Cyclooxygenase-2 Deficiency Leads to Intestinal Barrier Dysfunction and Increased Mortality During Polymicrobial Sepsis 1

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...

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Veröffentlicht in:The Journal of immunology (1950) 2011-10, Vol.187 (10), p.5255-5267
Hauptverfasser: Fredenburgh, Laura E., Velandia, Margarita M. Suarez, Ma, Jun, Olszak, Torsten, Cernadas, Manuela, Englert, Joshua A., Chung, Su Wol, Liu, Xiaoli, Begay, Cynthia, Padera, Robert F., Blumberg, Richard S., Walsh, Stephen R., Baron, Rebecca M., Perrella, Mark A.
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container_end_page 5267
container_issue 10
container_start_page 5255
container_title The Journal of immunology (1950)
container_volume 187
creator Fredenburgh, Laura E.
Velandia, Margarita M. Suarez
Ma, Jun
Olszak, Torsten
Cernadas, Manuela
Englert, Joshua A.
Chung, Su Wol
Liu, Xiaoli
Begay, Cynthia
Padera, Robert F.
Blumberg, Richard S.
Walsh, Stephen R.
Baron, Rebecca M.
Perrella, Mark A.
description 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, 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 (ZO-1), occludin, and claudin-1 in the ileum following CLP. Furthermore, PGD 2 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.
doi_str_mv 10.4049/jimmunol.1101186
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Suarez ; Ma, Jun ; Olszak, Torsten ; Cernadas, Manuela ; Englert, Joshua A. ; Chung, Su Wol ; Liu, Xiaoli ; Begay, Cynthia ; Padera, Robert F. ; Blumberg, Richard S. ; Walsh, Stephen R. ; Baron, Rebecca M. ; Perrella, Mark A.</creator><creatorcontrib>Fredenburgh, Laura E. ; Velandia, Margarita M. Suarez ; Ma, Jun ; Olszak, Torsten ; Cernadas, Manuela ; Englert, Joshua A. ; Chung, Su Wol ; Liu, Xiaoli ; Begay, Cynthia ; Padera, Robert F. ; Blumberg, Richard S. ; Walsh, Stephen R. ; Baron, Rebecca M. ; Perrella, Mark A.</creatorcontrib><description>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, 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 (ZO-1), occludin, and claudin-1 in the ileum following CLP. Furthermore, PGD 2 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. 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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, 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. 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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, 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. 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title Cyclooxygenase-2 Deficiency Leads to Intestinal Barrier Dysfunction and Increased Mortality During Polymicrobial Sepsis 1
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