A Critical Role of Leukotriene B4 in Neutrophil Migration to Infectious Focus in Cecal Ligation and Puncture Sepsis

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Abstract
Neutrophil migration to an infectious focus is essential for control and resolution of infection. Early studies demonstrated that the failure of such migration is observed in lethal sepsis induced by cecal ligation and puncture (L-CLP), whereas intense neutrophil migration is seen in sublethal CLP (SL-CLP). In this study, we found that inhibition of synthesis of prostaglandins or leukotriene B4 (LTB4) did not modify the failure of neutrophil migration or the survival rate of L-CLP mice. In addition, pretreatment of L-CLP mice with a platelet activating factor (PAF) receptor antagonist (UK74505), despite not interfering with the failure process, significantly increased (33%) the survival rate of the animals. Inhibitors of prostaglandin synthesis (indomethacin and meloxican) and UK74505 did not modify the neutrophil migration observed in SL-CLP. On the other hand, the blockade of LTB4 synthesis (MK886, a 5-lipoxygenase-activating protein inhibitor) or of its receptors (CP-105,696) resulted in reduced neutrophil migration to the peritoneal cavity in SL-CLP mice (62% and 60%, respectively), a consequent increase in the number of bacteria in the inflammatory focus, and a reduced survival rate of the animals (43% and 38%, respectively). Both SL-CLP and L-CLP animals presented significant levels of LTB4 in the peritoneal exudate (3- and 8-fold higher than sham group, respectively) and these were reduced by the pretreatment of mice with LTB4 inhibitors. In conclusion, our results suggest that LTB4, but not prostaglandins or PAF, is an important chemoattractant involved in neutrophil recruitment to infection sites in SL-CLP, a crucial event in confining the invading pathogens to a restricted area. However, in circumstances in which the infection turns to a lethal sepsis, LTB4 is not involved in the observed failure of neutrophil migration to the infectious focus.