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BML-111Attennuates Hemorrhagic Shock-inducedaute Lung Injury through Inhibiting Activation of MAPK Pathway in Rat

Author: WangGuangZhi
Tutor: YaoShangLong
School: Huazhong University of Science and Technology
Course: Anesthesiology
Keywords: BML-111 hemorrhagic shock acute lung injury inflammation MAPK
CLC: R459.7
Type: Master's thesis
Year: 2013
Downloads: 5
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Abstract

Objective Hemorrhagic shock activates cellular stress signals and can lead to systemicinflammatory response, organ injury, and death. Mitogen activated protein kinase (MAPK)act as sensors of tissue injury in models of ischemia/reperfusion (I/R) injury. Lipoxins (LXs)are endogenous lipid mediators with potent anti-infiammatory and pro-resolving actions.BML-111, a lipoxinA4-receptor agonist, promotes acute inflammatory resolution. Wehypothesized that BML-111attenuates hemorrhagic shock-induced acute lung injurythrough inhibiting activation of MAPK/AP-1pathway.Methods Pentobarbital-anesthetized male Sprague-Dawley rats were randomized into fourgroups：sham group, hemorrhagic shock/resuscitation group (HS group), BML-111treatment group(BML-111group), and BML-111plus BOC-2treatment group (BOC-2group). The left femoral artery was cannulated for monitoring mean arterial pressure andblood withdrawal, the right jugular vein was cannulated for resuscitation. Rats werehemorrhaged35%of total blood volume over10min via common carotid artery, followedby unresuscitated shock for30min. Rats were resuscitated by infusion of shed blood andtwo-fold volume saline. Resuscitation was completed in30min. Rats were resuscitatedby transfusion of the withdrawn blood and isotonic sodium chloride solution equivalent totwice the withdrawn of blood volume．Rats in the sham group underwent all surgicalprocedures, but they were not subjected to hemorrhage and resuscitation. In BML-111group and BOC-2group, BML-111(1mg/kg, intraperitoneally) was given at the beginningof resuscitation. Animals in BOC-2group received BOC-2(50μg/kg, intraperitoneally)after anesthesia. Rats were sacrficed at2h after completion of resuscitation. The left lungs were lavaged three times with2.5ml of ice-cold lavage buffer for bronchoalveolar lavagefluid. The right lung was clamped at the level of the mainstem bronchus, excised, rinsedwith cold phosphate buffered saline, for lung W/D ratio, histological analysis or frozen inliquid nitrogen and stored at–80°C for further research．Lung histology was examined byhaematoxylin and eosin staining. myeloperoxidase expression were measured byImmunohistochemistry.Content of IL-1β and IL-6in lung tissue were measured by ELISA.Cytosol content of phosphorylation of ERK, p38MAPK and JNK in the lung were mesuredby immunoblot analyses. The DNA binding activity of activator protein-1(AP-1) wasevaluated by electrophoretic mobility shift assays (EMSA).Rresults MAP in the sham group remained stable throughout the experiment. There wasno obvious significance among HS, BML-111and BOC-2groups. No significant tissuesdamage was observed in the sham group.Lung tissues from HS group were significantlydamaged with infiltration of inflammatory cells into interstitium and alveolar spaces,proteinaceous debris flling the airspaces, hyaline membrane deposition, thickening of thealveolar wall. W/D ratio, neutrophils count in BALF, pulmonary myeloperoxidaselevel,production of IL-1β and IL-6in lung, phosphorylation of MAPK and AP-1/DNAbinding activity were all upregulated in HS group incomparison with sham group.Treatment with BML-111reduced the lung damage and W/D ratio, neutrophils count inBALF,MPO level and production of IL-1β and IL-6in lung. Phosphorylation of MAPK andAP-1/DNA binding activity were also decreased by BML-111in lung. An antagonist of thelipoxinA4-receptor, reversed the protective effect of BML-111on the ALI induced byhemorrhagic shock.Conclusion This study indicates that BML-111inhibits inflammatory cytokineproduction at least in part via ERK, p38MAPK, JNK signaling pathways in hemorrhagicshock-induced acute lung injury. Therefore, BML-111may have therapeutic potential forhemorrhagic shock-induced acute lung injury.

BML-111Attennuates Hemorrhagic Shock-inducedaute Lung Injury through Inhibiting Activation of MAPK Pathway in Rat

Abstract

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