title: Activation of P2RY11 and ATP release by lipoxin A4 restores the airway surface liquid layer and epithelial repair in cystic fibrosis.
abstract: In cystic fibrosis (CF), the airway surface liquid (ASL) height is reduced as a result of impaired ion transport, which favors bacterial colonization and inflammation of the airway and leads to progressive lung destruction. Lipoxin (LX)A4, which promotes resolution of inflammation, is inadequately produced in the airways of patients with CF. We previously demonstrated that LXA4 stimulates an ASL height increase and epithelial repair. Here we report the molecular mechanisms involved in these processes. We found that LXA4 (1 nM) induced an apical ATP release from non-CF (NuLi-1) and CF (CuFi-1) airway epithelial cell lines and CF primary cultures. The ATP release induced by LXA4 was completely inhibited by antagonists of the ALX/FPR2 receptor and Pannexin-1 channels. LXA4 induced an increase in intracellular cAMP and calcium, which were abolished by the selective inhibition of the P2RY11 purinoreceptor. Pannexin-1 and ATP hydrolysis inhibition and P2RY11 purinoreceptor knockdown all abolished the increase of ASL height induced by LXA4. Inhibition of the A2b adenosine receptor did not affect the ASL height increase induced by LXA4, whereas the PKA inhibitor partially inhibited this response. The stimulation of NuLi-1 and CuFi-1 cell proliferation, migration, and wound repair by LXA4 was inhibited by the antagonists of Pannexin-1 channel and P2RY11 purinoreceptor. Taken together, our results provide evidence for a novel role of LXA4 in stimulating apical ATP secretion via Pannexin-1 channels and P2RY11 purinoreceptors activation leading to an ASL height increase and epithelial repair.
authors.affiliation: 1 National Children Research Centre, Dublin 12, Ireland.
authors.forename: Gerard
authors.initials: G
authors.lastname: Higgins
authors.forename: Paul
authors.initials: P
authors.lastname: Buchanan
authors.forename: Marianne
authors.initials: M
authors.lastname: Perriere
authors.forename: Mazen
authors.initials: M
authors.lastname: Al-Alawi
authors.forename: Richard W
authors.initials: RW
authors.lastname: Costello
authors.forename: Valia
authors.initials: V
authors.lastname: Verriere
authors.forename: Paul
authors.initials: P
authors.lastname: McNally
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Harvey
authors.forename: Valérie
authors.initials: V
authors.lastname: Urbach
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D019898:Autocrine Communication; D020013:Calcium Signaling; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D017630:Connexins / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D044045:Lipoxins / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D061251:Primary Cell Culture; D058919:Purinergic P2 Receptor Antagonists / Q000494:pharmacology; D044042:Receptors, Formyl Peptide / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D012038:Regeneration / Q000187:drug effects; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017630:Connexins; C105101:FPR2 protein, human; C442142:HSH2D protein, human; D044045:Lipoxins; D009419:Nerve Tissue Proteins; C109734:P2RY11 protein, human; C492764:PANX1 protein, human; D058919:Purinergic P2 Receptor Antagonists; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D018048:Receptors, Purinergic P2; C040527:lipoxin A4; D000255:Adenosine Triphosphate; D000242:Cyclic AMP
keywords: ATP release; P2RY11 receptor; Pannexin-1; cystic fibrosis; lipoxin A4