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Effects of biliverdin administration on acute lung injury induced by hemorrhagic shock and resuscitation in rats.

Kosaka J, Morimatsu H, Takahashi T, Shimizu H, Kawanishi S, Omori E, Endo Y, Tamaki N, Morita M, Morita K - PLoS ONE (2013)

Bottom Line: Biliverdin, a metabolite of heme catabolism, has been shown to have potent cytoprotective, anti-inflammatory, and anti-oxidant effects.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

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.

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Effect of BV administration after hemorrhagic shock and resuscitation (HSR) in the lungs.The rats were randomly divided into two groups: a HSR/Vehicle group, which was administered vehicle after HSR, and a HSR/BV group, which was administered BV after HSR. BV (35 mg/kg) or vehicle was injected via the femoral vein after resuscitation. (A) Representative images from five independent experiments (hematoxylin–eosin staining, original magnification ×200, scale bar  = 100 µm). (B) lung histopathological score 12 h after HSR. (C) Mitochondrial 8-OHdG levels in the lungs 3 h after HSR. Data are presented as means ± standard deviation (n = 5 per group). Statistical analysis was performed using Student’s t-test. *p<0.05 vs. HSR/Vehicle.
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pone-0063606-g007: Effect of BV administration after hemorrhagic shock and resuscitation (HSR) in the lungs.The rats were randomly divided into two groups: a HSR/Vehicle group, which was administered vehicle after HSR, and a HSR/BV group, which was administered BV after HSR. BV (35 mg/kg) or vehicle was injected via the femoral vein after resuscitation. (A) Representative images from five independent experiments (hematoxylin–eosin staining, original magnification ×200, scale bar  = 100 µm). (B) lung histopathological score 12 h after HSR. (C) Mitochondrial 8-OHdG levels in the lungs 3 h after HSR. Data are presented as means ± standard deviation (n = 5 per group). Statistical analysis was performed using Student’s t-test. *p<0.05 vs. HSR/Vehicle.

Mentions: To enhance clinical significance of our findings, we assessed the protective effects of BV administration after resuscitation. In histological examinations, HSR-induced lung injury appeared to be improved by BV administration (Fig. 7A), although the difference in the histopathological score did not reach statistical significance (Fig. 7B). However, mitochondrial 8-OHdG, a marker DNA oxidative damage, was significantly reduced by the administration of BV even after HSR (Fig. 7C).


Effects of biliverdin administration on acute lung injury induced by hemorrhagic shock and resuscitation in rats.

Kosaka J, Morimatsu H, Takahashi T, Shimizu H, Kawanishi S, Omori E, Endo Y, Tamaki N, Morita M, Morita K - PLoS ONE (2013)

Effect of BV administration after hemorrhagic shock and resuscitation (HSR) in the lungs.The rats were randomly divided into two groups: a HSR/Vehicle group, which was administered vehicle after HSR, and a HSR/BV group, which was administered BV after HSR. BV (35 mg/kg) or vehicle was injected via the femoral vein after resuscitation. (A) Representative images from five independent experiments (hematoxylin–eosin staining, original magnification ×200, scale bar  = 100 µm). (B) lung histopathological score 12 h after HSR. (C) Mitochondrial 8-OHdG levels in the lungs 3 h after HSR. Data are presented as means ± standard deviation (n = 5 per group). Statistical analysis was performed using Student’s t-test. *p<0.05 vs. HSR/Vehicle.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3646791&req=5

pone-0063606-g007: Effect of BV administration after hemorrhagic shock and resuscitation (HSR) in the lungs.The rats were randomly divided into two groups: a HSR/Vehicle group, which was administered vehicle after HSR, and a HSR/BV group, which was administered BV after HSR. BV (35 mg/kg) or vehicle was injected via the femoral vein after resuscitation. (A) Representative images from five independent experiments (hematoxylin–eosin staining, original magnification ×200, scale bar  = 100 µm). (B) lung histopathological score 12 h after HSR. (C) Mitochondrial 8-OHdG levels in the lungs 3 h after HSR. Data are presented as means ± standard deviation (n = 5 per group). Statistical analysis was performed using Student’s t-test. *p<0.05 vs. HSR/Vehicle.
Mentions: To enhance clinical significance of our findings, we assessed the protective effects of BV administration after resuscitation. In histological examinations, HSR-induced lung injury appeared to be improved by BV administration (Fig. 7A), although the difference in the histopathological score did not reach statistical significance (Fig. 7B). However, mitochondrial 8-OHdG, a marker DNA oxidative damage, was significantly reduced by the administration of BV even after HSR (Fig. 7C).

Bottom Line: Biliverdin, a metabolite of heme catabolism, has been shown to have potent cytoprotective, anti-inflammatory, and anti-oxidant effects.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

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.

Show MeSH
Related in: MedlinePlus