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Am J Physiol Lung Cell Mol Physiol 297: L864-L870, 2009. First published August 21, 2009; doi:10.1152/ajplung.00128.2009
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Abrogation of TGF-β1-induced fibroblast-myofibroblast differentiation by histone deacetylase inhibition

Weichao Guo,1 Bin Shan,2 Ross C. Klingsberg,2 Xiangmei Qin,2 and Joseph A. Lasky2

1Biomedical Sciences Program, ; 2Section of Pulmonary Diseases, Tulane Medical School, New Orleans, Louisiana

Submitted 16 April 2009 ; accepted in final form 16 August 2009

Idiopathic pulmonary fibrosis (IPF) is a devastating disease with no known effective pharmacological therapy. The fibroblastic foci of IPF contain activated myofibroblasts that are the major synthesizers of type I collagen. Transforming growth factor (TGF)-β1 promotes differentiation of fibroblasts into myofibroblasts in vitro and in vivo. In the current study, we investigated the molecular link between TGF-β1-mediated myofibroblast differentiation and histone deacetylase (HDAC) activity. Treatment of normal human lung fibroblasts (NHLFs) with the pan-HDAC inhibitor trichostatin A (TSA) inhibited TGF-β1-mediated {alpha}-smooth muscle actin ({alpha}-SMA) and {alpha}1 type I collagen mRNA induction. TSA also blocked the TGF-β1-driven contractile response in NHLFs. The inhibition of {alpha}-SMA expression by TSA was associated with reduced phosphorylation of Akt, and a pharmacological inhibitor of Akt blocked TGF-β1-mediated {alpha}-SMA induction in a dose-dependent manner. HDAC4 knockdown was effective in inhibiting TGF-β1-stimulated {alpha}-SMA expression as well as the phosphorylation of Akt. Moreover, the inhibitors of protein phosphatase 2A and 1 (PP2A and PP1) rescued the TGF-β1-mediated {alpha}-SMA induction from the inhibitory effect of TSA. Together, these data demonstrate that the differentiation of NHLFs to myofibroblasts is HDAC4 dependent and requires phosphorylation of Akt.

Akt; protein phosphatase; idiopathic pulmonary fibrosis; myosin light chain 2


Address for reprint requests and other correspondence: J. A. Lasky, 1430 Tulane Ave. SL-9, Tulane Medical School, New Orleans, LA 70112 (e-mail: jlasky{at}tulane.edu).






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