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

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 A(4) (LXA(4)) have been reported to be reduced in bronchoalveolar lavages of patients with CF. We investigated the ability of LXA(4) 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). LXA(4) 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 K-ATP channel opener pinacidil mimicked the LXA(4) effect on migration, proliferation, and epithelial repair, whereas the K-ATP channel inhibitor, glibenclamide, blocked the responses to LXA(4). LXA(4) did not affect potassium channel expression but significantly upregulated glibenclamide-sensitive (K-ATP) currents through the basolateral membrane of NuLi-1 and CuFi-1 cells. MAP kinase (ERK1/2) inhibitor, PD98059, also inhibited the LXA(4)-induced proliferation of NuLi-1 and CuFi-1 cells. Finally, both LXA(4) and pinacidil stimulated ERK-MAP kinase phosphorylation, whereas the effect of LXA(4) on ERK phosphorylation was inhibited by glibenclamide. Taken together, our results provided evidence for a role of LXA(4) 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 LXA(4), restoring levels in patients with CF, perhaps as a potential therapeutic strategy.