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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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Lung histopathological changes after hemorrhagic shock and resuscitation (HSR).Lungs from the HSR group rats treated with or without biliverdin (BV) administration were excised 12 h after resuscitation and subjected to histological analysis. (A) Representative images from five independent experiments (hematoxylin–eosin staining, original magnification ×200, scale bar  = 100 µm). (B) The severity of histopathological changes in the lungs was graded for congestion, edema, inflammation, and hemorrhage. A total of 10 areas of lung parenchyma from each rat were graded as 0 (no findings or normal), 1 (mild), 2 (moderate), or 3 (severe) for each of the four parameters. (C) The sum of histopathological scores for the four parameters were calculated (n = 5 per group). Data are presented as means ± standard deviation and were statistically evaluated using analysis of variance followed by Tukey–Kramer honestly significant difference test. *p<0.01 vs. vehicle/sham; †p<0.01 vs. BV/sham; #p<0.01 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-g001: Lung histopathological changes after hemorrhagic shock and resuscitation (HSR).Lungs from the HSR group rats treated with or without biliverdin (BV) administration were excised 12 h after resuscitation and subjected to histological analysis. (A) Representative images from five independent experiments (hematoxylin–eosin staining, original magnification ×200, scale bar  = 100 µm). (B) The severity of histopathological changes in the lungs was graded for congestion, edema, inflammation, and hemorrhage. A total of 10 areas of lung parenchyma from each rat were graded as 0 (no findings or normal), 1 (mild), 2 (moderate), or 3 (severe) for each of the four parameters. (C) The sum of histopathological scores for the four parameters were calculated (n = 5 per group). Data are presented as means ± standard deviation and were statistically evaluated using analysis of variance followed by Tukey–Kramer honestly significant difference test. *p<0.01 vs. vehicle/sham; †p<0.01 vs. BV/sham; #p<0.01 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: Next we examined the effects of BV administration prior to HS induction on HSR-induced lung injury. Histopathological analysis indicated that the vehicle/HSR group developed interstitial edema as identified by pronounced alveolar septal thickening with marked infiltration of inflammatory cells 12 h after HSR. However, sections from the sham groups appeared normal (Fig. 1, A). In contrast, BV administration prior to HSR obviously mitigated these pathological changes, including congestion, edema, inflammation, and hemorrhage (Fig. 1, A and B). The significant effects of BV were also confirmed by the scoring of histopathologic changes by an independent researcher blinded to the treatment. BV administration greatly suppressed lung injury as evidenced by decreased histopathological damage confirmed by a decrease in the total histopathologic score (Fig. 1, C).


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)

Lung histopathological changes after hemorrhagic shock and resuscitation (HSR).Lungs from the HSR group rats treated with or without biliverdin (BV) administration were excised 12 h after resuscitation and subjected to histological analysis. (A) Representative images from five independent experiments (hematoxylin–eosin staining, original magnification ×200, scale bar  = 100 µm). (B) The severity of histopathological changes in the lungs was graded for congestion, edema, inflammation, and hemorrhage. A total of 10 areas of lung parenchyma from each rat were graded as 0 (no findings or normal), 1 (mild), 2 (moderate), or 3 (severe) for each of the four parameters. (C) The sum of histopathological scores for the four parameters were calculated (n = 5 per group). Data are presented as means ± standard deviation and were statistically evaluated using analysis of variance followed by Tukey–Kramer honestly significant difference test. *p<0.01 vs. vehicle/sham; †p<0.01 vs. BV/sham; #p<0.01 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-g001: Lung histopathological changes after hemorrhagic shock and resuscitation (HSR).Lungs from the HSR group rats treated with or without biliverdin (BV) administration were excised 12 h after resuscitation and subjected to histological analysis. (A) Representative images from five independent experiments (hematoxylin–eosin staining, original magnification ×200, scale bar  = 100 µm). (B) The severity of histopathological changes in the lungs was graded for congestion, edema, inflammation, and hemorrhage. A total of 10 areas of lung parenchyma from each rat were graded as 0 (no findings or normal), 1 (mild), 2 (moderate), or 3 (severe) for each of the four parameters. (C) The sum of histopathological scores for the four parameters were calculated (n = 5 per group). Data are presented as means ± standard deviation and were statistically evaluated using analysis of variance followed by Tukey–Kramer honestly significant difference test. *p<0.01 vs. vehicle/sham; †p<0.01 vs. BV/sham; #p<0.01 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: Next we examined the effects of BV administration prior to HS induction on HSR-induced lung injury. Histopathological analysis indicated that the vehicle/HSR group developed interstitial edema as identified by pronounced alveolar septal thickening with marked infiltration of inflammatory cells 12 h after HSR. However, sections from the sham groups appeared normal (Fig. 1, A). In contrast, BV administration prior to HSR obviously mitigated these pathological changes, including congestion, edema, inflammation, and hemorrhage (Fig. 1, A and B). The significant effects of BV were also confirmed by the scoring of histopathologic changes by an independent researcher blinded to the treatment. BV administration greatly suppressed lung injury as evidenced by decreased histopathological damage confirmed by a decrease in the total histopathologic score (Fig. 1, C).

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