Acute lung injury (ALI) is a major complication following trauma. One potential etiology of ALI is described by the """"""""two hit"""""""" hypotheses. It proposes that an initial, mild stimulus, such as non-lethal hemorrhage, primes the immune system so that a second, seemingly innocuous stimulus (such as mild infection) leads to an exaggerated inflammatory response and the late development of ALI. In our laboratory, we can reliably reproduce ALI in a murine model by either intraperitoneal Lipopolysacharride (LPS) injection or hemorrhage followed by resuscitation with shed blood (FUR). However, when H/R mice are given LPS five days after OR, they do not demonstrate increased ALI, as predicted by the two hit hypothesis. This result differs. from other studies in which ALI developed when LPS was given one how after H/R. We hypothesize that it is the preexistence of counter- inflammatory cytoldnes, generated by prior MR, and at relatively high concentrations late after a first hit, that accounts for our findings. To test this hypothesis, we will measure counter-inflammatory cytokine gene and protein expression in our model, and then inhibit their activity to determine their relationship to the development of ALI after a second hit. If these agents can blunt ALI from a second hit, they would represent a potential therapy for patients at risk for ALI after trauma.
| Schulman, Andrew M; Claridge, Jeffrey A; Ghezel-Ayagh, Anousheh et al. (2003) Differential local and systemic tumor necrosis factor-alpha responses to a second hit of lipopolysaccharide after hemorrhagic shock. J Trauma 55:298-307 |
