title: MARESIN 1 PREVENTS LIPOPOLYSACCHARIDE-INDUCED NEUTROPHIL SURVIVAL AND ACCELERATES RESOLUTION OF ACUTE LUNG INJURY.
abstract: Acute lung injury (ALI) is characterized by lung inflammation and diffuse infiltration of neutrophils. Neutrophil apoptosis is recognized as an important control point in the resolution of inflammation. Maresin 1 (MaR1) is a new docosahexaenoic acid-derived proresolving agent that promotes the resolution of inflammation. However, its function in neutrophil apoptosis is unknown. In this study, isolated human neutrophils were incubated with MaR1, the pan-caspase inhibitor z-VAD-fmk, and lipopolysaccharide (LPS) to determine the mechanism of neutrophil apoptosis. Acute lung injury was induced by intratracheal instillation of LPS. In addition, mice were treated with MaR1 intravenously at the peak of inflammation and administered z-VAD-fmk intraperitoneally. We found that culture of isolated human neutrophils with LPS dramatically delayed neutrophil apoptosis through the phosphorylation of AKT, ERK, and p38 to upregulate the expression of the antiapoptotic proteins Mcl-1 and Bcl-2, which was blocked by pretreatment with MaR1 in vitro. In mice, MaR1 accelerated the resolution of inflammation in LPS-induced ALI through attenuation of neutrophil accumulation, pathohistological changes, and pulmonary edema. Maresin 1 promoted resolution of inflammation by accelerating caspase-dependent neutrophil apoptosis. Moreover, MaR1 also reduced the LPS-induced production of proinflammatory cytokines and upregulated the production of the anti-inflammatory cytokine interleukin-10. In contrast, treatment with z-VAD-fmk inhibited the proapoptotic action of MaR1 and attenuated the protective effects of MaR1 in LPS-induced ALI. Taken together, MaR1 promotes the resolution of LPS-induced ALI by overcoming LPS-mediated suppression of neutrophil apoptosis.
authors.affiliation: *Department of Critical Care Medicine †Institute of Anesthesia and Critical Care, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Gong
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Hong
authors.initials: H
authors.lastname: Qi
authors.forename: Zhou-Yang
authors.initials: ZY
authors.lastname: Wu
authors.forename: Hua-Qing
authors.initials: HQ
authors.lastname: Shu
authors.forename: Hong-Bin
authors.initials: HB
authors.lastname: Li
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.forename: Ya-Xin
authors.initials: YX
authors.lastname: Wang
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.forename: Min
authors.initials: M
authors.lastname: Tang
authors.forename: Yu-Dong
authors.initials: YD
authors.lastname: Ji
authors.forename: Shi-Ying
authors.initials: SY
authors.lastname: Yuan
authors.forename: Shang-Long
authors.initials: SL
authors.lastname: Yao
authors.forename: You
authors.initials: Y
authors.lastname: Shang
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy* / Q000473:pathology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D061945:Caspase Inhibitors / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004281:Docosahexaenoic Acids / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D008297:Male; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C535211:7,14-dihydroxydocosa-4,8,10,12,16,19-hexaenoic acid; D000590:Amino Acid Chloromethyl Ketones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D061945:Caspase Inhibitors; D008070:Lipopolysaccharides; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D004281:Docosahexaenoic Acids