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

doi:10.1016/j.jaci.2015.11.045

Journal of Allergy and Clinical Immunology

Volume 137, Issue 6, June 2016, Pages 1796-1806

https://doi.org/10.1016/j.jaci.2015.11.045 Get rights and content

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.

Section snippets

Subjects

Pediatric subjects (age, 6-12 years) were recruited among outpatients attending the Pulmonology/Allergy Clinic of the Italian National Research Council in Palermo. Asthma severity was diagnosed according to European Respiratory Society (ERS)/American Thoracic Society (ATS) guidelines.²⁸

Twelve children had intermittent asthma (IA), which was treated with short-acting β₂-agonists as requested during the last 3 months, and 17 children had SA, which was treated with high-dose inhaled

Demographic and functional characteristics of patients

The demographic and functional characteristics of patients are reported in Table I. Although FEV₁ values were less in children with SA, no significant differences were found among the 3 study groups in terms of FEV₁ values at all visits. We observed a significant FEV₁/forced vital capacity decrease in children with SA in comparison with that seen in HC subjects and in children with SA in comparison with that seen in children with IA at all visits. In children with IA, 24 exacerbations occurred

Discussion

For the first time, the present findings demonstrate that children with SA have diminished LXA₄ concentrations in ISSs, despite high-dose inhaled glucocorticoid treatment, in comparison with those in children with IA. In contrast to decreases in LXA₄ concentrations, LTB₄ concentrations were increased in children with asthma independent of severity. Decreased LXA₄ concentrations, associated with increased LTB₄ concentrations in induced sputum would determine an imbalance in bioactive lipid

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: Supported by the Italian National Research Council (CNR) and the European Union Framework Programme for Research, contract no. FOOD-CT-2004-506378, GA²LEN project, Global Allergy and Asthma European Network.

: Disclosure of potential conflict of interest: P. Chanez has received support for a clinical trial from Boehringer Ingelheim; has received grants and personal fees from Almirall, Boehringer Ingelheim, Centocor, GlaxoSmithKline, AstraZeneca, Novartis, Teva, Chiesi, and Schering Plough; has received personal fees from Merck Sharp Dohme; and has received a grant from Axis-Marseille University. The rest of the authors declare that they have no relevant conflicts of interest.

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Mechanisms of allergy and clinical immunologyAirway lipoxin A4/formyl peptide receptor 2–lipoxin receptor levels in pediatric patients with severe asthma

Background

Objective

Methods

Results

Conclusion

Section snippets

Subjects

Demographic and functional characteristics of patients

Discussion

Prostaglandins Other Lipid Mediat

Prostaglandins Other Lipid Mediat

Trends Pharmacol Sci

Biomed Pharmacother

J Allergy Clin Immunol

Biochem Biophys Res Commun

J Allergy Clin Immunol

The many faces of airway inflammation. Asthma and chronic obstructive pulmonary disease. Asthma Research Group

Am J Respir Crit Care Med

Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics

Am J Respir Crit Care Med

Asthma. From bronchoconstriction to airways inflammation and remodeling

Am J Respir Crit Care Med

Endogenous lipid mediators in the resolution of airway inflammation

Eur Respir J

Dampening inflammation

Nat Immunol

Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators

Nat Rev Immunol

Lipoxins: resolutionary road

Br J Pharmacol

Lipoxin A4 modulates adaptive immunity by decreasing memory B-cell responses via an ALX/FPR2-dependent mechanism

Eur J Immunol

Aspirin-triggered lipoxin A4 and B4 analogs block extracellular signal-regulated kinase-dependent TNF-alpha secretion from human T cells

J Immunol

Lipoxin-mediated inhibition of IL-12 production by DCs: a mechanism for regulation of microbial immunity

Nat Immunol

Aspirin-triggered 15-epi-lipoxin A4 (LXA4) and LXA4 stable analogues are potent inhibitors of acute inflammation: evidence for anti-inflammatory receptors

J Exp Med

Lipoxin A4 inhibits immune cell binding to salivary epithelium and vascular endothelium

Am J Physiol Cell Physiol

Cyclooxygenase 2 plays a pivotal role in the resolution of acute lung injury

J Immunol

Lipoxins are potential endogenous antiinflammatory mediators in asthma

Am J Respir Crit Care Med

Lipoxin (LX)A4 and aspirin-triggered 15-epi-LXA4 inhibit tumor necrosis factor 1alpha-initiated neutrophil responses and trafficking: regulators of a cytokine-chemokine axis

J Exp Med

Lipoxin A4 analogs attenuate induction of intestinal epithelial proinflammatory gene expression and reduce the severity of dextran sodium sulfate-induced colitis

J Immunol

Diminished lipoxin biosynthesis in severe asthma

Am J Respir Crit Care Med

Mechanisms of allergy and clinical immunology
Airway lipoxin A₄/formyl peptide receptor 2–lipoxin receptor levels in pediatric patients with severe asthma

Lipoxin A₄ modulates adaptive immunity by decreasing memory B-cell responses via an ALX/FPR2-dependent mechanism