• Ygal Benhamou, Julie Favre, Philippe Musette, Sylvanie Renet, Christian Thuillez, Vincent Richard, and Fabienne Tamion.
• Inserm U644, Institute for Biomedical Research and IFRMP 23, Rouen University Medical School, Rouen, France.
• Crit. Care Med. 2009 May 1;37(5):1724-8.

ObjectiveHemorrhagic shock followed by resuscitation (HS/R) promotes organ injury by priming cells of the innate immune system for inflammatory response. Toll-like receptors (TLRs) play an important role in signal transduction in shock/resuscitation conditions. Because proinflammatory mediators are a critical event in mesenteric endothelial injury induced by HS/R, we assessed the role of TLR4 or TLR2 in this setting.DesignLaboratory investigation.SettingResearch laboratory at Rouen University Medical School.SubjectsMale wild-type, TLR4(-/-) and TLR2(-/-) mice with the same C57BL/6 background.InterventionsMice were submitted to 30 minutes hemorrhagic shock followed by 1 hour resuscitation, after which mesenteric endothelial dysfunction, microvascular injury, and TNF[alpha] production were assessed.Measurements And Main ResultsHS/R markedly decreased nitric oxide-mediated mesenteric relaxations induced by acetylcholine, assessed ex vivo on a myograph. By contrast, in TLR4-deficient mice, HS/R did not impair the nitric oxide-mediated responses to acetylcholine. No protection was observed in TLR2-deficient mice. TLR4-deficient mice also displayed a significant reduction in fluid resuscitation and TNF[alpha] systemic production.ConclusionsTLR4 contributes to mesenteric endothelial dysfunction after hemorrhagic shock. This early TLR4-induced vascular injury may be an important trigger of the systemic inflammatory response occurring in this disease.

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