Sepsis is just one example of a pathologic condition associated with a NS-187 cytokine storm, the excessive and sustained production of numerous cytokines by immune cells. Much evidence derived from studies in animal and in human systems show that highly elevated levels of proinflammatory cytokines contribute to high mortality by septic shock. Our results demonstrate that, in addition to protecting against endotoxin-mediated high mortality, PAF induces remarkable changes in the production level of cytokines in response to LPS. In particular, two distinct patterns were observed. First, in LPS-induced endotoxemic mice, PAF administration resulted in prominent decrease in the production of circulating proinflammatory cytokines, including TNF-a, IL-1b, IL-12p70, and IFN-c. Second, PAF administration significantly increased production of the compensatory anti-inflammatory cytokine IL-10. Because anti-inflammatory cytokines are released as a regulatory mechanism in septic shock and several studies using animal models of sepsis have demonstrated that recombinant IL-10 has a protective effect against mortality and proinflammatory cytokine production, it is possible that augmented IL-10 production by PAF may contribute to a compensatory response during endotoxin shock. And also, we observed that PAF-mediated protection of mice from lethal endotoxemia could be blocked by prior administration of neutralizing anti-IL-10 antibodies, but not by an isotype control antibody. These results implicate that IL-10, as one of mechanisms involved in the capacity of PAF to protect mice from LPS-induced toxic shock, confers partially on systemic immune suppression. Exaggerated proinflammatory cytokines activity can result in symptoms of septic shock. Specially, TNF-a and IL-1b contributed to the increase in the SHP099 number of infiltrating neutrophils which play a critical role in bacterial clearance. Our data demonstrate that after LPS challenge, massive PMN infiltration in the lung and liver was promoted. In addition, the level of lung, liver, kidney MPO was increased. Interestingly, histological examination of liver and lung sections showed that PMN accumulation in PAF-administrated mice were significantly lower than those in LPS-challenged mice. Correspondingly, there was a trend toward a decrease in MPO levels in the lung, liver, kidney of PAF-treated endotoxemic mice. By analyzing serum biochemical parameters that assess liver damage and renal function, we fo
