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N-acetyl-heparin attenuates acute lung injury caused by acid aspiration mainly by antagonizing histones in mice.

Zhang Y, Zhao Z, Guan L, Mao L, Li S, Guan X, Chen M, Guo L, Ding L, Cong C, Wen T, Zhao J - PLoS ONE (2014)

Bottom Line: A significant correlation existed between the concentration of HCl aspirated and the circulating histones.Heparin/NAH (10 mg/kg) improved the lethality rate, blood gas, MPO activity, lung edema and pathological score.At the high dose, NAH provides better protection than heparin.

View Article: PubMed Central - PubMed

Affiliation: Research Center of Occupational Medicine, Third Hospital of Peking University, Beijing, China.

ABSTRACT
Acute lung injury (ALI) is the leading cause of death in intensive care units. Extracellular histones have recently been recognized to be pivotal inflammatory mediators. Heparin and its derivatives can bind histones through electrostatic interaction. The purpose of this study was to investigate 1) the role of extracellular histones in the pathogenesis of ALI caused by acid aspiration and 2) whether N-acetyl-heparin (NAH) provides more protection than heparin against histones at the high dose. ALI was induced in mice via intratracheal instillation of hydrochloric acid (HCl). Lethality rate, blood gas, myeloperoxidase (MPO) activity, lung edema and pathological changes were used to evaluate the degree of ALI. Heparin/NAH was administered intraperitoneally, twice a day, for 3 days or until death. Acid aspiration caused an obvious increase in extracellular histones. A significant correlation existed between the concentration of HCl aspirated and the circulating histones. Heparin/NAH (10 mg/kg) improved the lethality rate, blood gas, MPO activity, lung edema and pathological score. At a dose of 20 mg/kg, NAH still provided protection, however heparin tended to aggravate the injury due to hemorrhagic complications. The specific interaction between heparin and histones was verified by the binding assay. In summary, high levels of extracellular histones can be pathogenic in ALI caused by acid aspiration. By neutralizing extracellular histones, heparin/NAH can offer similar protection at the moderate doses. At the high dose, NAH provides better protection than heparin.

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Effect of heparin/NAH on survival rates in mice with acid aspiration caused ALI.After mice were challenged by lethal acid aspiration (0.3 mol/l, 2 µlg−1), either heparin or NAH was injected ip simultaneously, twice a day, for 3 days or until death. The control and the untreated mice underwent the same procedure and were injected with equivalent normal saline. The survival rates were recorded every 4 hours for 72 hours. Heparin improved the survival rates (n = 14) (3A). NAH also relieved the lethality rates, especially at the high dose (n = 14) (3B). Log-rank test was used for comparison of survival time. P<0.05 is viewed as statistically significant.
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pone-0097074-g003: Effect of heparin/NAH on survival rates in mice with acid aspiration caused ALI.After mice were challenged by lethal acid aspiration (0.3 mol/l, 2 µlg−1), either heparin or NAH was injected ip simultaneously, twice a day, for 3 days or until death. The control and the untreated mice underwent the same procedure and were injected with equivalent normal saline. The survival rates were recorded every 4 hours for 72 hours. Heparin improved the survival rates (n = 14) (3A). NAH also relieved the lethality rates, especially at the high dose (n = 14) (3B). Log-rank test was used for comparison of survival time. P<0.05 is viewed as statistically significant.

Mentions: After intratracheal instillation of HCl (0.3 mol/l, 2 µl g−1), mice were ip injected with heparin/NAH, twice a day, for 3 days or until death, in order to examine the protective effect of heparin/NAH on acid aspiration-induced lethality. Animal survival was recorded for 72 hours after acid aspiration. As shown in Figure 3A, the survival rates at 4 and 72 hours after acid aspiration were 42.9% and 7.1%, respectively, in mice treated by equivalent normal saline. Heparin could improve the survival rates. The dose of 5 mg/kg heparin slightly improved the survival rates at 4 and 72 hours, while 10 mg/kg heparin dramatically improved the survival rates to 85.7% and 42.9%, respectively. However when heparin dose reached 20 mg/kg, the survival rates decreased to 71.4% and 14.3%, respectively. As shown in Figure 3B, after acid aspiration treatment with 5 mg/kg NAH slightly improved the survival rates, while 10 mg/kg NAH significantly improved the survival rates at 4 and 72 hours to 71.4% and 42.9%, respectively. Unlike heparin, treatment with 20 mg/kg NAH further improved the survival rates to 78.6% and 57.1%, respectively.


