Failure of neutrophil migration toward infectious focus in severe sepsis: a critical event for the outcome of this syndrome

Sepsis is a systemic inflammatory response commonly caused by bacterial infection. We demonstrated that the outcome of sepsis induced by cecal ligation and puncture (CLP) correlates with the severity of the neutrophil migration failure towards infectious focus. Failure appears to be due to a decrease in the rolling and adhesion of neutrophil to endothelium cells. It seems that neutrophil migration impairment is mediated by the circulating inflammatory cytokines, such as TNF-alpha and IL-8, which induce the nitric oxide (NO) production systemically. It is supported by the fact that intravenous administration of these cytokines reduces the neutrophil migration induced by different inflammatory stimuli, and in severe sepsis the circulating concentrations of the cytokines and chemokines are significantly increased. Moreover, the neutrophil migration failure and the reduction in the rolling/adhesion were not observed in iNOS-/- mice and, aminoguanidine prevented this event. We also demonstrated that the failure of neutrophil migration is a Toll-4 receptor (TLR4) dependent mechanism, since it was not observed in TLR4 deficient mice. Furthermore, it was also observed that circulating neutrophils obtained from septic patients present failure of neutrophil chemotaxis toward fMLP, IL-8, and LTB4 and an increased in sera concentrations of NO3 and cytokines. In conclusion, we demonstrated that, in sepsis, failure of neutrophil migration is critical for the outcome and that NO is involved in the process.

Atualizaçäo sobre mediadores e modelos experimentais de sepse / Present understanding of mediators and experimental models of sepsis

A autora apresenta uma revisäo sobre a resposta inflamatória durante a sepse, abordando os principais mediadores envolvidos no processo, tais como citocinas e óxido nítrico, bem como o papel desses mediadores na evoluçäo da doença. Esse aspecto abordado näo é täo simples e pontual, pois a relevância desses mediadores inflamatórios, na sepse, varia de acordo com muitos fatores, entre eles, com o modelo experimental utilizado, a espécie animal e o estágio da doença. Ainda, seräo revisados os modelos experimentais mais utilizados para o estudo da sepse, discutindo-se as vantagens de cada modelo e a sua contribuiçäo para a compreensäo da doença. Näo há dúvida que os modelos experimentais, utilizados hoje em dia, contribuem bastante para o entendimento de sepse e choque séptico. Entretanto, é importante saber discernir os pontos fortes e fracos do modelo, possibilitando uma real extensäo dos resultados experimentais para testes clínicos.