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Chloride channel activity in human lung fibroblasts and myofibroblasts

Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee

Submitted 15 September 2004 ; accepted in final form 27 January 2005

It is well established that transforming growth factor (TGF)- stimulates human lung fibroblasts (HLF) to differentiate into myofibroblasts. We characterized lysophosphatidic acid (LPA)-activated Cl^– channel current (I_Cl-LPA) in cultured human lung fibroblasts and myofibroblasts and investigated the influence of I_Cl-LPA on fibroblast-to-myofibroblast differentiation. We recorded I_Cl-LPA using the amphotericin perforated-patch technique. We activated I_Cl-LPA using LPA or sphingosine-1-phosphate. We determined phenotype by Western blotting and immunohistochemistry using an anti--smooth muscle actin (SMA) antibody. RT-PCR was performed to determine which phospholipid growth factor receptors are present in HLF. We found that HLF cultured in TGF- (myofibroblasts) had significantly elevated -SMA levels and I_Cl-LPA current density compared with control fibroblasts. I_Cl-LPA activation was blocked by DIDS, 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), and the LPA receptor-specific antagonist dioctyl-glycerol pyrophosphate (1 µM). DIDS and NPPB, in a dose-dependent manner, significantly reduced -SMA levels in HLF stimulated with TGF-. These results demonstrate the receptor-mediated activation of I_Cl-LPA by LPA and sphingosine-1-phosphate in cultured human lung myofibroblasts, with only minimal I_Cl-LPA activity in fibroblasts. This Cl^– channel activity appears to play a critical role in the differentiation of human lung fibroblasts to myofibroblasts.

lysophosphatidic acid; sphingosine-1-phosphate; transforming growth factor-; -smooth muscle actin

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