Beschreibung:
<jats:sec><jats:title>Background and Purpose</jats:title><jats:p>Non‐steroidal anti‐inflammatory drugs (<jats:styled-content style="fixed-case">NSAID</jats:styled-content>s) have been shown to induce PG‐independent anti‐inflammatory actions. Here, we investigated the role of three different <jats:styled-content style="fixed-case">NSAID</jats:styled-content>s (naproxen, ibuprofen and oxaprozin) on neutrophil responses to <jats:styled-content style="fixed-case">CXCL</jats:styled-content>8 and <jats:styled-content style="fixed-case">C</jats:styled-content>5a.</jats:p></jats:sec><jats:sec><jats:title>Experimental Approach</jats:title><jats:p>Human neutrophils were isolated from healthy volunteers by dextran and <jats:styled-content style="fixed-case">F</jats:styled-content>icoll‐<jats:styled-content style="fixed-case">H</jats:styled-content>ypaque density gradients. Neutrophils were pre‐incubated with different concentrations (1–100 µM) of <jats:styled-content style="fixed-case">NSAIDs</jats:styled-content> or kinase inhibitors. Neutrophil degranulation into supernatants was tested by <jats:sc>elisa</jats:sc> and zymography. Neutrophil chemotaxis was determined using Boyden chambers. <jats:styled-content style="fixed-case">F</jats:styled-content>‐actin polymerization was determined by <jats:styled-content style="fixed-case">A</jats:styled-content>lexa‐<jats:styled-content style="fixed-case">F</jats:styled-content>luor 488‐conjugated phalloidin fluorescent assay. Integrin expression was assessed by flow cytometry. The phosphorylation of intracellular kinases was studied by <jats:styled-content style="fixed-case">W</jats:styled-content>estern blot.</jats:p></jats:sec><jats:sec><jats:title>Key Results</jats:title><jats:p>Pretreatment with <jats:styled-content style="fixed-case">NSAIDs</jats:styled-content> did not affect neutrophil degranulation, but inhibited neutrophil migration and polymerization of <jats:styled-content style="fixed-case">F</jats:styled-content>‐actin, in response to <jats:styled-content style="fixed-case">CXCL</jats:styled-content>8 and <jats:styled-content style="fixed-case">C</jats:styled-content>5a. Pretreatment with different <jats:styled-content style="fixed-case">NSAID</jats:styled-content>s prevented <jats:styled-content style="fixed-case">C</jats:styled-content>5a‐induced integrin (<jats:styled-content style="fixed-case">CD</jats:styled-content>11b) up‐regulation, while only ibuprofen reduced <jats:styled-content style="fixed-case">CXCL</jats:styled-content>8‐induced <jats:styled-content style="fixed-case">CD</jats:styled-content>11b up‐regulation. Pre‐incubation with naproxen or oxaprozin, but not ibuprofen, inhibited the <jats:styled-content style="fixed-case">PI</jats:styled-content>3<jats:styled-content style="fixed-case">K</jats:styled-content>/<jats:styled-content style="fixed-case">A</jats:styled-content>kt‐dependent chemotactic pathways. Both endogenous (released in cell supernatants) or exogenous (added to cell cultures) <jats:styled-content style="fixed-case">PGE</jats:styled-content><jats:sub>2</jats:sub> did not affect <jats:styled-content style="fixed-case">C</jats:styled-content>5a‐ or <jats:styled-content style="fixed-case">CXCL</jats:styled-content>8‐induced activities. Short‐term incubation with <jats:styled-content style="fixed-case">NSAID</jats:styled-content>s did not affect neutrophil <jats:styled-content style="fixed-case">PGE</jats:styled-content><jats:sub>2</jats:sub> release.</jats:p></jats:sec><jats:sec><jats:title>Conclusion and Implications</jats:title><jats:p>Treatment with <jats:styled-content style="fixed-case">NSAIDs</jats:styled-content> reduced <jats:styled-content style="fixed-case">C</jats:styled-content>5a‐ and <jats:styled-content style="fixed-case">CXCL</jats:styled-content>8‐induced neutrophil migration and <jats:styled-content style="fixed-case">F</jats:styled-content>‐actin polymerization via different mechanisms. Inhibition by ibuprofen was associated with integrin down‐regulation, while naproxen and oxaprozin blocked the <jats:styled-content style="fixed-case">PI</jats:styled-content>3<jats:styled-content style="fixed-case">K</jats:styled-content>/<jats:styled-content style="fixed-case">A</jats:styled-content>kt pathway. Both <jats:styled-content style="fixed-case">NSAID</jats:styled-content> actions were independent of <jats:styled-content style="fixed-case">COX</jats:styled-content> inhibition and <jats:styled-content style="fixed-case">PGE</jats:styled-content><jats:sub>2</jats:sub> release.</jats:p></jats:sec>