Downregulation of hepatic cytochrome p-450 isoforms and PPAR-γ:: Their role in hepatic injury and proinflammatory responses in a double-hit model of hemorrhage and sepsis
Downregulation of hepatic cytochrome p-450 isoforms and PPAR-γ:: Their role in hepatic injury and proinflammatory responses in a double-hit model of hemorrhage and sepsis
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DOI：
10.1016/j.jss.2006.04.019
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发表时间：
2007-01-01
影响因子：
2.2
通讯作者：
Wang, Ping
中科院分区：
文献类型：
--
作者：
Higuchi, Shinya;Wu, Rongqian;Wang, Ping
背景出血和脓毒症的“双重打击”模型模拟了进入外科重症监护室的危重M患者。尽管细胞色素（CYP）P-450亚型CYP 1A 2的蛋白表达在脓毒症晚期降低，但出血对CYP亚型和抗炎核受体过氧化物酶体增殖物激活受体-γ（PPAR-gamma）的影响尚未研究。我们假设出血下调了肝脏中的β-淀粉样蛋白亚型和PPAR-gamma，这在随后的脓毒症后产生组织损伤和促炎反应中起重要作用（即，材料和方法。将雄性Sprague道利大鼠分为四组。双重打击组动物出血（40 +/- 2 mm Hg，持续90分钟），然后进行液体复苏。出血后20 h通过盲肠结扎穿孔（CLP）诱导多菌性脓毒症，CLP后4 h处死动物。单纯损伤组于损伤后20 h处死。CLP单独组大鼠在脓毒症发作后4 h处死。假手术组动物既不出血也不CLP。P-450同种型的基因表达（即，使用RT-PCR测定肝脏中的CYP 1A 2和2C 11）和PPAR-gamma。丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、乳酸盐和促炎细胞因子（即，IL-6、TNF-α）。与假手术组相比，在初始应激后20 h，单独给予黄芪组大鼠肝脏CYP 1A 2、CYP 2C 11和PPAR-gamma的mRNA表达显著下调。双重打击似乎没有进一步降低β-淀粉样蛋白和PPAR-gamma基因表达。相比之下，AST、ALT、乳酸、IL-6和TNF-α的血清水平在感染或脓毒症动物中均未显著变化。而在出血和脓毒症双重打击后，上述器官损伤指标和细胞因子水平明显升高。肝脏CYP 1A 2、CYP 2C 11和PPAR-gamma在初始应激（出血）后下调。这些下调的CYP和PPAR-gamma似乎是导致二次应激（CLP）后器官损伤和促炎反应进展的重要因素。(c)2007爱思唯尔公司All rights reserved.
Background. The "double-hit" model of hemorrhage and sepsis mimics the critically M patient admitted to the surgical intensive care unit. Although the protein expression of a cytochrome (CYP) P-450 isoform CYP1A2 is reduced in the late stage of sepsis, the effect of hemorrhage on CYP isoforms and the anti-inflammatory nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has not been investigated. We hypothesized that hemorrhage down-regulates CYP isoforms and PPAR-gamma in the liver, which plays an important role in producing tissue injury and proinflammatory responses after the subsequent sepsis (i.e., double-hit).Materials and methods. Male Sprague Dawley rats were divided into four groups. Animals in the double-hit group underwent hemorrhage (40 +/- 2 mm Hg for 90 min) followed by fluid resuscitation. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) 20 h after hemorrhage, and the animals were sacrificed 4 h after CLP. Rats in the hemorrhage-alone group were sacrificed 20 h after the insult. Rats in the CLP-alone group were sacrificed 4 h after the onset of sepsis. Animals in the sham-operated group underwent neither hemorrhage nor CLP. The gene expression of P-450 isoforms (i.e., CYP1A2 and 2C11) and PPAR-gamma in the liver was determined using RT-PCR. Serum concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate, and proinflammatory cytokines (i.e., IL-6, TNF-alpha) were also assessed.Results. In the hemorrhage-alone group, hepatic mRNA expression of CYP1A2, CYP2C11, and PPAR-gamma was significantly down-regulated 20 h after the initial stress compared with sham-operated rats. Double-hit did not appear to further decrease CYP and PPAR-gamma gene expression. In contrast, serum levels of AST, ALT, lactate, IL-6, and TNF-a did not change significantly in either hemorrhaged or septic animals. Those organ injury indicators and cytokines, however, were significantly elevated after the double-hit of hemorrhage and sepsis.Conclusions. Hepatic CYP1A2, CYP2C11, and PPAR-gamma were down-regulated after the initial stress (hemorrhage). These down-regulated CYPs and PPAR-gamma seem to work as important factors contributing to the progression of organ injury and proinflammatory responses after the second stress (CLP). (c) 2007 Elsevier Inc. All rights reserved.