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Editorial Focus

N-acetylcysteine inhibits alveolar epithelial-mesenchymal transition

¹Heart and Lung Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona; ; ²Division of Pulmonary and Critical Care Medicine, Will Rogers Institute Pulmonary Research Center, Keck School of Medicine, University of Southern California, Los Angeles, California; ; ³Department of Pediatrics, University of Arizona College of Medicine, Phoenix, Arizona; and ; ⁴Department of Pediatrics, Creighton University, Omaha, Nebraska

Submitted 13 January 2009 ; accepted in final form 24 July 2009

The ability of transforming growth factor-β1 (TGF-β1) to induce epithelial-mesenchymal transition (EMT) in alveolar epithelial cells (AEC) in vitro and in vivo, together with the demonstration of EMT in biopsies of idiopathic pulmonary fibrosis (IPF) patients, suggests a role for TGF-β1-induced EMT in disease pathogenesis. We investigated the effects of N-acetylcysteine (NAC) on TGF-β1-induced EMT in a rat epithelial cell line (RLE-6TN) and in primary rat alveolar epithelial cells (AEC). RLE-6TN cells exposed to TGF-β1 for 5 days underwent EMT as evidenced by acquisition of a fibroblast-like morphology, downregulation of the epithelial-specific protein zonula occludens-1, and induction of the mesenchymal-specific proteins -smooth muscle actin (-SMA) and vimentin. These changes were inhibited by NAC, which also prevented Smad3 phosphorylation. Similarly, primary alveolar epithelial type II cells exposed to TGF-β1 also underwent EMT that was prevented by NAC. TGF-β1 decreased cellular GSH levels by 50–80%, whereas NAC restored them to 150% of those found in TGF-β1-treated cells. Treatment with glutathione monoethyl ester similarly prevented an increase in mesenchymal marker expression. Consistent with its role as an antioxidant and cellular redox stabilizer, NAC dramatically reduced intracellular reactive oxygen species production in the presence of TGF-β1. Finally, inhibition of intracellular ROS generation during TGF-β1 treatment prevented alveolar EMT, but treatment with H₂O₂ alone did not induce EMT. We conclude that NAC prevents EMT in AEC in vitro, at least in part through replenishment of intracellular GSH stores and limitation of TGF-β1-induced intracellular ROS generation. We speculate that beneficial effects of NAC on pulmonary function in IPF may be mediated by inhibitory effects on alveolar EMT.

alveolar epithelium; lung injury; idiopathic pulmonary fibrosis; transforming growth factor-β; glutathione; reactive oxygen species

This article has been cited by other articles:

				P. J. Wolters Could N-acetylcysteine slow progression of idiopathic pulmonary fibrosis by inhibiting EMT? Am J Physiol Lung Cell Mol Physiol, November 1, 2009; 297(5): L803 - L804. [Full Text] [PDF]