Effect of hemorrhagic shock on gut barrier function and expression of stress-related genes in normal and gnotobiotic mice

Abstract

We sought to determine whether gut-derived microbial factors influence the hepatic or intestinal inflammatory response to hemorrhagic shock and resuscitation (HS/R). Conventional and gnotobiotic mice contaminated with a defined microbiota without gram-negative bacteria were subjected to either a sham procedure or HS/R. Tissue samples were obtained 4 h later for assessing ileal mucosal permeability to FITC dextran and hepatic and ileal mucosal steady-state IL-6, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, and TNF mRNA levels. Whereas HS/R significantly increased ileal mucosal permeability in conventional mice, this effect was not apparent in gnotobiotic animals. HS/R markedly increased hepatic mRNA levels for several proinflammatory genes in both conventional and gnotobiotic mice. HS/R increased ileal mucosal IL-6 and COX-2 mRNA expression in conventional but not gnotobiotic mice. If gnotobiotic mice were contaminated with Escherichia coli C25, HS/R increased ileal mucosal permeability and upregulated expression of IL-6 and COX-2. These data support the view that the hepatic inflammatory response to HS/R is largely independent of the presence of potentially pathogenic gram-negative bacteria colonizing the gut, whereas the local mucosal response to HS/R is profoundly influenced by the microbial ecology within the lumen during and shortly after the period of hemorrhage.

Systemic inflammation and remote organ injury following trauma require HMGB1

“…However, our own studies using germ-free mice demonstrated that the presence or absence of intestinal flora does not impact the level of systemic inflammation in the setting of femur fracture (Levy RM, Prince JM, Mollen KP, Kaczorowski DJ, Liu S, Fink MP, Vodovotz Y, Billiar TR, unpublished results). These data are consistent with earlier results using gnotobiotic mice in the setting of hemorrhagic shock (47).…”

HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury

“…In this context, our findings suggest that the diminished intestinal TNF-␣, IL-1␤, and iNOS responses as well as the reduced pulmonary IL-1␤ response in partially deficient HIF-1␣ mice after T/HS may be linked to the attenuation of villous and lung injury. Support for this concept stems from earlier studies linking gut-derived factors such as IL-1␤, TNF-␣, and iNOS as well as enteric bacteria to intestinal barrier dysfunction and the development of both sepsisand T/HS-mediated distant organ injury (14,70). Additionally, HIF-1 activation has been implicated in the proinflammatory response of myeloid cells during sepsis and deletion of HIF-1␣ in myeloid cells afforded protection against LPS-induced mortality (53).…”

Anti-HMGB1 Neutralizing Antibody Ameliorates Gut Barrier Dysfunction and Improves Survival after Hemorrhagic Shock

“…In previous studies, we have shown that HS/R in mice leads to ileal mucosal hyperpermeability and increases bacterial translocation to MLN as early as 4 h after resuscitation (7,8,11). Prompted by the data presented here indicating that treatment with anti-HMGB1 antibody ameliorated gut barrier dysfunction assessed at 24 h after resuscitation, we sought to determine whether this therapy would also ameliorate gut barrier dysfunction at the 4-h time point.…”

“…Intestinal barrier dysfunction, manifested by increased mucosal permeability to hydrophilic macromolecules and/or increased bacterial translocation to mesenteric lymph nodes (MLN), occurs following hemorrhagic shock and resuscitation (HS/R) in rodents (6)(7)(8)(9)(10)(11)(12)(13). These findings may have clinical implications, because increased intestinal permeability has been shown to be associated with an increased risk of complications, MODS, or even mortality in critically ill patients (14)(15)(16)(17).…”