Effect Of Angiotensin System On LPS/D-Gal-Induced Acute Liver Failure And Its Mechanisms

Objective:Lipopolysaccharide(LPS)is an Endotoxin which exists as a major glycolipid component of the outer membrane of gram-negative bacteria and other microorganisms.It is considered as a potent inducer of the innate immune system that often causes septic shock and endoxemia.It typically consists of three parts:a hydrophobic domain known as lipid A(or endotoxin),a distal polysaccharide(or O-antigen)and a nonrepeating �core�(oligosaccharide).Meanwhile,LPS is a crucial immune booster that can trigger excessive inflammatory responses and may lead to immunopathology.Liver is a vital detoxification organ which exerts removal of endotoxin function.It accepts endotoxins via portal blood from the intestine.When liver function is normal,endotoxins are engulfed by liver macrophages and do not flood into the peripheral blood stream.While liver failure,there is often a increased overflow of endotoxin with decreased endotoxin clearance resulting in systemic endotoxemia.on the other hand,liver is the target organ most vulnerable to LPS.Endotoxemia and liver failure often coexist and interact with each other,thus form a vicious circle leading to serious consequences.How to break some chains of the circle should be deserving our deeply probe into.Lipopolysaccharide(LPS)and D-galactosamine(D-Gal)-induced acute liver injure has been recognized as a ideal model resembling clinical acute liver failure.This model is simulated the pathological processes of the internal and external endotoxemia occurred in FHF appropriately and provides the first evidence for clinical studies.The present study aims to verify the potential role of Angiotensin system in LPS/D-Gal induced ALF and seek for new therapeutic targets of ALF further.Methods:1.Establish the model of acute liver failure induced by LPS/D-Gal to evaluate the potential pharmacological properties of captopril/ losartan/diminazene(DIZE)or vehicle were administered 0.5 h prior to LPS/D-Gal challenge.2.The mice in different groups were sacrificed at 1.5 h after LPS/D-Gal challenge.The liver and The blood samples were harvested for measuring the levels of TNF-?,IL-6 both in liver and in serum.The activity of NF-?B p65 and the phosphorylated JNK,p38 MAPK were tested by western blot.3.The mice in different groups were sacrificed at 6 h after LPS/D-Gal challenge.The blood and liver samples were harvested for determining the levels of serum aminotransferases(ALT and AST),the following contents including hepatic Ang? ? myeloperoxidase(MPO),nitrogen monoxide(NO),malondialdehyde(MDA)and superoxide dismutase(SOD),the activities of caspase-3,-8,-9 and the protein level of cleaved caspase-3 were tested.In addition,the liver tissues were stained with hematoxylin-eosin(HE)routinely for morphological evaluation and hepatic apoptosis was determining by TUNEL analysis.Results:The results indicated that treatment with captopril/DIZE significantly alleviated LPS/D-Gal-induced acute liver failure supported by following data While there are no similar positive effects of losartan:1.Captopril/DIZE dramatically reduced the serum levels of alanine aminotransferase(ALT)and aspartate aminotransferase(AST),alleviated the histopathological damage of the liver tissue and enhanced the survival rate of LPS/D-Gal-challenged mice.2.Captopril/DIZE decreased the levels of Ang?,TNF-?,IL-6,MPO obviously and increased the level of NO.3.Captopril/DIZE relieved the tissue damage caused by oxidative stress by increasing the activity of SOD and decreasing the productin of MDA.4.Captopril/DIZE inhibited the activities of caspase-3,-8,-9,downregulated the protein level of cleaved caspase-3 and reduced the number of TUNEL-positive cells in liver sections from LPS/D-Gal-exposed mice.5.Captopril/DIZE suppressed the phosphorylation of JNK,p38 MAPK and the activity of NF-?B p65 prominently.Conclusion:These results suggested that ACEI and ACE2 agonist might have potential value in acute live failure,while ARB might have little such effect.