Interactions of Toll-like receptors (TLR) with non-microbial factors plays 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 (TLR4mut) mice would be more resistant to T/HS-induced gut injury and neutrophil (PMN) priming than their wild-type (WT) littermates and found that both were significantly reduced in the TLR4mut mice. Additionally, the in vivo and ex vivo PMN priming effect of T/HS intestinal lymph observed in the WT mice was abrogated in TLR4mut 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. PMN depletion studies showed that T/HS lymph-induced acute lung injury (ALI) was PMN-dependent, since lung injury was totally abrogated in PMN-depleted animals. Since 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 non-microbial TLR4 ligands. HMGB1, heat shock protein (Hsp)-70, Hsp27 and hyaluronic acid, since all have been implicated in ischemia-reperfusion-induced tissue injury. None of these ‘danger’ proteins appeared to be involved, since 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.

Small volume resuscitation with HTS is more effective than RL and nafamostat in limiting T/HS-induced acute lung injury, neutrophil activation and red blood cell injury.

The type of resuscitation regimen used influenced the extent of organ injury and cellular activation or dysfunction observed after T/HS with different resuscitation regimens showing varying effects depending on the cell or organ tested. Thus, when testing novel fluid resuscitation regimen, attention must be paid to the control resuscitation regimen used.

No abstract

No abstract