Cigarette Smoke Enhances the Expression of Profibrotic Molecules in Alveolar Epithelial Cells

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disease of unknown etiology. A growing body of evidence indicates that it may result from an aberrant activation of alveolar epithelium, which induces the expansion of the fibroblast population, their differentiation to myofibroblasts and the excessive accumulation of extracellular matrix. The mechanisms that activate the alveolar epithelium are unknown, but several studies indicate that smoking is the main environmental risk factor for the development of IPF. In this study we explored the effect of cigarette smoke on the gene expression profile and signaling pathways in alveolar epithelial cells. Lung epithelial cell line from human (A549), was exposed to cigarette smoke extract (CSE) for 1, 3, and 5 weeks at 1, 5 and 10% and gene expression was evaluated by complete transcriptome microarrays. Signaling networks were analyzed with the Ingenuity Pathway Analysis software. At 5 weeks of exposure, alveolar epithelial cells acquired a fibroblast-like phenotype. At this time, gene expression profile revealed a significant increase of more than 1000 genes and deregulation of canonical signaling pathways such as TGF-β and Wnt. Several profibrotic genes involved in EMT were over-expressed, and incomplete EMT was observed in these cells, and corroborated in mouse (MLE-12) and rat (RLE-6TN) epithelial cells. The secretion of activated TGF-β1 increased in cells exposed to cigarette smoke, which decreased when the integrin alpha v gene was silenced. These findings suggest that the exposure of alveolar epithelial cells to CSE induces the expression and release of a variety of profibrotic genes, and the activation of TGF-β1, which may explain at least partially, the increased risk of developing IPF in smokers.

The Association between Smoking and Epiretinal Membrane

“…Although the pathogenesis of ERM has not yet been fully elucidated, the formation and progression of ERM can be regarded as a fibrotic process because the pathologic findings include increased ECM protein deposition and membrane contraction in which myofibroblasts play a crucial role1. Several studies have demonstrated that exposure to cigarette smoke extracts can provoke activation of the TGF β pathway and the epithelial-mesenchymal transition (EMT)4445, and thereby up-regulate numerous genes involved in fibrosis and the accumulate of ECM28 and these processes are also known to plays a crucial roles in the pathogenesis of ERM. However, the results of epidemiologic studies of the relationship between smoking and risk of ERM have remained inconclusive.…”

“…Additionally, smoking-associated fibrosis has recently been described by several researchers2627. Checa et al 28 demonstrated that cigarette smoke extract induced the expression of a variety of profibrotic genes, and the activation of TGF-β1, resulting in the excessive accumulation of ECM and the activation of myofibroblasts, which also plays a crucial role in the pathogenesis of ERM1. Thus, it is of great interest to examine whether smoking behavior is related to ERM.…”

Plasma membrane wounding and repair in pulmonary diseases

“…Furthermore, introduction of tobacco exposure biomarker rather than solely relying on smoking history provided more definitive proof for the link between smoking exposures and development of ARDS (32). Cigarette smoking causes a collection of pathophysiological changes such as inducing profibrotic gene expression, weakening of the immune system, and stimulating proinflammatory responses (40,46,182). Existing data showed that smoking can increase permeability of alveolar epithelial cells (116) and that of the endothelium (93,224), and such action was largely attributed to ROS production (41).…”

Clinical characteristics and factors associated with mortality in idiopathic pulmonary fibrosis: An experience from a tertiary care center in Pakistan

“…1 It has a global prevalence of 20 cases per 100 000 people for males and 13 cases per 100 000 people for females. 4,7 The heterogeneous clinical course of IPF also has an impact on mortality. The average survival duration after diagnosis is 2-4 years.…”

“…[4][5][6] Smoking is the most consistent environmental risk factor for the development of IPF, and studies suggest a history of smoking worsens the prognosis. 4,7 The heterogeneous clinical course of IPF also has an impact on mortality. Depending on the clinical variant of IPF that a patient presents with, their prognosis can be significantly altered.…”