Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
J Immunol. 2011 Nov 15;187(10):5255-67. doi: 10.4049/jimmunol.1101186. Epub 2011 Oct 3.
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 (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, PGD(2), 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, occludin, and claudin-1 in the ileum following CLP. Furthermore, PGD(2) attenuated cytokine-induced hyperpermeability and zonula occludens-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.
脓毒症仍然是危重病患者死亡的主要原因，尽管重症监护领域取得了现代进展。肠道屏障功能障碍可导致继发性细菌易位和多器官功能障碍综合征在脓毒症中发展。环氧化酶（COX）-2在脓毒症期间在肠道中高度上调，我们假设它可能在腹膜炎诱导的多微生物脓毒症期间维持肠道上皮屏障功能中起关键作用。COX-2（-/-）和 COX-2（+/+）BALB/c 小鼠接受盲肠结扎和穿刺（CLP）或假手术。通过骨髓移植产生 COX-2 嵌合小鼠，并进行 CLP。C2BBe1 细胞，一种肠上皮细胞系，用 COX-2 抑制剂 NS-398、PGD（2）或载体处理，并与细胞因子刺激。与 COX-2（+/+）小鼠相比，CLP 后 COX-2（-/-）小鼠发生了更严重的菌血症和更高的死亡率。嵌合 COX-2 的小鼠表现出受者表型，表明回肠上皮 COX-2 的表达可减轻 CLP 后的菌血症。COX-2 的缺失显著增加了回肠的上皮通透性，并降低了 CLP 后回肠中紧密连接蛋白 zonula occludens-1、occludin 和 claudin-1 的表达。此外，PGD（2）可减轻 NS-398 处理的 C2BBe1 细胞中细胞因子诱导的通透性增加和 zonula occludens-1 下调。我们的研究结果表明，COX-2 的缺失与肠上皮通透性增加有关，并导致腹膜炎诱导的脓毒症期间细菌易位增加和死亡率增加。总之，我们的结果表明，回肠上皮细胞中 COX-2 的表达是脓毒症期间紧密连接蛋白表达和肠道屏障功能的关键调节剂。
