-HL085613 and NIEHS Environmental Health Sciences Center grant ES01247. We apologize for not citing many original articles due to lack of space.
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