Effects of Biliverdin Administration on Acute Lung Injury Induced by Hemorrhagic Shock and Resuscitation in Rats

Yasumasa Endo,Manabu Morita,Hiroko Shimizu,Naofumi Tamaki,Hiroshi Morimatsu,Emiko Omori,Toru Takahashi,Junko Kosaka,Susumu Kawanishi,Kiyoshi Morita

doi:10.1371/journal.pone.0063606

Yasumasa Endo, Manabu Morita + Show 8 more

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https://doi.org/10.1371/journal.pone.0063606

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Abstract

Hemorrhagic shock and resuscitation induces pulmonary inflammation that leads to acute lung injury. Biliverdin, a metabolite of heme catabolism, has been shown to have potent cytoprotective, anti-inflammatory, and anti-oxidant effects. This study aimed to examine the effects of intravenous biliverdin administration on lung injury induced by hemorrhagic shock and resuscitation in rats. Biliverdin or vehicle was administered to the rats 1 h before sham or hemorrhagic shock-inducing surgery. The sham-operated rats underwent all surgical procedures except bleeding. To induce hemorrhagic shock, rats were bled to achieve a mean arterial pressure of 30 mmHg that was maintained for 60 min, followed by resuscitation with shed blood. Histopathological changes in the lungs were evaluated by histopathological scoring analysis. Inflammatory gene expression was determined by Northern blot analysis, and oxidative DNA damage was assessed by measuring 8-hydroxy-2′ deoxyguanosine levels in the lungs. Hemorrhagic shock and resuscitation resulted in prominent histopathological damage, including congestion, edema, cellular infiltration, and hemorrhage. Biliverdin administration prior to hemorrhagic shock and resuscitation significantly ameliorated these lung injuries as judged by histopathological improvement. After hemorrhagic shock and resuscitation, inflammatory gene expression of tumor necrosis factor-α and inducible nitric oxide synthase were increased by 18- and 8-fold, respectively. Inflammatory gene expression significantly decreased when biliverdin was administered prior to hemorrhagic shock and resuscitation. Moreover, after hemorrhagic shock and resuscitation, lung 8-hydroxy-2' deoxyguanosine levels in mitochondrial DNA expressed in the pulmonary interstitium increased by 1.5-fold. Biliverdin administration prior to hemorrhagic shock and resuscitation decreased mitochondrial 8-hydroxy-2' deoxyguanosine levels to almost the same level as that in the control animals. We also confirmed that biliverdin administration after hemorrhagic shock and resuscitation had protective effects on lung injury. Our findings suggest that biliverdin has a protective role, at least in part, against hemorrhagic shock and resuscitation-induced lung injury through anti-inflammatory and anti-oxidant mechanisms.

Highlights

Hemorrhagic shock and resuscitation (HSR) causes a systematic inflammatory response that leads to multiple organ failure.[1,2] Acute lung injury (ALI) after HSR is a major cause of dysfunction in other organs because of the systemic release of inflammatory mediators.[3]
Effect of BV adminisitration on serum bilirubin levels It is well known that BV catalyzes to bilirubin by biliverdin reductase (BVR); we examined the effects of BV administration at various doses (0, 15, 35, 70, and 100 mg/kg) on serum bilirubin levels
We found that BV administration significantly decreased the gene expression of inflammatory mediators such as tumor necrosis factor (TNF)-a and inducible nitric oxide synthase (iNOS)

Summary

Introduction

Hemorrhagic shock and resuscitation (HSR) causes a systematic inflammatory response that leads to multiple organ failure.[1,2] Acute lung injury (ALI) after HSR is a major cause of dysfunction in other organs because of the systemic release of inflammatory mediators.[3]. Bilirubin is considered toxic in high concentrations because it exerts harmful effects on the central nervous system.[6] The antioxidant activity of bilirubin was shown in for the first time in the 1980s.[7] It is well known that the potent anti-oxidant action of bilirubin is amplified by the biliverdin (BV)/bilirubin redox cycle mediated by biliverdin reductase (BVR).[8] BVR converts BV to bilirubin, which is converted back into BV through the actions of reactive oxygen species (ROS). BV has been shown to play a cytoprotective role in various experimental models of oxidative tissue injury without abnormally elevating serum bilirubin levels.[9,10,11,12,13] In particular, it has been already shown that biliverdin administration improves acute lung injury induced by lipopolysaccharide (LPS).[13] protective effects of biliverdin administration should be determined in other settings to elucidate its mechanistic details

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