PLOS ONE_8_5_e63606.pdf 6.7 MB
Kosaka, Junko Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci
Takahashi, Toru Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci
Shimizu, Hiroko Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci
Kawanishi, Susumu Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci
Omori, Emiko Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci
Endo, Yasumasa Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Prevent Dent
Tamaki, Naofumi Univ Tokushima, Grad Sch, Dept Prevent Dent, Inst Hlth Biosci
Morita, Manabu Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Prevent Dent Kaken ID researchmap
Morita, Kiyoshi Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci
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-alpha 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.
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© 2013 Kosaka et al.
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