title: BML-111 attenuates hemorrhagic shock-induced acute lung injury through inhibiting activation of mitogen-activated protein kinase pathway in rats.
abstract: BACKGROUND
  Hemorrhagic shock activates cellular stress signals and can lead to systemic inflammatory response, organ injury, and death. Mitogen-activated protein kinase (MAPK) acts as a sensor of tissue injury in models of ischemia-reperfusion injury. Lipoxins are endogenous lipid mediators with potent anti-inflammatory and pro-resolving actions. We hypothesized that BML-111 (a lipoxin A4-receptor agonist) attenuates hemorrhagic shock-induced acute lung injury (ALI) through inhibiting activation of the MAPK pathway.
  
  
  METHODS
  We randomized Sprague-Dawley rats into four groups: sham, hemorrhagic shock-resuscitation (HS), HS plus BML-111 (BML-111), and HS plus BML-111 and BOC-2 (BOC-2). Two hours after resuscitation, we collected samples of lung. We obtained bronchoalveolar lavage fluid for neutrophil count. We performed optical microscopy to examine pathologic changes in lungs. Wet/dry ratios, myeloperoxidase expression, interleukin (IL)-1β and IL-6 levels in lung were measured. We evaluated MAPK activation and the DNA binding activity of activator protein-1 in lung.
  
  
  RESULTS
  Treatment with BML-111 reduced the lung damage and wet/dry ratio, neutrophil count in bronchoalveolar lavage fluid, expression of myeloperoxidase, and production of IL-1β and IL-6 in lung. Phosphorylation of MAPK was also decreased by BML-111 in lung. Furthermore, the DNA binding activity of activator protein-1 was blocked by BML-111. An antagonist of the lipoxin A4-receptor, BOC-2, reversed the protective effect of BML-111 on ALI induced by hemorrhagic shock.
  
  
  CONCLUSIONS
  This study indicates that BML-111 attenuated hemorrhagic shock-induced ALI via the MAPK/activator protein-1 signaling pathway. Therefore, BML-111 may have therapeutic potential for hemorrhagic shock-induced ALI.
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: Hong-Bin
authors.initials: HB
authors.lastname: Li
authors.forename: Guang-Zhi
authors.initials: GZ
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Gong
authors.forename: Zhou-Yang
authors.initials: ZY
authors.lastname: Wu
authors.forename: Si
authors.initials: S
authors.lastname: Guo
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.forename: Yu-Dong
authors.initials: YD
authors.lastname: Ji
authors.forename: Min
authors.initials: M
authors.lastname: Tang
authors.forename: Shi-Ying
authors.initials: SY
authors.lastname: Yuan
authors.forename: You
authors.initials: Y
authors.lastname: Shang
authors.forename: Shang-Long
authors.initials: SL
authors.lastname: Yao
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D004195:Disease Models, Animal; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044067:Receptors, Lipoxin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects; D012771:Shock, Hemorrhagic / Q000150:complications*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology
chemical_list: C530770:5(S),6(R)-7-trihydroxyheptanoic acid, methyl ester; D006538:Heptanoic Acids; D053583:Interleukin-1beta; D015850:Interleukin-6; D009842:Oligopeptides; D044067:Receptors, Lipoxin; D018808:Transcription Factor AP-1; C482540:lipoxin A(4) receptor, rat; C033373:butyloxycarbonyl-phenylalanyl-leucyl-phenylalanyl-leucyl-phenylalanine; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Acute lung injury; BML-111; Hemorrhagic shock; Inflammation; MAPK