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This Article Full Text Full Text (PDF) All Versions of this Article: 297/1/L115    most recent 90587.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Nasreen, N. Articles by Antony, V. B. PubMed PubMed Citation Articles by Nasreen, N. Articles by Antony, V. B.

Pleural mesothelial cell transformation into myofibroblasts and haptotactic migration in response to TGF-β1 in vitro

¹Division of Pulmonary and Critical Care Medicine, Department of Medicine, College of Medicine, University of Florida and ²Malcolm Randall Department of Veterans Affairs Medical Center, Gainesville, Florida

Submitted 25 November 2008 ; accepted in final form 25 April 2009

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology characterized by the development of subpleural foci of myofibroblasts that contribute to the exuberant fibrosis noted in the pulmonary parenchyma. Pleural mesothelial cells (PMC) are metabolically dynamic cells that cover the lung and chest wall as a monolayer and are in intimate proximity to the underlying lung parenchyma. The precise role of PMC in the pathogenesis of pulmonary parenchymal fibrosis remains to be identified. Transforming growth factor (TGF)-β1, a cytokine known for its capacity to induce proliferative and transformative changes in lung cells, is found in significantly higher quantities in the lungs of patients with IPF. High levels of TGF-β1 in the subpleural milieu may play a key role in the transition of normal PMC to myofibroblasts. Here we demonstrate that PMC activated by TGF-β1 undergo epithelial-mesenchymal transition (EMT) and respond with haptotactic migration to a gradient of TGF-β1 and that the transition of PMC to myofibroblasts is dependent on smad-2 signaling. The EMT of PMC was marked by upregulation of -smooth muscle actin (-SMA), fibroblast specific protein-1 (FSP-1), and collagen type I expression. Cytokeratin-8 and E-cadherin expression decreased whereas vimentin remained unchanged over time in transforming PMC. Knockdown of smad-2 gene by silencing small interfering RNA significantly suppressed the transition of PMC to myofibroblasts and significantly inhibited the PMC haptotaxis. We conclude that PMC undergo EMT when exposed to TGF-β1, involving smad-2 signaling, and PMC may be a possible source of myofibroblasts in IPF.

smad-2; fibroblast-specific protein-1; -smooth muscle actin; transforming growth factor-β1; epithelial-mesenchymal transition