ACTIVATION OF TOLL-LIKE RECEPTOR 4 IS NECESSARY FOR TRAUMA HEMORRHAGIC SHOCK-INDUCED GUT INJURY AND POLYMORPHONUCLEAR NEUTROPHIL PRIMING

作者：Reino Diego C; Palange David; Feketeova Elenora; Bonitz Robert P; Xu Da Zhong; Lu Qi; Sheth Sharvil U; Pena Geber; Ulloa Luis; De Maio Antonio; Feinman Rena; Deitch Edwin A^*

来源：Shock, 2012, 38(1): 107-114.

DOI：10.1097/SHK.0b013e318257123a

• Mesenteric lymph
• shock
• MODS
• hemorrhage
• danger model

Interactions of toll-like receptors (TLRs) with nonmicrobial factors play a major role in the pathogenesis of early trauma-hemorrhagic shock (T/HS)-induced organ injury and inflammation. Thus, we tested the hypothesis that TLR4 mutant (TLR4(mut)) mice would be more resistant to T/HS-induced gut injury and polymorphonuclear neutrophil (PMN) priming than their wild-type littermates and found that both were significantly reduced in the TLR4(mut) mice. In addition, the in vivo and ex vivo PMN priming effect of T/HS intestinal lymph observed in the wild-type mice was abrogated in TLR4(mut) mice as well the TRIFmut-deficient mice and partially attenuated in Myd88(-/-) mice, suggesting that TRIF activation played a more predominant role than MyD88 in T/HS lymph-induced PMN priming. Polymorphonuclear neutrophil depletion studies showed that T/HS lymph-induced acute lung injury was PMN dependent, because lung injury was totally abrogated in PMN-depleted animals. Because the lymph samples were sterile and devoid of endotoxin or bacterial DNA, we investigated whether the effects of T/HS lymph was related to endogenous nonmicrobial TLR4 ligands. High-mobility group box 1 protein 1, heat shock protein 70, heat shock protein 27, and hyaluronic acid all have been implicated in ischemia-reperfusion-induced tissue injury. None of these "danger" proteins appeared to be involved, because their levels were similar between the sham and shock lymph samples. In conclusion, TLR4 activation is important in T/HS-induced gut injury and in T/HS lymph-induced PMN priming and lung injury. However, the T/HS-associated effects of TLR4 on gut barrier dysfunction can be uncoupled from the T/HS lymph-associated effects of TLR4 on PMN priming.

• 出版日期2012-7