title: Lipoxin A₄-mediated KATP potassium channel activation results in cystic fibrosis airway epithelial repair.
abstract: The main cause of morbidity and mortality in cystic fibrosis (CF) is progressive lung destruction as a result of persistent bacterial infection and inflammation, coupled with reduced capacity for epithelial repair. Levels of the anti-inflammatory mediator lipoxin A₄ (LXA₄) have been reported to be reduced in bronchoalveolar lavages of patients with CF. We investigated the ability of LXA₄ to trigger epithelial repair through the initiation of proliferation and migration in non-CF (NuLi-1) and CF (CuFi-1) airway epithelia. Spontaneous repair and cell migration were significantly slower in CF epithelial cultures (CuFi-1) compared with controls (NuLi-1). LXA₄ triggered an increase in migration, proliferation, and wound repair of non-CF and CF airway epithelia. These responses to LXA₄ were completely abolished by the ALX/FPR2 receptor antagonist, Boc2 and ALX/FPR2 siRNA. The KATP channel opener pinacidil mimicked the LXA₄ effect on migration, proliferation, and epithelial repair, whereas the KATP channel inhibitor, glibenclamide, blocked the responses to LXA₄. LXA₄ did not affect potassium channel expression but significantly upregulated glibenclamide-sensitive (KATP) currents through the basolateral membrane of NuLi-1 and CuFi-1 cells. MAP kinase (ERK1/2) inhibitor, PD98059, also inhibited the LXA₄-induced proliferation of NuLi-1 and CuFi-1 cells. Finally, both LXA₄ and pinacidil stimulated ERK-MAP kinase phosphorylation, whereas the effect of LXA₄ on ERK phosphorylation was inhibited by glibenclamide. Taken together, our results provided evidence for a role of LXA₄ in triggering epithelial repair through stimulation of the ALX/FPR2 receptor, KATP potassium channel activation, and ERK phosphorylation. This work suggests exogenous delivery of LXA₄, restoring levels in patients with CF, perhaps as a potential therapeutic strategy.
authors.affiliation: National Children's Research Center, Our Lady's Children Hospital, Dublin, Ireland.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Buchanan
authors.forename: Paul
authors.initials: P
authors.lastname: McNally
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Harvey
authors.forename: Valerie
authors.initials: V
authors.lastname: Urbach
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005419:Flavonoids / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D054086:KATP Channels / Q000096:biosynthesis* / Q000235:genetics; D044045:Lipoxins / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D044042:Receptors, Formyl Peptide / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C105101:FPR2 protein, human; D005419:Flavonoids; D007004:Hypoglycemic Agents; D054086:KATP Channels; D044045:Lipoxins; D047428:Protein Kinase Inhibitors; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C040527:lipoxin A4; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D005905:Glyburide
keywords: ATP-sensitive potassium channels; cystic fibrosis; epithelial repair; lipoxin