Inhibition of Fas signaling prevents hepatic injury and improves organ blood flow during sepsis
Inhibition of Fas signaling prevents hepatic injury and improves organ blood flow during sepsis
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DOI：
10.1067/msy.2001.116540
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发表时间：
2001-08-01
期刊：
影响因子：
3.8
通讯作者：
Ayala, A
中科院分区：
文献类型：
--
作者：
Chung, CS;Yang, S;Ayala, A
背景Fas/Fas配体（FasL）系统是细胞凋亡的主要途径之一，在肝脏、胃肠道等多种疾病的发生、发展中起重要作用。研究表明，FasL缺陷在遭受多微生物脓毒症的小鼠中提供存活优势。然而，Fas/FasL在脓毒症中对器官损伤的作用程度尚不清楚。因此，本研究的目的是确定在脓毒症期间体内施用Fas信号传导抑制剂是否保留器官连接。对雄性成年C3 H/HeN小鼠进行盲肠结扎和穿孔（CLP）或假CLP（sham）。CLP后12小时，小鼠接受Fas受体融合蛋白（FasFP）（200 μ g/kg体重）或盐水载体。脓毒症发作后24小时，用放射性微球测量心输出量和器官血流量。评估血浆丙氨酸氨基转移酶、天冬氨酸氨基转移酶和乳酸脱氢酶水平作为窝仔损伤指标。通过酶联免疫吸附试验测定全身细胞因子的变化。数据表明，尽管在CLP后24小时，肝、肠、肾、脾和心脏中的心输出量和器官血流量显著降低，但用FasFP治疗维持了测量的血液动力学参数，并改善了肝、肠和心脏血流量（P <0.05），并部分恢复了脾和肾血流量。此外，FasFP治疗显著减弱了丙氨酸氨基转移酶、天冬氨酸氨基转移酶、乳酸脱氢酶和白细胞介素10的全身性升高（P <0.05）。这些结果不仅表明Fas/FasL介导的过程在诱导器官损伤中起作用，而且表明抑制Fas/FasL通路可能代表一种新的治疗方式，用于维持器官灌注和预防脓毒症期间的肝损伤。
Background. Fas/Fas ligand (FasL) system is one of the major pathways triggering apoptosis that has been shown to play an important role in development and pathogenesis of various diseases including liver and gastrointestinal diseases. Studies indicate that FasL deficiency provides a survival advantage in mice subjected to polymicrobial sepsis. However, the extent to which Fas/FasL contributes to organ injury during sepsis is unclear. Thus, the aim of this study was to determine whether in vivo administration of a Fas-signaling inhibitor during sepsis preserves organ Junction.Methods. Male adult C3H/HeN mice were subjected to cecal ligation and puncture (CLP) or sham CLP (sham). Twelve hours after CLP, mice received either Fas-receptor fusion protein (FasFP) (200 mug/kg body weight) or the saline vehicle. Twenty-four hours after the onset of sepsis, cardiac output and organ blood flow were measured with radioactive microspheres. Plasma levels of alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase were assessed as indexes of litter damage. Changes in systemic cytokines were measured by enzyme-linked immunosorbent assay.Results. The data indicate that although cardiac output and organ blood flow in the liver, intestine, kidneys, spleen, and heart decreased markedly at 24 hours after CLP, treatment with FasFP maintained the measured hemodynamic parameters and improved hepatic, intestinal, and heart bloodflow (P < .05) and partially restored spleen and renal bloodflow. Moreover, FasFP treatment markedly attenuated the systemic rise in alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and interleukin 10 (P < .05).Conclusions. These results not only indicate that there is a role for Fas/FasL-mediated processes in the induction of organ injury but suggest that inhibition of Fas/FasL pathway may represent a novel therapeutic modality for maintaining organ perfusion and preventing liver injury during sepsis.