Patterns of vasoregulatory gene expression in the liver response to ischemia/reperfusion and endotoxemia

Oxidative stress and inflammatory reactions associated with stresses that m ay lead to shock promote hepatic microcirculatory dysfunction, which may le ad to hepatic injury. Because altered liver microcirculation may result fro m an imbalance in the expression of stress-induced vasoactive mediators, ou r study was conducted to investigate changes in the expression of genes enc oding endothelin-l (ET-1), its receptors, ETA and ETB, heme-oxygenase 1 (HO -1), and inducible nitric oxide synthase (iNOS), using two different rat mo dels of liver stress: ischemia/reperfusion of the liver and lipopolysacchar ide (LPS)-induced endotoxemia. In ischemia/reperfusion experiments, rats we re subjected to 1 h hepatic ischemia, followed by 6 h of reperfusion. Endot oxemia was induced by i.p. injection of LPS (1 mg/mL/kg body weight); rats were studied after 6 h. mRNA levels were estimated using semiquantitative r everse transcriptase-polymerase chain reaction (RT-PCR) on total RNA sample s prepared from experimental and sham control rat livers. In the ischemic r eperfused livers the levels of mRNA for ET-I, ETB, HO-1, and iNOS were sign ificantly elevated, The fold increase versus sham was 2.5 +/- 1.1 (ET-1), 2 .1 +/- 1.3 (ETB), 2.1 +/- .8 (HO-1), and 6.4 +/- 3.9 (iNOS). In contrast, t he expression of ETA receptor gene was reduced after ischemia/reperfusion ( to 73 +/- 1% of sham). In the separate experiments we analyzed the same mRN As levels after 1 h of ischemia (no reperfusion), and did not detect any ch anges, During endotoxemia we observed a marked increase in iNOS mRNA level (>24-fold), as well as a marked elevation of the other four mRNAs. The fold increase versus sham was 6.1 +/- 1.7, ET-1); 1.5 +/- .3 (ETA); 1.6 +/- .4 (ETB); and 2.4 +/- .34 (HO-1). These results show that liver stress, induce d by ischemia/reperfusion or LPS injection have characteristic patterns of vasoregulatory genes expression indicating that, although both stresses res ult in an increase in specific vascular reactivity, different pathways are involved in inducing the hepatic vascular stress response.