Lipoxin A₄-mediated KATP potassium channel activation results in cystic fibrosis airway epithelial repair

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 305; no. 2; p. L193
• Main Authors: Buchanan, Paul J, McNally, Paul, Harvey, Brian J, Urbach, Valerie
• Format: Journal Article
• Language: English
• Published: United States 15-07-2013
• Subjects: Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Cell Line, Transformed; Cell Proliferation - drug effects; Cystic Fibrosis - genetics; Cystic Fibrosis - metabolism; Cystic Fibrosis - pathology; Cystic Fibrosis - therapy; Epithelial Cells - metabolism; Epithelial Cells - pathology; Flavonoids - pharmacology; Glyburide - pharmacology; Humans; Hypoglycemic Agents - pharmacology; KATP Channels - biosynthesis; KATP Channels - genetics; Lipoxins - pharmacology; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Phosphorylation - drug effects; Phosphorylation - genetics; Protein Kinase Inhibitors - pharmacology; Receptors, Formyl Peptide - agonists; Receptors, Formyl Peptide - genetics; Receptors, Formyl Peptide - metabolism; Receptors, Lipoxin - agonists; Receptors, Lipoxin - genetics; Receptors, Lipoxin - metabolism; Respiratory Mucosa - metabolism; Respiratory Mucosa - pathology; epithelial repair; lipoxin; ATP-sensitive potassium channels; cystic fibrosis
• ISSN: 1522-1504
• DOI: 10.1152/ajplung.00058.2013

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.