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  • In vivo modulation of the inflammatory response by nonsteroidal antiinflammatory drug-related compounds that trigger L-selectin shedding.

In vivo modulation of the inflammatory response by nonsteroidal antiinflammatory drug-related compounds that trigger L-selectin shedding.

European journal of immunology (2012-09-15)
Ada Herrera-García, María Domínguez-Luis, Mayte Arce-Franco, Judith López-Fernández, Manuel Feria, Olga Barreiro, Francisco Sánchez-Madrid, Federico Díaz-González
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.

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Diphenylamine, ReagentPlus®, 99%
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Diphenylamine, PESTANAL®, analytical standard
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Diphenylamine solution, certified reference material, 5000 μg/mL in methanol
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