Koch Alexander, Zimmermann Henning W, Gassler Nikolaus, Jochum Christoph, Weiskirchen Ralf, Bruensing Jan, Buendgens Lukas, Dückers Hanna, Bruns Tony, Gerken Guido, Neumann Ulf P, Adams David H, Trautwein Christian, Canbay Ali, Tacke Frank
Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany.
Liver Int. 2014 Oct;34(9):1330-9. doi: 10.1111/liv.12512. Epub 2014 Mar 19.
BACKGROUND & AIMS: Acute liver failure (ALF) is a life-threatening condition with a high mortality rate. The expression of urokinase plasminogen activator receptor (uPAR, CD87) and release of its shedded receptor into serum as soluble uPAR (suPAR) have been closely related to immune activation and prognosis in systemic inflammation and cirrhosis. We now aimed at investigating the clinical relevance and cellular source of uPAR and circulating suPAR in ALF.
Serum suPAR concentrations were measured in 48 ALF patients and 62 healthy controls from a German liver transplantation centre. Hepatic immune cell subsets and uPAR expression were studied by FACS, qPCR and immunohistochemistry.
Circulating suPAR levels were significantly increased in ALF patients, independent from the underlying aetiology, in comparison to controls. Serum suPAR concentrations were closely correlated with parameters reflecting liver cell injury, decreased liver function and the model of end-stage liver disease (MELD) score in ALF patients. By immunohistochemistry from explanted livers, ALF was associated with distinct immune cell accumulation and strong up-regulation of intrahepatic uPAR mRNA expression. CD87 (uPAR) expression was specifically detected on intrahepatic 'non-classical' monocytes (CD14(+) CD16(+) ), NKT and CD56(dim) NK cells isolated from human liver, but not on parenchymal or other non-parenchymal hepatic cell types. Membrane-bound uPAR was rapidly cleaved from monocytes upon inflammatory stimulation by lipopolysaccharide (LPS) and partially by co-cultured lymphocytes.
Similar to its prognostic properties in patients with sepsis or cirrhosis, intrahepatic uPAR activation and serum suPAR concentrations might serve as an interesting biomarker in ALF.
急性肝衰竭（ALF）是一种危及生命的疾病，死亡率很高。尿激酶型纤溶酶原激活物受体（uPAR，CD87）的表达及其脱落受体以可溶性uPAR（suPAR）形式释放到血清中，这与全身炎症和肝硬化中的免疫激活及预后密切相关。我们现在旨在研究ALF中uPAR和循环suPAR的临床相关性及细胞来源。
在一个德国肝移植中心，对48例ALF患者和62例健康对照者测定血清suPAR浓度。通过流式细胞术、定量聚合酶链反应（qPCR）和免疫组织化学研究肝脏免疫细胞亚群和uPAR表达。
与对照组相比，ALF患者循环suPAR水平显著升高，与潜在病因无关。血清suPAR浓度与反映肝细胞损伤、肝功能下降和ALF患者终末期肝病模型（MELD）评分的参数密切相关。通过对移植肝脏进行免疫组织化学检测，发现ALF与明显的免疫细胞聚集和肝内uPAR mRNA表达的强烈上调有关。在从人肝脏分离出的肝内“非经典”单核细胞（CD14(+) CD16(+)）、自然杀伤T细胞（NKT）和CD56(dim)自然杀伤（NK）细胞上特异性检测到CD87（uPAR）表达，但在实质或其他非实质肝细胞类型上未检测到。脂多糖（LPS）炎性刺激后，单核细胞上的膜结合uPAR迅速被切割，共培养的淋巴细胞也能部分切割。
与脓毒症或肝硬化患者的预后特性相似，肝内uPAR激活和血清suPAR浓度可能是ALF中一个有趣的生物标志物。
