亚大块肝坏死在慢加急性肝衰竭发生中的核心作用及相关发病机制假说

It remains unclear what is the pathogenic mechanism underling acute-on chronic liver failure among cirrhotics.To clarify the central pathological characteristics and pathophysiologic mechanism is the key scientific point when we investigate this entity nowadays.Applicant conducted a prospective cohort study on HBV-related acute-on chronic liver failure from 2008.We enrolled cirrhotic patients who underwent liver transplantation.As a result,entire liver could be used for systematic pathological observation.Via the histological assessment of almost 300 liver tissues,we unearthed that submassive hepatic necrosis is the pivotal pathological feature. The abstract of this research has been accepted for presentation at the forthcoming International Liver Congress 2014 by EASL and the article has been revised back by HEPATOLOGY. On the basis of prophase research,applicant put forward a new hypothesis"PINRO",i.e.,Predisposition(liver cirrhosis)->Injury(precipitating events)->Submassive Necrosis->Deterioration of liver function(First Response)/Deranged systemic inflammatory response(Second Response)-> multiple Organ failure.We need this foundation to perform further verification from three aspects,clinical features(the severity of disease and clinical outcomes) , gene expression(hepatic metabolism and immune response)and animal models studying by comparision of acute-on chronic liver failure patients with submassive hepatic necrosis and classical liver cirrhotics.

肝硬化基础上发生的慢加急性肝衰竭（ACLF）发病机制尚未阐明，明确其关键病理特征及阐明相应病理生理机制是研究的关键科学问题。申请者自2008年开展HBV相关慢加急肝衰竭患者前瞻性队列研究，入组均为可获得整个疾病肝脏的肝硬化移植患者，以对大块肝组织进行系统病理观察。通过近三百例肝脏病理分析，发现亚大块肝坏死（SMHN）是ACLF关键病理特征。研究已被2014年欧洲肝病年会（EASL）录用为会议发言，同时HEPATOLOGY杂志修回中。申请人在上述研究基础上，提出亚大块肝坏死为关键环节的ACLF发病机制 "PINRO"新假说，即肝硬化-> 肝损诱因->亚大块坏死->肝功能衰竭/严重免疫紊乱->多脏器功能衰竭。拟通过本项资助从临床表现及转归、肝脏基因表达谱改变（肝脏合成及免疫应答）以及建立阻断大面积肝脏坏死动物模型三个层面研究诱因打击、亚大块坏死以及肝功能快速恶化/脏器衰竭的相互关系以验证假说。