title: In vivo modulation of the inflammatory response by nonsteroidal antiinflammatory drug-related compounds that trigger L-selectin shedding.
abstract: Diphenylamine-based nonsteroidal antiinflammatory drugs (NSAIDs) are able to cause in vitro the shedding of L-selectin. The aim of this work was to determine the physio-logic relevance of L-selectin shedding in the antiinflammatory effect exerted by NSAIDs in vivo. Chemical compounds structurally related to NSAIDs - including diphenyl-amine, N-phenylanthranilic acid (N-Ph), diphenylacetic acid - as well as the traditional NSAID indomethacin were studied using the zymosan air-pouch mouse model. Animals intramuscularly pretreated with indomethacin or N-Ph, but not with diphenyl-amine or diphenylacetic acid, showed a significant dose-dependent reduction in the number of neutrophils compared with untreated animals (N-Ph, IC50 = 6.7 mg/kg). Except for indomethacin, none of these compounds caused any significant reduction in cyclooxygenase-1 activity in vivo. In flow chamber experiments, N-Ph reduced the capability of human neutrophils to pass across the endothelial barrier by interfering with leukocyte rolling step on HUVEC. N-Ph, but not diphenylacetic acid, induced activation-independent L-selectin shedding in mouse neutrophils. Interestingly, N-Ph exerted an antiinflammatory effect similar to that of the anti-L-selectin blocking antibody Mel-14, although no additive action was observed when both compounds were combined. These data suggest that the L-selectin shedding induced by NSAIDs may be involved in the antiinflammatory action exerted by these compounds in clinical settings.
authors.affiliation: Servicio de Reumatología, Hospital Universitario de Canarias, La Laguna, Spain.
authors.forename: Ada
authors.initials: A
authors.lastname: Herrera-García
authors.forename: María
authors.initials: M
authors.lastname: Domínguez-Luis
authors.forename: Mayte
authors.initials: M
authors.lastname: Arce-Franco
authors.forename: Judith
authors.initials: J
authors.lastname: López-Fernández
authors.forename: Manuel
authors.initials: M
authors.lastname: Feria
authors.forename: Olga
authors.initials: O
authors.lastname: Barreiro
authors.forename: Francisco
authors.initials: F
authors.lastname: Sánchez-Madrid
authors.forename: Federico
authors.initials: F
authors.lastname: Díaz-González
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D002460:Cell Line; D051545:Cyclooxygenase 1 / Q000378:metabolism; D004159:Diphenylamine / Q000008:administration & dosage* / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D019041:L-Selectin / Q000378:metabolism*; D007958:Leukocyte Count; D036904:Leukocyte Rolling / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D019041:L-Selectin; D004159:Diphenylamine; D051545:Cyclooxygenase 1