Impairment of the antifibrotic effect of hepatocyte growth factor in lung fibroblasts from African Americans: possible role in systemic sclerosis.

Abstract

To compare the composition of cytokines in African American and Caucasian patients with systemic sclerosis (SSc; scleroderma) and in healthy individuals, particularly the expression and function of hepatocyte growth factor (HGF). Bronchoalveolar lavage (BAL) fluid samples were analyzed using cytokine array techniques. HGF in plasma and cell culture medium samples was measured by enzyme-linked immunosorbent assay. Connective tissue growth factor (CTGF), type I collagen expression, and c-Met receptor phosphorylation were studied by immunoblotting. Overall greater expression of cytokines in BAL fluid from African American patients as compared with Caucasian patients was observed. Significant increases in HGF concentrations were detected in BAL fluid, plasma, and fibroblast culture medium from Caucasian SSc patients. In contrast, African American SSc patients did not demonstrate an increase in HGF. Recombinant HGF readily abolished CTGF expression and collagen accumulation in lung fibroblasts isolated from Caucasian SSc patients. Pretreatment of lung fibroblasts with neutralizing anti-c-Met antibody abolished the effects of HGF on CTGF expression and collagen accumulation, suggesting that the antifibrotic activity of HGF is mediated via c-Met receptor tyrosine kinase. Whereas recombinant HGF rapidly induced c-Met receptor phosphorylation in lung fibroblasts from Caucasian patients, c-Met receptor phosphorylation was significantly reduced in lung fibroblasts from African American subjects. Moreover, recombinant HGF failed to prevent CTGF expression and collagen accumulation in lung fibroblasts derived from African American subjects. Ethnic differences exist in terms of antifibrotic HGF expression in lung fibroblasts derived from Caucasian and African American subjects. Reduced levels of HGF as well as a deficiency in c-Met receptor function appear to be present in African American patients with SSc. These findings may explain in part the greater disease severity and worse prognosis observed in African Americans with SSc.