Lipoxin Armediated Katp potassium channel activation results in cystic fibrosis airway epithelial repair.

摘要

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 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 K_(ATP) channel inhibitor, glibenclamide, blocked the responses to LXA_4. LXA4 did not affect potassium channel expression but significantly upregulated glibenclamide-sensitive (K_(ATP)) currents through the ba-solateral 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.