Critical Care Medicine

Adult Critical Care

Cyclooxygenase-2 Deficiency Leads to Intestinal Barrier Dysfunction and Increased Mortality during Polymicrobial Sepsis

Fredenburgh LE, Velandia MMS, Ma J, et al (Brigham and Women’s Hosp, Boston, MA; et al) J Immunol 187:5255-5267, 2011^§

Abstract

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, 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, occludin, and claudin-1 in the ileum following CLP. Furthermore, PGD₂ 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 (Fig 3).

Figure 3 COX-2–deficient mice have increased ileal inflammation following peritonitis-induced polymicrobial sepsis. COX-2^+/+ and COX-2^−/− mice underwent CLP with a 19-g needle (one hole). Ileums were harvested 48 h following CLP. A, Representative H&E staining (a–d), Alcian blue staining (e–h), CD45 immunostaining (i–l), and Ly-6G immunostaining (m–p) in COX-2^+/+ and COX-2^−/− mice following sham surgery (left two panels) and CLP (right two panels). Arrows indicate cells staining positive for CD45 (l) and Ly-6G (p) in COX-2^−/− mice following CLP. B, Histologic scoring of mucosal injury in H&E-stained ileums following sham (COX-2^−/−, n = 4; COX-2^+/+, n = 5) and CLP (COX-2^−/−, n = 7; COX-2^+/+, n = 9) from two independent experiments. *p < 0.05, versus COX-2^−/− sham, **p < 0.05, versus COX-2^+/+ sham, χ² test for trend). C, Quantitation of goblet cell number (three mice/condition) per crypt-villus in COX-2^−/− and COX-2^+/+ mice following sham and CLP. Quantitation of CD45 (D) and Ly-6G (E) immunostaining in ileums of COX-2^−/− and COX-2^+/+ mice (two to five mice/condition) demonstrates that COX-2^−/− mice have significantly increased neutrophilic inflammation in the ileum compared with COX-2^+/+ mice following CLP. *p < 0.05, COX-2^−/− mice after CLP versus COX-2^−/− mice after sham and versus COX-2^+/+ mice after CLP, Mann–Whitney U test. For interpretation of the references to color in this figure legend, the reader is referred to web version of this article. (Reprinted from Fredenburgh LE, Velandia MMS, Ma J, et al. Cyclooxygenase-2 deficiency leads to intestinal barrier dysfunction and increased mortality during polymicrobial sepsis. J Immunol. 2011;187:5255-5267, with permission from The American Association of Immunologists, Inc.)

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