Abstract
Chronic Obstructive Pulmonary Disease (COPD) is an important lung and airway disease which affects the lives of around 200 million people worldwide and is predicted to be the third most frequent cause of death in the world by 2030. Cigarette smoking (CS) is accepted as the main risk factor for
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development of COPD. Unfortunately, the limited knowledge on disease mechanism hampers an effective treatment of this disease. Thus, understanding of the pathway and mechanism leading to the inflammatory process by CS may lead to better therapeutic approaches in COPD. The pathological hallmark of COPD is emphysema and bronchiolitis and is based on the inflammatory response of the innate and adaptive immune system to the inhalation of toxic particles and gases. The inflamed airways of COPD patients contain several inflammatory cells including neutrophils, macrophages, T lymphocytes, mast cells (MCs) and dendritic cells (DCs). In contrast to other inflammatory cells, not much research has been performed on the role of DC subsets and MCs in COPD. Thus, we aimed to investigate the putative role of DC subsets and MCs in the pathogenesis of COPD by using in vitro and in vivo models. Special attention was given to effects of CS on signaling and activity of these cells in the inflammatory process. We found that modulation of DC subsets in acute and chronic models of smoke-exposed mice alters the CS-induced lung inflammation and function. Our findings suggest that different DC subsets are involved attraction and activation of inflammatory cells in COPD. CS directly or indirectly induces inflammation and tissue damage by triggering activation and differentiation of DCs. Furthermore, CS extract (in vitro) stimulates maturation of newly differentiated and immature DCs, while it induces defective and silent DCs from BM precursors. Although caution should be taken to translate these findings into humans and clinical settings, it is tempting to speculate that these effects could contribute to the vulnerability of COPD patients to viruses and bacteria. In addition, we show that homing of mast cells was changed in smoking animal. Besides, mast cells may be a source of TGF-β production after CS exposure, which could modulate the expression of tryptase in mast cells. Tryptase could -in turn- play a role in recruitment of neutrophils. Moreover, we found that CS extract (in vitro) suppressed the expression of c-kit and FcεRI of developing mast cells. This suppressive effect may account for the reduced allergic response seen in animal models of CS induced emphysema. In conclusion, this thesis suggests that both functional activities of DCs and mast cells can be affected by CS exposure. Different cellular subsets may be differentially influenced by CS components, which could also be related to their developmental status and cellular localization and the time of exposure. Ultimately results in altered innate and adaptive immune response. Pharmacological intervention of activation of DC subsets and mast cells might open new routes of interference in the pathogenesis of COPD.
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