Aspirin-triggered resolvin D1 reduces mucosal inflammation and promotes resolution in a murine model of acute lung injury.
Acute lung injury (ALI) is a severe illness with excess mortality and no specific therapy. Protective actions were recently uncovered for docosahexaenoic acid-derived mediators, including D-series resolvins. Here, we used a murine self-limited model of hydrochloric acid-induced ALI to determine the effects of aspirin-triggered resolvin D1 (AT-RvD1; 7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid) on mucosal injury. RvD1 and its receptor ALX/FPR2 were identified in murine lung after ALI. AT-RvD1 (~0.5-5 μg kg(-1)) decreased peak inflammation, including bronchoalveolar lavage fluid (BALF) neutrophils by ~75%. Animals treated with AT-RvD1 had improved epithelial and endothelial barrier integrity and decreased airway resistance concomitant with increased BALF epinephrine levels. AT-RvD1 inhibited neutrophil-platelet heterotypic interactions by downregulating both P-selectin and its ligand CD24. AT-RvD1 also significantly decreased levels of BALF pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, Kupffer cells, and tumor necrosis factor-α, and decreased nuclear factor-κB-phosphorylated p65 nuclear translocation. Taken together, these findings indicate that AT-RvD1 displays potent mucosal protection and promotes catabasis after ALI.
Pulmonary and Critical Care Medicine, Department of Internal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
O
O
Eickmeier
H
H
Seki
O
O
Haworth
J N
JN
Hilberath
F
F
Gao
M
M
Uddin
R H
RH
Croze
T
T
Carlo
M A
MA
Pfeffer
B D
BD
Levy
D055371:Acute Lung Injury / Q000378:metabolism* / Q000473:pathology*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000403:Airway Resistance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology*; D001792:Blood Platelets / Q000378:metabolism; D015824:Blood-Air Barrier / Q000503:physiopathology; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000096:biosynthesis / Q000378:metabolism*; D004837:Epinephrine / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000276:immunology; D011654:Pulmonary Edema / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D044042:Receptors, Formyl Peptide / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology; D051996:Transcription Factor RelA / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000894:Anti-Inflammatory Agents, Non-Steroidal; C509871:HSH2 protein, mouse; D018836:Inflammation Mediators; D044042:Receptors, Formyl Peptide; D051996:Transcription Factor RelA; C481578:formyl peptide receptor 2, mouse; C518399:resolvin D1; D004281:Docosahexaenoic Acids; C062894:17-hydroxy-4,7,10,13,15,19-docosahexaenoic acid; D001241:Aspirin; D004837:Epinephrine