Abstract
Cigarette smoke (CS) is the primary cause of Chronic Obstructive Pulmonary Disease (COPD), and an important pathophysiologic event in COPD is CS-induced apoptosis in lung endothelial cells (EC). Cortactin (CTTN) is a cytoskeletal actin-binding regulatory protein with modulation by Src-mediated tyrosine phosphorylation. Based upon data demonstrating reduced CTTN mRNA levels in the lungs of smokers compared to non-smokers, we hypothesized a functional role for CTTN in CS-induced mitochondrial ROS generation and apoptosis in lung EC. Exposure of cultured human lung EC to CS condensate (CSC) led to the rearrangement of the actin cytoskeleton and increased CTTN tyrosine phosphorylation (within hours). Exposure to CS significantly increased EC mitochondrial ROS generation and EC apoptosis. The functional role of CTTN in these CSC-induced EC responses was explored using cortactin siRNA to reduce its expression, and by using a blocking peptide for the CTTN SH3 domain, which is critical to cytoskeletal interactions. CTTN siRNA or blockade of its SH3 domain resulted in significantly increased EC mitochondrial ROS and apoptosis and augmented CSC-induced effects. Exposure of lung EC to e-cigarette condensate demonstrated similar results, with CTTN siRNA or SH3 domain blocking peptide increasing lung EC apoptosis. These data demonstrate a novel role for CTTN in modulating lung EC apoptosis induced by CS or e-cigarettes potentially providing new insights into COPD pathogenesis.
Highlights
Cigarette smoking (CS), a leading cause of morbidity and mortality in the US, is the most significant factor for the development of Chronic Obstructive Pulmonary Disease (COPD) [1,2]
Regarding the pathogenesis of CS-induced COPD, it is known that continuous exposure to nicotine and other CS-toxic substances leads to the development of chronic bronchitis and emphysema characterized by an enhanced inflammatory response, increased macrophage and neutrophil infiltration, protease-antiprotease imbalance, remodeling of the airways, and loss of elastic properties of the parenchyma [3]
Adding to this prior literature, the major findings of our current study are the following: i) Gene expression of CTTN is reduced in human lung tissues from smokers compared to nonsmokers; ii) CS condensate (CSC) caused actin cytoskeleton rearrangement in cultured human lung endothelial cell (EC); iii) CSC and e-cigarette extract in
Summary
Cigarette smoking (CS), a leading cause of morbidity and mortality in the US, is the most significant factor for the development of Chronic Obstructive Pulmonary Disease (COPD) [1,2]. Regarding the pathogenesis of CS-induced COPD, it is known that continuous exposure to nicotine and other CS-toxic substances leads to the development of chronic bronchitis and emphysema characterized by an enhanced inflammatory response, increased macrophage and neutrophil infiltration, protease-antiprotease imbalance, remodeling of the airways, and loss of elastic properties of the parenchyma [3]. There is no effective treatment available to improve or reverse smoking-related lung damage, and additional studies to elucidate CS-induced cellular mechanisms are needed. CS directly causes lung endothelial cell (EC) activation and inflammation leading to enhanced EC apoptosis and increased barrier permeability [4,5,6]. The signaling pathways underlying CS-induced lung EC dysfunction remain poorly understood
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