Effects of peripheral benzodiazepine receptor ligand Ro5-4864 in four animal models of acute lung injury

Abstract Background Acute lung injury (ALI) is a syndrome of inflammation and increased permeability of the blood–gas barrier. It is associated with high morbidity and mortality. Despite intensive research, treatments remain limited. The aim of the present study was to investigate the protective eff...

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Published in:The Journal of surgical research 2013-06, Vol.182 (2), p.277-284
Main Authors: Kaynar, Gulcan, MS, Yurdakan, Gamze, MD, Comert, Fusun, MD, Yilmaz-Sipahi, Emine, MD
Format: Article
Language:English
Subjects:
Acute lung injury
Acute Lung Injury - drug therapy
Acute Lung Injury - mortality
Acute Lung Injury - pathology
Animals
Benzodiazepinones - therapeutic use
Cecal ligation and puncture
Disease Models, Animal
GABA-A Receptor Agonists - therapeutic use
Lipopolysaccharide
Lipopolysaccharides - toxicity
Lung - pathology
Male
Mesenteric ischemia/reperfusion
Peripheral benzodiazepine receptor
Rats
Rats, Wistar
Receptors, GABA-A - physiology
Ro5-4864
Surgery
Survival Rate
Thiourea - analogs & derivatives
Thiourea - toxicity
α-Naphthylthiourea
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Summary:Abstract Background Acute lung injury (ALI) is a syndrome of inflammation and increased permeability of the blood–gas barrier. It is associated with high morbidity and mortality. Despite intensive research, treatments remain limited. The aim of the present study was to investigate the protective efficacy of a specific peripheral benzodiazepine receptor ligand, Ro5-4864, in experimental models of ALI in rats. Methods ALI was generated by four different methods: (1) intravenous (tail vein) injection of  Escherichia coli (0111:B4) lipopolysaccaride (LPS), (2) cecal ligation and puncture (CLP), (3) mesenteric ischemia/reperfusion, and (4) intraperitoneal injection of α-naphthylthiourea (ANTU). Ro5-4864 was administered to rats intraperitoneally 30 min before ANTU and LPS administration or intravenously 15 min before reperfusion and CLP. The levels of pulmonary edema (lung weight/body weight ratio) and pleural effusion were measured, and the severity of ALI was scored (0–3). Results Ro5-4864 showed a dose-dependent and significant prophylactic effect on the ANTU-induced lung weight/body weight and pleural effusion/body weight ratios and histopathologic scores. Ro5-4864 also showed significant prophylactic effects against the LPS-induced lung weight/body weight ratio and histopathologic scores. Ro5-4864 significantly decreased the intra-alveolar edema and perialveolar hemorrhage scores in the CLP group. However, we found no prophylactic effect of Ro5-4864 on mesenteric ischemia/reperfusion-induced ALI at the dose used (2 mg/kg intraperitoneally). Conclusions These results have demonstrated, for the first time, a protective effect of Ro5-4864 on experimental ALI induced by ANTU, LPS, and CLP. Ro5-4864 might be a useful therapeutic agent for lung diseases, including ALI, in intensive care patients.
ISSN:0022-4804
1095-8673
DOI:10.1016/j.jss.2012.10.023