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: Hong-Bin Li, Guang-Zhi Wang, Jie Gong, Zhou-Yang Wu, Si Guo, Bo Li, Mei Liu, Yu-Dong Ji, Min Tang, Shi-Ying Yuan, You Shang, Shang-Long Yao
• Journal: The Journal of surgical research (J Surg Res) Vol. 183 Issue 2 Pg. 710-9 (Aug 2013) ISSN: 1095-8673 [Electronic] United States
• PMID: 23558258 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• 5(S),6(R)-7-trihydroxyheptanoic acid, methyl ester
• Heptanoic Acids
• Interleukin-1beta
• Interleukin-6
• Oligopeptides
• Receptors, Lipoxin
• Transcription Factor AP-1
• lipoxin A(4) receptor, rat
• butyloxycarbonyl-phenylalanyl-leucyl-phenylalanyl-leucyl-phenylalanine
• Mitogen-Activated Protein Kinase Kinases

Topics

• Acute Lung Injury (etiology, metabolism, prevention & control)
• Animals
• Disease Models, Animal
• Heptanoic Acids (pharmacology, therapeutic use)
• Interleukin-1beta (metabolism)
• Interleukin-6 (metabolism)
• Lung (drug effects, metabolism, pathology)
• Male
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors, drug effects, physiology)
• Oligopeptides (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Lipoxin (agonists, antagonists & inhibitors, drug effects)
• Shock, Hemorrhagic (complications)
• Signal Transduction (drug effects, physiology)
• Transcription Factor AP-1 (antagonists & inhibitors, drug effects, physiology)