title: Tepoxalin blocks neutrophil migration into cutaneous inflammatory sites by inhibiting Mac-1 and E-selectin expression.
abstract: Inflammation is characterized by the migration of polymorphonuclear leukocytes from the vasculature into the tissue causing profound injury. Adhesion and migration of neutrophils across the vascular bed are governed by a series of complex events including cytokine/chemokine production which in turn orchestrates the temporal expression of a cohort of adhesion molecules mediating the migration. Many of these adhesion molecules and their inducers are under the control of inflammatory response transcriptional factors such as NF kappa B and AP-1. Recently we showed tepoxalin, previously known as a dual cyclooxygenase/lipoxygenase (CO/LO) inhibitor, to be a potent inhibitor of NF kappa B-induced transcription in vitro. In this study, we demonstrated that when administered in vivo, tepoxalin but not naproxen (a nonsteroidal anti-inflammatory drug, NSAID) or zileuton (an LO inhibitor), effectively inhibits neutrophil migration into inflammatory sites in murine skin stimulated by either lipopolysaccharide (LPS) or tumor necrosis factor-alpha. Immunohistochemical analysis indicates that 10-50 mg/kg of tepoxalin inhibits neutrophil migration. It also effectively blocks the upregulation of Mac-1 (CD11b/CD18) on neutrophils. Quantitative polymerase chain reaction Mac-1 analysis shows that LPS-induced transcription of E-selectin mRNA was dramatically suppressed by both 25 and 50 mg/kg of tepoxalin, whereas the level of ICAM-1 was only affected by 50 mg/kg of tepoxalin. Since it has been documented that the expression of E-selectin and Mac-1 is regulated either directly or indirectly by the transcription factor NF kappa B, our studies provide in vivo evidence that tepoxalin is a potent inhibitor of NF kappa B-mediated events in animal models and this novel molecular mechanism clearly defines it as a new class of anti-inflammatory compounds.
authors.affiliation: Discovery Research, R. W. Johnson Pharmaceutical Research Institute, Ontario, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Zhou
authors.forename: B L
authors.initials: BL
authors.lastname: Pope
authors.forename: E
authors.initials: E
authors.lastname: Chourmouzis
authors.forename: W P
authors.initials: WP
authors.lastname: Fung-Leung
authors.forename: C Y
authors.initials: CY
authors.lastname: Lau
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001483:Base Sequence; D001667:Binding, Competitive / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects* / Q000276:immunology; D019040:E-Selectin / Q000096:biosynthesis / Q000187:drug effects*; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000187:drug effects; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D016177:Macrophage-1 Antigen / Q000096:biosynthesis / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009288:Naproxen / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology*; D012867:Skin / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D019040:E-Selectin; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D016177:Macrophage-1 Antigen; D011720:Pyrazoles; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D009288:Naproxen; C073135:tepoxalin; C063449:zileuton; D006918:Hydroxyurea