Cyclooxygenase-2 deficiency leads to intestinal barrier dysfunction and increased mortality during polymicrobial sepsis.
Cyclooxygenase-2 deficiency leads to intestinal barrier dysfunction and increased mortality during polymicrobial sepsis.
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DOI：
10.4049/jimmunol.1101186
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发表时间：
2011-11-15
期刊：
影响因子：
--
通讯作者：
Perrella MA
中科院分区：
文献类型：
--
作者：
Fredenburgh LE;Velandia MM;Ma J;Olszak T;Cernadas M;Englert JA;Chung SW;Liu X;Begay C;Padera RF;Blumberg RS;Walsh SR;Baron RM;Perrella MA
尽管现代重症监护取得了进步，脓毒症仍然是重症患者死亡的主要原因。肠道屏障功能障碍可能导致继发性细菌移位和脓毒症期间多器官功能障碍综合征的发展。在脓毒症期间，环氧合酶-2 (COX-2) 在肠道中高度上调，我们假设它可能在腹膜炎诱导的多种微生物脓毒症期间维持肠上皮屏障功能至关重要。 COX-2−/− 和 COX-2+/+ BALB/c 小鼠接受盲肠结扎和穿刺 (CLP) 或假手术。 COX-2 嵌合小鼠通过骨髓移植获得并接受 CLP。 C2BBe1 细胞是一种肠上皮细胞系，用 COX-2 抑制剂 NS-398、PGD2 或载体处理，并用细胞因子刺激。与 CLP 后的 COX-2+/+ 小鼠相比，COX-2−/− 小鼠出现严重菌血症并增加死亡率。 COX-2 嵌合小鼠表现出受体表型，表明回肠上皮 COX-2 表达可减轻 CLP 后的菌血症。 CLP 后，COX-2 的缺失显着增加了回肠上皮的通透性，并减少了回肠中紧密连接蛋白 zonula occlusionns-1 (ZO-1)、occludin 和 claudin-1 的表达。此外，PGD2 减弱了 NS-398 处理的 C2BBe1 细胞中细胞因子诱导的通透性过高和 ZO-1 下调。我们的研究结果表明，COX-2 的缺乏与肠上皮通透性增强有关，并导致腹膜炎引起的败血症期间细菌移位过度和死亡率增加。综上所述，我们的结果表明，回肠中 COX-2 的上皮表达是脓毒症期间紧密连接蛋白表达和肠屏障功能的关键调节剂。
Sepsis remains the leading cause of death in critically ill patients despite modern advances in critical care. Intestinal barrier dysfunction may lead to secondary bacterial translocation and the development of the multiple organ dysfunction syndrome during sepsis. Cyclooxygenase-2 (COX-2) is highly upregulated in the intestine during sepsis and we hypothesized that it may be critical in the maintenance of intestinal epithelial barrier function during peritonitis-induced polymicrobial sepsis. COX-2−/− and COX-2+/+ BALB/c mice underwent cecal ligation and puncture (CLP) or sham surgery. Mice chimeric for COX-2 were derived by bone marrow transplantation and underwent CLP. C2BBe1 cells, an intestinal epithelial cell line, were treated with the COX-2 inhibitor NS-398, PGD2, or vehicle and stimulated with cytokines. COX-2−/− mice developed exaggerated bacteremia and increased mortality compared with COX-2+/+ mice following CLP. Mice chimeric for COX-2 exhibited the recipient phenotype suggesting that epithelial COX-2 expression in the ileum attenuates bacteremia following CLP. Absence of COX-2 significantly increased epithelial permeability of the ileum and reduced expression of the tight junction proteins zonula occludens-1 (ZO-1), occludin, and claudin-1 in the ileum following CLP. Furthermore, PGD2 attenuated cytokine-induced hyperpermeability and ZO-1 downregulation in NS-398-treated C2BBe1 cells. Our findings reveal that absence of COX-2 is associated with enhanced intestinal epithelial permeability and leads to exaggerated bacterial translocation and increased mortality during peritonitis-induced sepsis. Taken together, our results suggest that epithelial expression of COX-2 in the ileum is a critical modulator of tight junction protein expression and intestinal barrier function during sepsis.
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