BML-111 attenuates acute lung injury in endotoxemic mice.

Abstract

BACKGROUND:

BML-111 is a lipoxin receptor agonist that has protective effects in various lung injury models. We tried to elucidate whether BML-111 could mitigate lung injury in a mouse model of endotoxemia and endothelial hyperpermeability in vitro.

METHODS:

The effect of BML-111 on lung injury was evaluated using C57BL/6 mice and human umbilical vein endothelial cells (HUVECs). Male C57BL/6 mice were intraperitoneally injected with normal saline, BML-111, and/or the lipoxin receptor antagonist Boc-2. Then, either lipopolysaccharide (LPS) or normal saline was given intraperitoneally. Lung injury was assessed by a pathohistologic examination for neutrophil infiltration, pulmonary endothelial permeability, and inflammatory cytokines in lung tissue and bronchoalveolar lavage fluid. HUVECs were treated with or without BML-111 before incubation with LPS for 24 h. Boc-2 was also tested as a novel inhibitor of BML-111. A Transwell assay was used to evaluate the permeability of HUVECs. Junction protein expression was also assessed.

RESULTS:

BML-111 significantly improved the mouse survival rate, reduced body weight loss, attenuated the pulmonary pathologic changes, inhibited neutrophil infiltration and proinflammatory cytokine production, and mitigated endothelial hyperpermeability. The decreased expression of junction proteins induced by LPS in lung tissue and endothelial cells were upregulated by BML-111. In addition, BML-111 inhibited the activation of the Akt, ERK1/2, and p38 MAPK signaling pathways. However, the beneficial effects of BML-111 were abolished by Boc-2.

CONCLUSIONS:

BML-111 attenuated lung injury in endotoxemic mice and mitigated endothelial hyperpermeability by upregulating the expression of junction proteins.

• Authors: Min Tang, Lin Chen, Bo Li, Yaxin Wang, Shengnan Li, Aiqing Wen, Shanglong Yao, You Shang
• Journal: The Journal of surgical research (J Surg Res) Vol. 200 Issue 2 Pg. 619-30 (Feb 2016) ISSN: 1095-8673 [Electronic] United States
• PMID: 26432471 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• 5(S),6(R)-7-trihydroxyheptanoic acid, methyl ester
• Biomarkers
• Heptanoic Acids
• Lipopolysaccharides
• Protective Agents
• Tight Junction Proteins

Topics

• Acute Lung Injury (metabolism, mortality, prevention & control)
• Animals
• Biomarkers (metabolism)
• Capillary Permeability (drug effects)
• Endothelium, Vascular (drug effects, metabolism)
• Endotoxemia (complications, metabolism)
• Heptanoic Acids (pharmacology, therapeutic use)
• Human Umbilical Vein Endothelial Cells (drug effects, metabolism)
• Humans
• Injections, Intraperitoneal
• Lipopolysaccharides
• Male
• Mice
• Mice, Inbred C57BL
• Protective Agents (pharmacology, therapeutic use)
• Random Allocation
• Tight Junction Proteins (metabolism)
• Up-Regulation (drug effects)