Lovastatin decreases acute mucosal inflammation via 15-epi-lipoxin A4.
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 A(4) (15-epi-LXA(4)). During interactions between human neutrophils and airway epithelial cells, the statin-induced increase in 15-epi-LXA(4) was associated with increased 14,15-epoxyeicosatrienoic acid (14,15-EET) generation. When added to activated neutrophils, 14,15-EET enhanced 15-epi-LXA(4) biosynthesis. In a murine model of airway mucosal injury and inflammation, lovastatin increased 15-epi-LXA(4) formation in vivo and markedly decreased acute lung inflammation. Administration of 15-epi-LXA(4) also inhibited lung inflammation in an additive manner with lovastatin. Together, these results indicate that statin-triggered 15-epi-LXA(4) 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.
Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
A
A
Planagumà
M A
MA
Pfeffer
G
G
Rubin
R
R
Croze
M
M
Uddin
C N
CN
Serhan
B D
BD
Levy
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000276:immunology / Q000378:metabolism; D000208:Acute Disease; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000276:immunology* / Q000378:metabolism; D044045:Lipoxins / Q000276:immunology* / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D011014:Pneumonia / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism
D000924:Anticholesteremic Agents; D018836:Inflammation Mediators; D044045:Lipoxins; C040527:lipoxin A4; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D008148:Lovastatin; D015126:8,11,14-Eicosatrienoic Acid