title: Effects of biliverdin administration on acute lung injury induced by hemorrhagic shock and resuscitation in rats.
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.
authors.affiliation: Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Kosaka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Morimatsu
authors.forename: Toru
authors.initials: T
authors.lastname: Takahashi
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shimizu
authors.forename: Susumu
authors.initials: S
authors.lastname: Kawanishi
authors.forename: Emiko
authors.initials: E
authors.lastname: Omori
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Endo
authors.forename: Naofumi
authors.initials: N
authors.lastname: Tamaki
authors.forename: Manabu
authors.initials: M
authors.lastname: Morita
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Morita
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D055371:Acute Lung Injury / Q000097:blood / Q000188:drug therapy* / Q000209:etiology*; D000818:Animals; D051402:Aquaporin 5 / Q000378:metabolism; D001663:Bilirubin / Q000097:blood; D001664:Biliverdine / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D011654:Pulmonary Edema / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000097:blood / Q000150:complications*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D051402:Aquaporin 5; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D000080242:8-Hydroxy-2'-Deoxyguanosine; D052247:Nitric Oxide Synthase Type II; D003849:Deoxyguanosine; D001664:Biliverdine; D001663:Bilirubin