Wnt agonist attenuates liver injury and improves survival after hepatic ischemia/reperfusion.

摘要: The Wnt/β-catenin signaling pathway is well characterized in stem cell biology and plays a critical role liver development, regeneration, homeostasis. We hypothesized that pharmacologic activation of Wnt protects against hepatic ischemia/reperfusion (I/R) injury through its known proliferative antiapoptotic properties. Sprague-Dawley rats underwent 70% ischemia by microvascular clamping the hilum left median lobes for 90 min, followed reperfusion. agonist (2-amino-4-[3,4-(methylenedioxy)benzylamino]-6-(3-methoxyphenyl)pyrimidine, 5 mg/kg body weight) or vehicle (20% dimethyl sulfoxide saline) 0.5 mL was injected i.p. 1 h before infused i.v. over 30 min right after ischemia. Blood tissue samples from pretreated groups were collected 24 reperfusion, survival study performed. Hepatic expression β-catenin downstream target gene Axin2 decreased I/R, whereas restored their to sham levels. blunted I/R-induced elevations aspartate aminotransferase, alanine lactate dehydrogenase significantly improved microarchitecture liver. proliferation determined Ki67 immunostaining increased with treatment, inflammatory cascades dampened agonist-treated animals, as demonstrated attenuations interleukin 6, myeloperoxidase, inducible nitric oxide synthase, nitrotyrosine. also amount apoptosis, evidenced decreases both TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) staining caspase 3 activity Finally, 10-day rate 27% group 73% 55% postischemia treatment group. Thus, we propose direct stimulation may represent novel therapeutic approach I/R.