Messaris Evangelos, Kekis Panagiotis, Memos Nicolaos, Chatzigianni Emmy, Menenakos Evangelos, Leandros Emanuel, Konstadoulakis Manousos M
Laboratory of Surgical Research, First Department of Propaedeutic Surgery, Athens Medical School, Hippokration Hospital, 11527 Vas, Sofias Ave 114, Athens, Greece.
World J Surg. 2007 Apr;31(4):787-94. doi: 10.1007/s00268-005-0742-1.
BACKGROUND: Intestinal epithelial cell apoptosis has been reported in sepsis as a mechanism of organ failure. The aim of this study was to clarify the role of apoptosis-regulating proteins (bcl-2, bax, cytochrome-c, and caspase-8) in septic rats by studying their expression in gastric and intestinal epithelial cells. METHODS: Adult Wistar rats were subjected to the cecal ligation and puncture (CLP) model of sepsis and randomly divided into two study groups. Sixty-two animals were sacrificed 6, 12, 24, 36, 48, and 60 h post-procedure, and 50 animals served as the survival study group. Sham-operated animals (n = 40) were used as controls. Gastric and intestinal tissue was excised, and immunohistochemical detection of bcl-2, bax, cytochrome-c, and caspase-8 protein expression was performed. RESULTS: In gastric mucosa, sepsis induced upregulation of bax and downregulation of caspase-8 expression (p = 0.053 and p = 0.05, respectively). Both bax and caspase-8 were upregulated as early as 6 h post CLP and progressively decreased (p = 0.001, p = 0.004 respectively). In contrast, the expression of the anti-apoptotic bcl-2 was upregulated progressively during the sepsis syndrome (p = 0.03). In intestine, sepsis induced a fourfold upregulation of the cytoprotective bcl-2 (p = 0.0001), accompanied by a remarkable increase in bax (p = 0.002) and caspase-8 (p = 0.0001) expression and a decrease in cytochrome-c expression (p = 0.02). The time distribution of the apoptosis regulators followed the same pattern as in gastric tissue, showing an upregulation of the proapoptotic bax and cytochrome c (p = 0.04) during the early phases and a progressively increased expression of bcl-2 during the late phases (p = 0.0001). Bax expression in gastric epithelium of subjects with septic syndrome was detrimental to survival (p = 0.0001), whereas the expression of the cytoprotective bcl-2 in intestinal epithelium appeared to favor a good prognosis (p = 0.0001). CONCLUSIONS: Sepsis results in alterations of apoptosis regulators in gastrointestinal cells. Alterations of bax and bcl-2 expression in gastric and intestinal epithelial cells may predict the outcome in septic rats.
背景：脓毒症时肠上皮细胞凋亡被报道是器官衰竭的一种机制。本研究旨在通过研究凋亡调节蛋白（bcl-2、bax、细胞色素c和半胱天冬酶-8）在胃和肠上皮细胞中的表达，阐明其在脓毒症大鼠中的作用。 方法：成年Wistar大鼠采用盲肠结扎穿孔（CLP）脓毒症模型，并随机分为两个研究组。术后6、12、24、36、48和60小时处死62只动物，50只动物作为生存研究组。假手术动物（n = 40）作为对照。切除胃和肠组织，进行bcl-2、bax、细胞色素c和半胱天冬酶-8蛋白表达的免疫组化检测。 结果：在胃黏膜中，脓毒症诱导bax上调和半胱天冬酶-8表达下调（分别为p = 0.053和p = 0.05）。CLP术后6小时bax和半胱天冬酶-8均上调，并逐渐下降（分别为p = 0.001，p = 0.004）。相反，抗凋亡蛋白bcl-2的表达在脓毒症综合征期间逐渐上调（p = 0.03）。在肠道中，脓毒症诱导细胞保护蛋白bcl-2上调四倍（p = 0.0001），同时bax（p = 0.002）和半胱天冬酶-8（p = 0.0001）表达显著增加，细胞色素c表达下降（p = 0.02）。凋亡调节因子的时间分布与胃组织相同，早期促凋亡蛋白bax和细胞色素c上调（p = 0.04），晚期bcl-2表达逐渐增加（p = 0.0001）。脓毒症综合征患者胃上皮中bax的表达对生存有害（p = 0.0001），而肠上皮中细胞保护蛋白bcl-2的表达似乎有利于良好预后（p = 0.0001）。 结论：脓毒症导致胃肠道细胞凋亡调节因子发生改变。胃和肠上皮细胞中bax和bcl-2表达的改变可能预测脓毒症大鼠的预后。
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