Dominguez Marlene, Miquel Rosa, Colmenero Jordi, Moreno Montserrat, García-Pagán Joan-Carles, Bosch Jaime, Arroyo Vicente, Ginès Pere, Caballería Juan, Bataller Ramón
Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, CIBER de Enfermedades Hepáticas y Digestivas, Barcelona, Catalonia, Spain.
Gastroenterology. 2009 May;136(5):1639-50. doi: 10.1053/j.gastro.2009.01.056. Epub 2009 Jan 31.
BACKGROUND & AIMS: Alcoholic hepatitis (AH) is characterized by hepatocellular damage, inflammation, and fibrosis. We performed a prospective study to associate hepatic expression of the CXC subfamily of chemokines with histology findings and prognosis of patients with AH.
Liver biopsy samples from 105 patients with AH and 5 normal liver samples (controls) were evaluated for steatosis, inflammation, fibrosis, and cholestasis. Computer-based morphometric analysis assessed the numbers of infiltrating CD3+ T cells and CD15+ cells (neutrophils); terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining was used to quantify apoptosis. Expression of CXC and CC chemokines and selected signaling components were assessed by quantitative reverse-transcription polymerase chain reaction; protein levels of interleukin (IL)-8 and Gro-alpha also were determined by immunohistochemistry. Serum levels of IL-8 and Gro-alpha were measured by enzyme-linked immunosorbent assay. The Cox regression model identified variables associated with mortality.
Most patients (75%) had severe AH; their 90-day mortality rate was 21.9%. In AH liver samples, expression of the CXC subfamily members IL-8, Gro-alpha, CXCL5, CXCL6, CXCL10, and platelet factor 4 was up-regulated and compared with controls. The CC chemokine CCL2, but not CCL5, also was up-regulated. Higher expression levels of IL-8, CXCL5, Gro-gamma, and CXCL6 were associated with worse prognosis. Expression of CXC components correlated with neutrophil infiltration and the severity of portal hypertension. In the multivariate analysis, IL-8 protein levels were an independent predictor of 90-day mortality. IL-8 and Gro-alpha serum levels did not correlate with prognosis.
Hepatic expression of CXC components correlates with prognosis of patients with AH. Reagents that target CXC chemokines might be developed as therapeutics.
酒精性肝炎（AH）的特征为肝细胞损伤、炎症和纤维化。我们进行了一项前瞻性研究，以探讨趋化因子CXC亚家族的肝脏表达与AH患者的组织学表现及预后之间的关系。
对105例AH患者的肝活检样本和5例正常肝脏样本（对照）进行脂肪变性、炎症、纤维化和胆汁淤积评估。基于计算机的形态计量分析评估浸润的CD3 + T细胞和CD15 +细胞（中性粒细胞）数量；采用末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记染色法对细胞凋亡进行定量分析。通过定量逆转录聚合酶链反应评估CXC和CC趋化因子及选定信号成分的表达；白细胞介素（IL）-8和Gro-α的蛋白水平也通过免疫组织化学法测定。采用酶联免疫吸附测定法测量血清IL-8和Gro-α水平。Cox回归模型确定与死亡率相关的变量。
大多数患者（75%）患有严重AH；其90天死亡率为21.9%。在AH肝脏样本中，CXC亚家族成员IL-8、Gro-α、CXCL5、CXCL6、CXCL10和血小板因子4的表达上调，并与对照进行比较。CC趋化因子CCL2（而非CCL5）也上调。IL-8、CXCL5、Gro-γ和CXCL6的较高表达水平与较差的预后相关。CXC成分的表达与中性粒细胞浸润及门静脉高压的严重程度相关。在多变量分析中，IL-8蛋白水平是90天死亡率的独立预测指标。IL-8和Gro-α血清水平与预后无关。
CXC成分的肝脏表达与AH患者的预后相关。靶向CXC趋化因子的试剂可能会被开发为治疗药物。
