Lysophosphatidic acid-activated Cl^- current activity in human systemic sclerosis skin fibroblasts

Objectives: SSc (scleroderma) is an often fatal disease characterized by widespread tissue fibrosis. Fibroblasts play a key role in SSc-associated fibrosis. This study was designed to determine: (i) whether fibroblasts isolated from skin of patients with SSc have increased lysophosphatidic acid-activated Cl^- current (ICl_LPA) activity vs healthy controls; (ii) whether myofibroblast differentiation is involved in SSc skin fibrosis; and (iii) whether SSc fibroblasts have different proliferation rates vs controls. Methods: Skin biopsies were taken from involved and uninvolved skin of SSc patients and controls. Whole-cell perforated patch-clamping was used to measure ICl_LPA activity in fibroblasts isolated and cultured from these biopsies. Western blotting was used to measure α-smooth muscle actin (α-SMA). Proliferation was measured using a colorimetric assay. Results: Fibroblasts cultured from SSc skin show significantly increased ICl_LPA activity following LPA exposure compared with control skin fibroblasts. α-SMA protein was significantly increased in cultured SSc skin fibroblasts vs controls. No significant differences in proliferation rates were found. Conclusions: Elevated ICl_LPA activity is a hallmark of SSc skin fibroblasts. Blocking ICl_LPA activation may be a new therapeutic approach for treating SSc-associated fibrosis.