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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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Related in: MedlinePlus

Effect of anti-H4 antibody on survival rates in mice with acid aspiration caused ALI.Anti-H4 antibody (20 mg/ml) or the IgG control (20 mg/ml) were given once intravenously just before acid aspiration (0.3 mol/l, 2 µl g−1). The untreated mice all died within 24 hours (n = 12). Eight of 12 mice Pre-treated with anti-H4 antibody survived the challenge for 72 hours, but the IgG control did not improve the survival rates. Log-rank test was used for comparison of survival time. P<0.05 is viewed as statistically significant.
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pone-0097074-g002: Effect of anti-H4 antibody on survival rates in mice with acid aspiration caused ALI.Anti-H4 antibody (20 mg/ml) or the IgG control (20 mg/ml) were given once intravenously just before acid aspiration (0.3 mol/l, 2 µl g−1). The untreated mice all died within 24 hours (n = 12). Eight of 12 mice Pre-treated with anti-H4 antibody survived the challenge for 72 hours, but the IgG control did not improve the survival rates. Log-rank test was used for comparison of survival time. P<0.05 is viewed as statistically significant.

Mentions: To verify whether the extracellular histones are the major mediators of damage, mice were pre-treated with specific anti-H4 antibody or nonspecific mouse IgG just prior to acid aspiration. As shown in Figure 2, all mice died within 24 hours (n = 12) after aspiration of a lethal dose of acid (0.3 mol/l, 2 µl g−1). However, 8 of 12 mice that were pre-treated with intravenous anti-H4 (20 mg/kg) survived for 72 hours, whereas pre-treatment with the non-specific mouse IgG (20 mg/kg) did not improve the survival rates. The difference of survival rates between the mice treated with anti-H4 and those treated with IgG was statistically significant by the log-rank test (p = 0.0085).


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 anti-H4 antibody on survival rates in mice with acid aspiration caused ALI.Anti-H4 antibody (20 mg/ml) or the IgG control (20 mg/ml) were given once intravenously just before acid aspiration (0.3 mol/l, 2 µl g−1). The untreated mice all died within 24 hours (n = 12). Eight of 12 mice Pre-treated with anti-H4 antibody survived the challenge for 72 hours, but the IgG control did not improve the survival rates. 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-g002: Effect of anti-H4 antibody on survival rates in mice with acid aspiration caused ALI.Anti-H4 antibody (20 mg/ml) or the IgG control (20 mg/ml) were given once intravenously just before acid aspiration (0.3 mol/l, 2 µl g−1). The untreated mice all died within 24 hours (n = 12). Eight of 12 mice Pre-treated with anti-H4 antibody survived the challenge for 72 hours, but the IgG control did not improve the survival rates. Log-rank test was used for comparison of survival time. P<0.05 is viewed as statistically significant.
Mentions: To verify whether the extracellular histones are the major mediators of damage, mice were pre-treated with specific anti-H4 antibody or nonspecific mouse IgG just prior to acid aspiration. As shown in Figure 2, all mice died within 24 hours (n = 12) after aspiration of a lethal dose of acid (0.3 mol/l, 2 µl g−1). However, 8 of 12 mice that were pre-treated with intravenous anti-H4 (20 mg/kg) survived for 72 hours, whereas pre-treatment with the non-specific mouse IgG (20 mg/kg) did not improve the survival rates. The difference of survival rates between the mice treated with anti-H4 and those treated with IgG was statistically significant by the log-rank test (p = 0.0085).

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