Impairment of the antifibrotic effect of hepatocyte growth factor in lung fibroblasts from African Americans - Possible role in systemic sclerosis

Medical University of South Carolina, Charleston, South Carolina, United States
Arthritis & Rheumatology (Impact Factor: 7.76). 07/2007; 56(7):2432-42. DOI: 10.1002/art.22713
Source: PubMed


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.

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Available from: Carol A Feghali-Bostwick, Dec 29, 2014
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    • "Some autocrine fibroblast factors counteract fibrosis, such as the hepatocyte growth factor (HGF). HGF is a protein produced by fibroblasts and acts by binding the receptor tyrosine kinase c-Met expressed on nearby epithelial cells, endothelial cells, and fibroblasts (Bogatkevich et al., 2007a,b; Crestani et al., 2012). HGF also plays an important role in wound healing, angiogenesis, and tumorigenesis. "
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    • "Enzyme-Linked Immunosorbent Assay (ELISA) for Hepatocyte Growth Factor (HGF). Levels of HGF were measured in 50 μL samples of cell culture medium using Quantikine human HGF ELISA kit (R & D Systems, Minneapolis, Minn) according to manufacturer's instructions as described previously [16] "
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