Abstract
The widespread use of statins for hypercholesterolemia has uncovered pleiotropic anti-inflammatory properties that were unexpected based on the drugs' original design; yet, mechanisms for these protective actions remain uncertain. In this study lovastatin triggered biosynthesis of the anti-inflammatory and pro-resolving mediator 15-epi-lipoxin A4 (15-epi-LXA4). During interactions between human neutrophils and airway epithelial cells, the statin-induced increase in 15-epi-LXA4 was associated with increased 14,15-epoxyeicosatrienoic acid (14,15-EET) generation. When added to activated neutrophils, 14,15-EET enhanced 15-epi-LXA4 biosynthesis. In a murine model of airway mucosal injury and inflammation, lovastatin increased 15-epi-LXA4 formation in vivo and markedly decreased acute lung inflammation. Administration of 15-epi-LXA4 also inhibited lung inflammation in an additive manner with lovastatin. Together, these results indicate that statin-triggered 15-epi-LXA4 generation during human leukocyte–airway epithelial cell interactions is an endogenous mechanism for statin-mediated tissue protection at mucosal surfaces that may also be relevant in the statins' ability to stimulate the resolution of inflammation.
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