FAILURE OF NEUTROPHIL MIGRATION TO INFECTIOUS FOCUS AND CARDIOVASCULAR CHANGES ON SEPSIS IN RATS: EFFECTS OF THE INHIBITION OF NITRIC OXIDE PRODUCTION, REMOVAL OF INFECTIOUS FOCUS, AND ANTIMICROBIAL TREATMENT

Abstract

Recently, we demonstrated that mice under lethal sepsis present failure of neutrophil migration (FNM) to infectious focus, which is mediated by nitric oxide. The aims of the present study were to investigate whether FNM is also observed in severe sepsis induced by cecal ligation and puncture in rats and the effects of the prevention of nitric oxide production and of the elimination of the infectious focus through peritoneal lavage or by antimicrobial treatment on FNM and disease outcome. Rats were submitted to several septic stimuli (low, moderate, and severe) by cecal ligation and puncture. Severe septic stimulus animals presented FNM to the peritoneal cavity that was accompanied by large numbers of bacteria in the peritoneal cavity, blood, and liver and lung tissues; high cytokines (tumor necrosis factor alpha, interleukin [IL] 1beta, IL-6, cytokine-induced neutrophil chemoattractant 1, and IL-10) concentrations in the infection site, sera, and lung tissues; marked hypotension; and high mortality rate. The exhaustive lavage of the peritoneal cavity to reduce the infectious focus did not ameliorate the disease outcome. The association of lavage procedure with aminoguanidine treatment re-established neutrophil migration, but only delayed the death of the animals. In contrast, the antimicrobial treatment of severe septic stimulus animals with sulfamethoxazole and trimethoprim significantly improved the survival rate of the severe septic stimulus but did not re-establish neutrophil migration. However, the association of aminoguanidine plus sulfamethoxazole and trimethoprim brought about a significant increase in the survival rate and re-established neutrophil migration to infectious focus; reduced the colony-forming units in the peritoneal cavity, blood, and lung tissues; and caused an improvement in the cardiovascular performance. The results showed, for the first time, that the pharmacological prevention of FNM to the infectious focus associated with the antimicrobial therapy could be a new beneficial strategy for the treatment of sepsis syndrome.