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Airway lipoxin A4/formyl peptide receptor 2–lipoxin receptor levels in pediatric patients with severe asthma

Published:March 11, 2016DOI:https://doi.org/10.1016/j.jaci.2015.11.045

      Background

      Lipoxins are biologically active eicosanoids with anti-inflammatory properties. Lipoxin A4 (LXA4) signaling blocks asthmatic responses in human and experimental model systems. There is evidence that patients with respiratory diseases, including severe asthma (SA), display defective generation of lipoxin signals despite glucocorticoid therapy.

      Objective

      We investigated airway levels of formyl peptide receptor 2–lipoxin receptor (FPR2/ALXR), LXA4, and its counterregulatory compound, leukotriene B4 (LTB4), in patients with childhood asthma. We addressed the potential interplay of the LXA4-FPR2/ALXR axis and glucocorticoids in the resolution of inflammation.

      Methods

      We examined LXA4 and LTB4 concentrations in induced sputum supernatants from children with intermittent asthma (IA), children with SA, and healthy control (HC) children. In addition, we investigated FPR2/ALXR expression in induced sputum cells obtained from the study groups. Finally, we evaluated in vitro the molecular interaction between LXA4 and glucocorticoid receptor–based mechanisms.

      Results

      We found that children with SA have decreased LXA4 concentrations in induced sputum supernatants in comparison with children with IA. In contrast to decreases in LXA4 concentrations, LTB4 concentrations were increased in children with asthma independent of severity. LXA4 concentrations negatively correlated with LTB4 concentrations and with exacerbation numbers in children with SA. FPR2/ALXR expression was reduced in induced sputum cells of children with SA compared with that seen in HC subjects and children with IA. Finally, we describe in vitro the existence of crosstalk between LXA4 and glucocorticoid receptor at the cytosolic level mediated by G protein–coupled FPR2/ALXR in peripheral blood granulocytes isolated from HC subjects, children with IA, and children with SA.

      Conclusion

      Our findings provide evidence for defective LXA4 generation and FPR2/ALXR expression that, associated with increased LTB4, might be involved in a reduction in the ability of inhaled corticosteroids to impair control of airway inflammation in children with SA.

      Key words

      Abbreviations used:

      ATS (American Thoracic Society), ERS (European Respiratory Society), FP (Fluticasone propionate), FPR2/ALXR (Formyl peptide receptor 2–lipoxin receptor), GR (Glucocorticoid receptor), GRE (Glucocorticoid response element), HC (Healthy control), IA (Intermittent asthma), ISS (Induced sputum supernatant), LTB4 (Leukotriene B4), LXA4 (Lipoxin A4), PBG (Peripheral blood granulocyte), p-GR (Phosphorylated glucocorticoid receptor), RT (Room temperature), SA (Severe asthma)
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