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Abstract: Extracellular ATP is a signaling molecule that often serves as a danger signal to alert the immune system of tissue damage. This molecule activates P2 nucleotide receptors, that include the ionotropic P2X receptors and metabotropic P2Y receptors. Recently, it has been reported that ATP accumulates in the airways of both asthmatic patients and sensitized mice after allergen challenge. The role and function of ATP in the pathogenesis of chronic obstructive pulmonary diseases (COPD) are not well understood. In this study we investigated the effect of cigarette smoke on purinergic receptors and ATP release by neutrophils. Neutrophils and their mediators are key players in the pathogenesis of lung emphysema. Here we demonstrated that in an in vivo model of cigarette smoke-induced lung emphysema, the amount of ATP was increased in the bronchoalveolar lavage fluid. Moreover, activation of neutrophils with cigarette smoke extract induced ATP release. Treatment of neutrophils with apyrase (catalyses the hydrolysis of ATP to yield AMP) and suramin (P2-receptor antagonist) abrogated the release of CXCL8 and elastase induced by cigarette smoke extract and exogenous ATP. These observations indicate that activation of purinergic signaling by cigarette smoke may take part in the pathogenesis of lung emphysema. [Copyright &y& Elsevier]

Abstract: Chronic Obstructive Pulmonary Disease (COPD) is an important lung and airway disease which affects the lives of around 200 million people worldwide. 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, and dendritic cells (DC). The potential role of DCs as mediators of inflammation in the airways of smokers and COPD patients is poorly understood. The current study investigated the role of DC subsets in an animal model of cigarette smoke-induced lung emphysema through the expansion or depletion of DC subsets. Expansion of both myeloid DC (mDC) and plasmacytoid DC (pDC) by Flt3L treatment induced a decline in macrophage numbers and increased the levels of fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) in the bronchoalveolar lavage (BAL) fluid of smoke-exposed animals. The increase in the mean linear intercept (Lm) following Flt3L treatment was decreased by pDC depletion. In conclusion, pharmacological modulation of DC subsets may have an effect on the development of airway responses and emphysema as indicated by the decline in macrophage numbers and the increase in FGF and VEGF levels in the bronchoalveolar lavage fluid. Moreover, the depletion of pDCs decreased the Lm which might suggest a role for pDC in the pathogenesis of lung emphysema. [Copyright &y& Elsevier]