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.
Alves-Filho
José Carlos
JC
Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, USP, Ribeirão Preto, SP 14049-900, Brasil.
Benjamim
Claudia
C
Tavares-Murta
Beatriz Martins
BM
Cunha
Fernando Q
FQ
D000818:Animals; D002465:Cell Movement / Q000276:immunology / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D051379:Mice; D009504:Neutrophils / Q000276:immunology / Q000502:physiology*; D009569:Nitric Oxide / Q000096:biosynthesis*; D012720:Severity of Illness Index; D018746:Systemic Inflammatory Response Syndrome / Q000276:immunology* / Q000503:physiopathology
D016207:Cytokines; D009569:Nitric Oxide