title: Airway lipoxin A4/formyl peptide receptor 2-lipoxin receptor levels in pediatric patients with severe asthma.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Institute of Biomedicine and Molecular Immunology, Unit of Immunopathology and Pharmacology of the Respiratory System, Italian National Research Council, Palermo, Italy. Electronic address: gagliardo@ibim.cnr.it.
authors.forename: Rosalia
authors.initials: R
authors.lastname: Gagliardo
authors.affiliation: Département des Maladies Respiratoires, AP-HM, Aix Marseille Université, Marseille, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Gras
authors.affiliation: Institute of Biomedicine and Molecular Immunology, Unit of Immunopathology and Pharmacology of the Respiratory System, Italian National Research Council, Palermo, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: La Grutta
authors.affiliation: Département des Maladies Respiratoires, AP-HM, Aix Marseille Université, Marseille, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Chanez
authors.affiliation: Institute of Biomedicine and Molecular Immunology, Unit of Immunopathology and Pharmacology of the Respiratory System, Italian National Research Council, Palermo, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Di Sano
authors.affiliation: Institute of Biomedicine and Molecular Immunology, Unit of Immunopathology and Pharmacology of the Respiratory System, Italian National Research Council, Palermo, Italy.
authors.forename: Giusy D
authors.initials: GD
authors.lastname: Albano
authors.affiliation: Med Bio Med, Montpellier, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Vachier
authors.affiliation: Institute of Biomedicine and Molecular Immunology, Unit of Immunopathology and Pharmacology of the Respiratory System, Italian National Research Council, Palermo, Italy.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Montalbano
authors.affiliation: Institute of Biomedicine and Molecular Immunology, Unit of Immunopathology and Pharmacology of the Respiratory System, Italian National Research Council, Palermo, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Anzalone
authors.affiliation: Institute of Biomedicine and Molecular Immunology, Unit of Immunopathology and Pharmacology of the Respiratory System, Italian National Research Council, Palermo, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Bonanno
authors.affiliation: Institute of Biomedicine and Molecular Immunology, Unit of Immunopathology and Pharmacology of the Respiratory System, Italian National Research Council, Palermo, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Riccobono
authors.affiliation: Institute of Biomedicine and Molecular Immunology, Unit of Immunopathology and Pharmacology of the Respiratory System, Italian National Research Council, Palermo, Italy.
authors.forename: Mark
authors.initials: M
authors.lastname: Gjomarkaj
authors.affiliation: Institute of Biomedicine and Molecular Immunology, Unit of Immunopathology and Pharmacology of the Respiratory System, Italian National Research Council, Palermo, Italy.
authors.forename: Mirella
authors.initials: M
authors.lastname: Profita
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology / Q000627:therapeutic use; D001249:Asthma / Q000175:diagnosis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D015415:Biomarkers; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D007975:Leukotriene B4 / Q000378:metabolism; D044045:Lipoxins / Q000378:metabolism*; D008297:Male; D010766:Phosphorylation; D044042:Receptors, Formyl Peptide / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000378:metabolism*; D012129:Respiratory Function Tests; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D012882:Skin Tests; D013183:Sputum
chemical_list: D000305:Adrenal Cortex Hormones; D015415:Biomarkers; C105101:FPR2 protein, human; D044045:Lipoxins; D044042:Receptors, Formyl Peptide; D011965:Receptors, Glucocorticoid; D044067:Receptors, Lipoxin; C040527:lipoxin A4; D007975:Leukotriene B4; D007073:Immunoglobulin E
keywords: Childhood asthma; formyl peptide receptor 2–lipoxin receptor; glucocorticosteroids; induced sputum; inflammation/resolution; lipoxin A(4)