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

Medicine

Journal of Gerontology & Geriatric Research

Author(s): Buchanan PJ, McNally P, Harvey BJ, Urbach V

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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. This article was published in Am J Physiol Lung Cell Mol Physiol and referenced in Journal of Gerontology & Geriatric Research

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