title: 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.
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias, Ismael Cosío Villegas, Ciudad de México, México.
authors.forename: Marco
authors.initials: M
authors.lastname: Checa
authors.affiliation: Department of Pediatrics, Division of Respiratory Medicine, University of California San Diego, and Rady Children's Hospital of San Diego, San Diego, California, United States of America.
authors.forename: James S
authors.initials: JS
authors.lastname: Hagood
authors.affiliation: Instituto Nacional de Medicina Genómica, Ciudad de México, México.
authors.forename: Rafael
authors.initials: R
authors.lastname: Velazquez-Cruz
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias, Ismael Cosío Villegas, Ciudad de México, México.
authors.forename: Victor
authors.initials: V
authors.lastname: Ruiz
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias, Ismael Cosío Villegas, Ciudad de México, México.
authors.forename: Carolina
authors.initials: C
authors.lastname: García-De-Alba
authors.affiliation: Instituto Nacional de Medicina Genómica, Ciudad de México, México.
authors.forename: Claudia
authors.initials: C
authors.lastname: Rangel-Escareño
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias, Ismael Cosío Villegas, Ciudad de México, México.
authors.forename: Francisco
authors.initials: F
authors.lastname: Urrea
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias, Ismael Cosío Villegas, Ciudad de México, México.
authors.forename: Carina
authors.initials: C
authors.lastname: Becerril
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias, Ismael Cosío Villegas, Ciudad de México, México.
authors.forename: Martha
authors.initials: M
authors.lastname: Montaño
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias, Ismael Cosío Villegas, Ciudad de México, México.
authors.forename: Semiramis
authors.initials: S
authors.lastname: García-Trejo
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias, Ismael Cosío Villegas, Ciudad de México, México.
authors.forename: José
authors.initials: J
authors.lastname: Cisneros Lira
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias, Ismael Cosío Villegas, Ciudad de México, México.
authors.forename: Arnoldo
authors.initials: A
authors.lastname: Aquino-Gálvez
authors.affiliation: Facultad de Ciencias, Universidad Nacional Autónoma de México, Ciudad de México, México.
authors.forename: Annie
authors.initials: A
authors.lastname: Pardo
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias, Ismael Cosío Villegas, Ciudad de México, México.
authors.forename: Moisés
authors.initials: M
authors.lastname: Selman
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D005786:Gene Expression Regulation; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D017208:Rats, Wistar; D015398:Signal Transduction; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects*; D014026:Nicotiana / Q000009:adverse effects*; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D000951:Antigens, Neoplasm; D016023:Integrins; D012906:Smoke; D016212:Transforming Growth Factor beta; C073878:integrin alphavbeta6