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* Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; and
SAIC Frederick, Frederick Cancer Research and Development Center, Frederick, Maryland
Correspondence: Steven M. Holland, M.D., Laboratory of Host Defenses, National Institute of Allergy and Infectious Disease, National Institutes of Health, 10 Center Drive, Dr. MSc. 1886, Bethesda, MD 20892. E-mail: smh{at}nih.gov
Leukotriene B4 (LTB4) 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 LTB4 can act independently of C5a. Previously, LTB4 and C5a have been shown in vitro to be inactivated by metabolites of superoxide. In the current study, we examined the fate of LTB4 in the p47phox-/- mouse model of chronic granulomatous disease (CGD) in which the phagocyte NADPH oxidase is unable to produce superoxide. p47phox-/- mice generated more thioglycollate-elicited peritoneal leukocytosis than wild-type mice. Pretreatment with zileuton caused a 76% reduction in peritoneal leukocytosis in p47phox-/- 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 LTB4 (1 µg/mouse), total recovered peritoneal LTB4 was similar between p47phox-/- and wild-type mice at 10 and 30 min, but was approximately fivefold greater in p47phox-/- mice at 180 min. These data suggest that LTB4 and C5a have separate but overlapping roles in thioglycollate-elicited peritonitis, and at least the leukotriene component is, in turn, regulated by reactive oxidants.
Key Words: chronic granulomatous disease • LTB4 • C5a • zileuton • superoxide
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