Hepatocyte growth factor (HGF) prevents the apoptotic and anti-angiogenic effect of hypercholesterolemia on hepatocytes in liver allografts
B. Handan Ozdemir1, Gonca Ozgun1, Aysegul Yucel Polat1, Nihan Haberal1, Gokhan Moray2, Mehmet A. Haberal2.
1Pathology, Baskent University, Ankara, Turkey; 2Transplantation, Baskent University, Ankara, Turkey
Background: Hypercholesterolemia (HC) impairs angiogenesis and induces apoptosis in livers. This hyperlipidemic impairment of angiogenesis reported to associated with reduced bFGF. HGF stimulates proliferation, angiogenesis, and plays a critical role in the regeneration process of the liver. HGF also acted as a metabolic regulator and increases in patients with hyperlipidemia. We evaluate whether HGF has a protective effect on hepatocytes of recipients with HC.
Methods: Biopsies of 68 patients scored for steatosis, fibrosis, and inflammation. Angiogenesis highlighted with CD31 and apoptosis evaluated with the TUNNEL method. Expression of HGF, bFGF, TNF-α, and TGF-β evaluated by immunohistochemistry. Follow-up biopsies analyzed for the development of LF during 18 months after the initial biopsy.
Results: The degree of angiogenesis and bFGF decreases while the degree of apoptosis and macrophage increases with increasing level of cholesterol and triglycerides (p<0.001). Liver TGF-β and TNF-α expression found to increase with increasing serum cholesterol and triglycerides (p<0.01). The development of LF showed a significant correlation with the degree of mean cholesterol level, TGF-β, and TNF-α expression (P<0.001). HGF shows a significant correlation with the degree of angiogenesis and inverse correlation with apoptosis, macrophage infiltration, TGF-β, and TNF-α expression (p<0.001). The development of LF decreases with increasing expression of HGF (p<0.001). Of 30 patients with HC, 15 showed HGF expression (Group1) while remaining did not (Group2). The degree of angiogenesis found higher in Group1 than Group 2 (p<0.001).Group1 showed lower degree of apoptosis, TGF-β, TNF-α, and lower incidence of LF than Group2 (p<0.001). Mean graft survival was 39±6,3, 62±8,2, and 116±7 months for patients with negative, focal, and diffuse HGF expression, respectively (p<0.001).
Conclusion: HGF is critical for organo-protection and liver regeneration under pathophysiological conditions. We suggest that HGF-based drugs show promise as part of a new arsenal in the fight to suppress allograft failure.
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