N-acetyl-heparin attenuates acute lung injury caused by acid aspiration mainly by antagonizing histones in mice.

Zhang Y, Zhao Z, Guan L, Mao L, Li S, Guan X, Chen M, Guo L, Ding L, Cong C, Wen T, Zhao J - PLoS ONE (2014)

Effect of heparin/NAH on survival rates in mice with acid aspiration caused ALI.After mice were challenged by lethal acid aspiration (0.3 mol/l, 2 µlg−1), either heparin or NAH was injected ip simultaneously, twice a day, for 3 days or until death. The control and the untreated mice underwent the same procedure and were injected with equivalent normal saline. The survival rates were recorded every 4 hours for 72 hours. Heparin improved the survival rates (n = 14) (3A). NAH also relieved the lethality rates, especially at the high dose (n = 14) (3B). Log-rank test was used for comparison of survival time. P<0.05 is viewed as statistically significant.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016230&req=5

pone-0097074-g003: Effect of heparin/NAH on survival rates in mice with acid aspiration caused ALI.After mice were challenged by lethal acid aspiration (0.3 mol/l, 2 µlg−1), either heparin or NAH was injected ip simultaneously, twice a day, for 3 days or until death. The control and the untreated mice underwent the same procedure and were injected with equivalent normal saline. The survival rates were recorded every 4 hours for 72 hours. Heparin improved the survival rates (n = 14) (3A). NAH also relieved the lethality rates, especially at the high dose (n = 14) (3B). Log-rank test was used for comparison of survival time. P<0.05 is viewed as statistically significant.
Mentions: After intratracheal instillation of HCl (0.3 mol/l, 2 µl g−1), mice were ip injected with heparin/NAH, twice a day, for 3 days or until death, in order to examine the protective effect of heparin/NAH on acid aspiration-induced lethality. Animal survival was recorded for 72 hours after acid aspiration. As shown in Figure 3A, the survival rates at 4 and 72 hours after acid aspiration were 42.9% and 7.1%, respectively, in mice treated by equivalent normal saline. Heparin could improve the survival rates. The dose of 5 mg/kg heparin slightly improved the survival rates at 4 and 72 hours, while 10 mg/kg heparin dramatically improved the survival rates to 85.7% and 42.9%, respectively. However when heparin dose reached 20 mg/kg, the survival rates decreased to 71.4% and 14.3%, respectively. As shown in Figure 3B, after acid aspiration treatment with 5 mg/kg NAH slightly improved the survival rates, while 10 mg/kg NAH significantly improved the survival rates at 4 and 72 hours to 71.4% and 42.9%, respectively. Unlike heparin, treatment with 20 mg/kg NAH further improved the survival rates to 78.6% and 57.1%, respectively.

Bottom Line: A significant correlation existed between the concentration of HCl aspirated and the circulating histones.Heparin/NAH (10 mg/kg) improved the lethality rate, blood gas, MPO activity, lung edema and pathological score.At the high dose, NAH provides better protection than heparin.

View Article: PubMed Central - PubMed

Affiliation: Research Center of Occupational Medicine, Third Hospital of Peking University, Beijing, China.

ABSTRACT
Acute lung injury (ALI) is the leading cause of death in intensive care units. Extracellular histones have recently been recognized to be pivotal inflammatory mediators. Heparin and its derivatives can bind histones through electrostatic interaction. The purpose of this study was to investigate 1) the role of extracellular histones in the pathogenesis of ALI caused by acid aspiration and 2) whether N-acetyl-heparin (NAH) provides more protection than heparin against histones at the high dose. ALI was induced in mice via intratracheal instillation of hydrochloric acid (HCl). Lethality rate, blood gas, myeloperoxidase (MPO) activity, lung edema and pathological changes were used to evaluate the degree of ALI. Heparin/NAH was administered intraperitoneally, twice a day, for 3 days or until death. Acid aspiration caused an obvious increase in extracellular histones. A significant correlation existed between the concentration of HCl aspirated and the circulating histones. Heparin/NAH (10 mg/kg) improved the lethality rate, blood gas, MPO activity, lung edema and pathological score. At a dose of 20 mg/kg, NAH still provided protection, however heparin tended to aggravate the injury due to hemorrhagic complications. The specific interaction between heparin and histones was verified by the binding assay. In summary, high levels of extracellular histones can be pathogenic in ALI caused by acid aspiration. By neutralizing extracellular histones, heparin/NAH can offer similar protection at the moderate doses. At the high dose, NAH provides better protection than heparin.

Show MeSH
Related in: MedlinePlus