Antifibrotic effect of hepatocyte growth factor is impaired in lung fibroblasts isolated from African‐Americans

Pulmonary fibrosis is the leading cause of mortality in systemic sclerosis (scleroderma, SSc) with significantly higher mortality rates in African‐American scleroderma patients. Using cytokine antibody array we found that antifibrotic glycoprotein hepatocyte growth factor (HGF) is reduced in bronchoalveolar lavage fluid (BALF) from African‐American SSc patients compared to Caucasian SSc patients. Decreased levels of HGF in BALF correlated with decreased amounts of HGF in plasma and were further confirmed by ELISA. Conditioned medium from lung fibroblasts isolated from African‐American SSc patients contained less HGF than medium from lung fibroblasts isolated from Caucasian SSc patients. Recombinant HGF readily abolished connective tissue growth factor (CTGF) expression and collagen accumulation in normal lung fibroblasts stimulated with TGFβ and in SSc lung fibroblasts isolated from Caucasians. Pretreatment of lung fibroblasts with neutralizing antic‐Met antibody diminished the effects of HGF on CTGF expression and collagen accumulation suggesting that the antifibrotic activity of HGF in lung fibroblasts is mediated via c‐Met receptor tyrosine kinase. However, recombinant HGF failed to prevent CTGF expression and collagen accumulation in lung fibroblasts isolated from African‐Americans. The data suggest that in African‐American scleroderma patients in addition to the reduced level of HGF, deficiency in c‐Met receptor expression and/or function may be observed. These findings may explain in part the greater severity and worse prognosis for African‐American scleroderma patients. Support by Scleroderma Foundation, NIH K01 AR051052 and P60 AR049459.