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.
Planagumà
A
A
Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Pfeffer
M A
MA
Rubin
G
G
Croze
R
R
Uddin
M
M
Serhan
C N
CN
Levy
B D
BD
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