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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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Levels of 8-hydroxy-2′ deoxyguanosine (8-OHdG) in the lungs after hemorrhagic shock and resuscitation (HSR).Lungs from the HSR group rats treated with or without biliverdin (BV) were excised 3 h after resuscitation and mitochondrial 8-OHdG levels were measured. Data are presented as means ± standard deviation (n = 5 per group). Statistical analysis was performed using analysis of variance followed by Tukey–Kramer honestly significant difference test. *p<0.05 vs. vehicle/sham; †p<0.05 vs. BV/sham; #p<0.05 vs. vehicle/HSR. Vehicle/sham, vehicle-administered animals subjected to sham surgery; BV/sham, BV-administered animals subjected to sham surgery; vehicle/HSR, vehicle-administered animals subjected to HSR; BV/HSR, BV-administered animals subjected to HSR.
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pone-0063606-g005: Levels of 8-hydroxy-2′ deoxyguanosine (8-OHdG) in the lungs after hemorrhagic shock and resuscitation (HSR).Lungs from the HSR group rats treated with or without biliverdin (BV) were excised 3 h after resuscitation and mitochondrial 8-OHdG levels were measured. Data are presented as means ± standard deviation (n = 5 per group). Statistical analysis was performed using analysis of variance followed by Tukey–Kramer honestly significant difference test. *p<0.05 vs. vehicle/sham; †p<0.05 vs. BV/sham; #p<0.05 vs. vehicle/HSR. Vehicle/sham, vehicle-administered animals subjected to sham surgery; BV/sham, BV-administered animals subjected to sham surgery; vehicle/HSR, vehicle-administered animals subjected to HSR; BV/HSR, BV-administered animals subjected to HSR.

Mentions: To examine oxidative DNA damage, we measured 8-OHdG levels in lung tissue and performed immunohistochemical analysis. HSR increased mitochondrial 8-OHdG levels in the lung by 1.5-fold compared with sham surgery (Fig. 5). BV administration before HSR significantly decreased mitochondrial 8-OHdG levels to almost the same level as that in the sham groups (Fig. 5). According to immunohistochemistry, 8-OHdG-positive cells were negligibly detected in the sham groups (Fig. 6A and I). However, strong positive signals (green color) for 8-OHdG were predominantly observed in the pulmonary interstitium of the HSR groups (Fig. 6C and K). In contrast, BV administration quenched 8-OHdG signals in the lungs of animals in the HSR groups (Fig. 6D and L). These results revealed that BV administration significantly inhibited HSR-induced oxidative DNA damage.


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)

Levels of 8-hydroxy-2′ deoxyguanosine (8-OHdG) in the lungs after hemorrhagic shock and resuscitation (HSR).Lungs from the HSR group rats treated with or without biliverdin (BV) were excised 3 h after resuscitation and mitochondrial 8-OHdG levels were measured. Data are presented as means ± standard deviation (n = 5 per group). Statistical analysis was performed using analysis of variance followed by Tukey–Kramer honestly significant difference test. *p<0.05 vs. vehicle/sham; †p<0.05 vs. BV/sham; #p<0.05 vs. vehicle/HSR. Vehicle/sham, vehicle-administered animals subjected to sham surgery; BV/sham, BV-administered animals subjected to sham surgery; vehicle/HSR, vehicle-administered animals subjected to HSR; BV/HSR, BV-administered animals subjected to HSR.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0063606-g005: Levels of 8-hydroxy-2′ deoxyguanosine (8-OHdG) in the lungs after hemorrhagic shock and resuscitation (HSR).Lungs from the HSR group rats treated with or without biliverdin (BV) were excised 3 h after resuscitation and mitochondrial 8-OHdG levels were measured. Data are presented as means ± standard deviation (n = 5 per group). Statistical analysis was performed using analysis of variance followed by Tukey–Kramer honestly significant difference test. *p<0.05 vs. vehicle/sham; †p<0.05 vs. BV/sham; #p<0.05 vs. vehicle/HSR. Vehicle/sham, vehicle-administered animals subjected to sham surgery; BV/sham, BV-administered animals subjected to sham surgery; vehicle/HSR, vehicle-administered animals subjected to HSR; BV/HSR, BV-administered animals subjected to HSR.
Mentions: To examine oxidative DNA damage, we measured 8-OHdG levels in lung tissue and performed immunohistochemical analysis. HSR increased mitochondrial 8-OHdG levels in the lung by 1.5-fold compared with sham surgery (Fig. 5). BV administration before HSR significantly decreased mitochondrial 8-OHdG levels to almost the same level as that in the sham groups (Fig. 5). According to immunohistochemistry, 8-OHdG-positive cells were negligibly detected in the sham groups (Fig. 6A and I). However, strong positive signals (green color) for 8-OHdG were predominantly observed in the pulmonary interstitium of the HSR groups (Fig. 6C and K). In contrast, BV administration quenched 8-OHdG signals in the lungs of animals in the HSR groups (Fig. 6D and L). These results revealed that BV administration significantly inhibited HSR-induced oxidative DNA damage.

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