Thioglycollate peritonitis in mice lacking C5, 5-lipoxygenase, or p47(phox): complement, leukotrienes, and reactive...

Leukotriene B(4) (LTB(4)) is an easily diffusible proinflammatory chemotactic factor that has been posited to prime the initial inflammatory response for the action of other mediators, including C5a. 5-Lipoxygenase-deficient (5LX(-/-)) and C5-deficient mice only generated about 50% as much peritoneal leukocytosis as wild-type mice following intraperitoneal (IP) challenge with the sterile irritant, thioglycollate (P<0.005). Pretreatment of C5- mice with the specific 5-lipoxygenase inhibitor, zileuton, reduced peritoneal leukocytosis to almost unstimulated levels, suggesting that LTB(4) can act independently of C5a. Previously, LTB(4) and C5a have been shown in vitro to be inactivated by metabolites of superoxide. In the current study, we examined the fate of LTB(4) in the p47(phox-/-) mouse model of chronic granulomatous disease (CGD) in which the phagocyte NADPH oxidase is unable to produce superoxide. p47(phox-/-) mice generated more thioglycollate-elicited peritoneal leukocytosis than wild-type mice. Pretreatment with zileuton caused a 76% reduction in peritoneal leukocytosis in p47(phox-/-) mice (P<0.005) and a 54% reduction in wild-type mice (P<0.05), whereas pretreatment with dexamethasone or toradol (a cyclooxygenase inhibitor) had no effect. Following IP LTB(4) (1 microg/mouse), total recovered peritoneal LTB(4) was similar between p47(phox-/-) and wild-type mice at 10 and 30 min, but was approximately fivefold greater in p47(phox-/-) mice at 180 min. These data suggest that LTB(4) and C5a have separate but overlapping roles in thioglycollate-elicited peritonitis, and at least the leukotriene component is, in turn, regulated by reactive oxidants.