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

Abstract

Buchanan PJ, McNally P, Harvey BJ, Urbach V. Lipoxin A4-mediated K ATP potassium channel activation results in cystic fibrosis airway epithelial repair. Am J Physiol Lung Cell Mol Physiol 305: L193-L201, 2013. First published May 17, 2013 doi:10.1152/ajplung.00058.2013The 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 LXA 4 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, K ATP 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.

FPR2/ALXR Agonists and the Resolution of Inflammation

“…It was shown that LXA 4 triggered an increase in migration, proliferation, and wound repair of both non-CF and CF airway epithelia. 215 The fact that these responses were completely abolished by FPR2/ALXR antagonists and FPR2/ ALXR siRNA suggests that providing FPR2/ALXR agonists to CF patients might be a potential therapeutic approach.…”

CFTR and lung homeostasis

“…In the present studies, Buchanan et al (10) show that LXA 4 increases cell proliferation and migration and wound healing in CF airway cultures and stimulates ATPactivated potassium (K ATP ) currents to enhance epithelial repair (10). They suggest that this anti-inflammatory response attenuation would be therapeutic in helping to block the lung damage and thereby stabilize lung function (10).…”

“…There is a cumulative damage to the lungs in CF over time because of the chronic bacterial infections and continuous inflammatory responses (10). To test whether epithelial repair could be stimulated with an anti-inflammatory mediator, Buchanan et al (10) tested whether lipoxin A 4 (LXA 4 ), an eicosanoid formed from arachidonic acid, is beneficial in CF by suppressing the inflammatory damage to the lungs.…”

“…To test whether epithelial repair could be stimulated with an anti-inflammatory mediator, Buchanan et al (10) tested whether lipoxin A 4 (LXA 4 ), an eicosanoid formed from arachidonic acid, is beneficial in CF by suppressing the inflammatory damage to the lungs. Lipoxins have been proposed as therapeutics in asthma lung inflammation (6).…”

Modulation of the Activities of Neuronal Ion Channels by Fatty Acid-Derived Pro-Resolvents

“…Lipoxins have been shown to promote the activity and/or expression of many different types of ion channels including epithelial Na + channels, cystic fibrosis transmembrane conductance regulators, ATP-sensitive K + channels, Ca 2+ -activated anion channels, pannexin 1 hemichannels, and canonical subtype of TRP channels (TRPCs). These effects lead to beneficial outcomes with respect to fluid secretion in the airway (Pang et al, 2011; Verriere et al, 2012; Buchanan et al, 2013; Wang et al, 2013; Yang et al, 2013; Al-Alawi et al, 2014; Higgins et al, 2014, 2015; Qi et al, 2015). Recent studies showing similarly beneficial effects from treatment of other n−3 type pro-resolvents have also emerged in the airway field (Hiram et al, 2014; Wang et al, 2014; Colby et al, 2016).…”