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This Article Full Text Full Text (PDF) All Versions of this Article: 293/1/L212    most recent 00475.2006v1 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 ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Vyas-Read, S. Articles by Willis, B. C. Search for Related Content PubMed PubMed Citation Articles by Vyas-Read, S. Articles by Willis, B. C.

Nitric oxide attenuates epithelial-mesenchymal transition in alveolar epithelial cells

¹Division of Neonatal-Perinatal Medicine, ²Division of Pulmonary and Vascular Biology, and ³Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas

Submitted 8 December 2006 ; accepted in final form 8 May 2007

Patients with interstitial lung diseases, such as idiopathic pulmonary fibrosis (IPF) and bronchopulmonary dysplasia (BPD), suffer from lung fibrosis secondary to myofibroblast-mediated excessive ECM deposition and destruction of lung architecture. Transforming growth factor (TGF)-1 induces epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AEC) to myofibroblasts both in vitro and in vivo. Inhaled nitric oxide (NO) attenuates ECM accumulation, enhances lung growth, and decreases alveolar myofibroblast number in experimental models. We therefore hypothesized that NO attenuates TGF-1-induced EMT in cultured AEC. Studies of the capacity for endogenous NO production in AEC revealed that endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) are expressed and active in AEC. Total NOS activity was 1.3 pmol·mg protein^–1·min^–1 with 67% derived from eNOS. TGF-1 (50 pM) suppressed eNOS expression by more than 60% and activity by 83% but did not affect iNOS expression or activity. Inhibition of endogenous NOS with L-NAME led to spontaneous EMT, manifested by increased -smooth muscle actin (-SMA) expression and a fibroblast-like morphology. Provision of exogenous NO to TGF-1-treated AEC decreased stress fiber-associated -SMA expression and decreased collagen I expression by 80%. NO-treated AEC also retained an epithelial morphology and expressed increased lamellar protein, E-cadherin, and pro-surfactant protein B compared with those treated with TGF- alone. These findings indicate that NO serves a critical role in preserving an epithelial phenotype and in attenuating EMT in AEC. NO-mediated regulation of AEC fate may have important implications in the pathophysiology and treatment of diseases such as IPF and BPD.

alveolar epithelium; lung injury; nitric oxide synthases; pulmonary fibrosis; transforming growth factor-