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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 degree of acid aspiration caused ALI in mice.After acid aspiration (0.1 mol/l, 2 µl g−1), different doses of heparin/NAH (2.5, 5, 10, 20 mg/kg, ip) were injected, twice a day, for 3 days. Heparin/NAH improved blood gas (4A), lung edema (4B), MPO activity of lung tissue (4C) and pathological changes (4D, 4E). In Figure 4E: (a) control group, (b) acid aspiration group, (c, d, e, f) groups treated by heparin, (g, h, i, j) groups treated by NAH. Data are presented as mean±SD (n = 6). The hematoxylin and eosin (HE) stained lung sections are representative of 3 similar samples. Original magnification×200. *p<0.05 vs. the control group, **p<0.01 vs. the control group; #p<0.05 vs. the injury group, ##p<0.01 vs. the injury group.
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pone-0097074-g004: Effect of heparin/NAH on degree of acid aspiration caused ALI in mice.After acid aspiration (0.1 mol/l, 2 µl g−1), different doses of heparin/NAH (2.5, 5, 10, 20 mg/kg, ip) were injected, twice a day, for 3 days. Heparin/NAH improved blood gas (4A), lung edema (4B), MPO activity of lung tissue (4C) and pathological changes (4D, 4E). In Figure 4E: (a) control group, (b) acid aspiration group, (c, d, e, f) groups treated by heparin, (g, h, i, j) groups treated by NAH. Data are presented as mean±SD (n = 6). The hematoxylin and eosin (HE) stained lung sections are representative of 3 similar samples. Original magnification×200. *p<0.05 vs. the control group, **p<0.01 vs. the control group; #p<0.05 vs. the injury group, ##p<0.01 vs. the injury group.

Mentions: Mice were ip injected with heparin/NAH, twice a day, for 3 days after acid aspiration (0.1 mol/l, 2 µl g−1). The degree of ALI was evaluated by blood gas, MPO activity, lung edema and pathological changes. As shown in Figure 4A, hypoxemia was much more evident in the injury group than in the control group. Heparin/NAH improved the blood gas. The dose of 5 mg/kg slightly relieved the decrease in PaO2, while 10 mg/kg dramatically improved PaO2. At 20 mg/kg, NAH provided better protection than 10 mg/kg, whereas the protection provided by heparin nearly disappeared. The change in PaCO2 and pH was not evident among different groups at predetermined time points (data not shown).


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 degree of acid aspiration caused ALI in mice.After acid aspiration (0.1 mol/l, 2 µl g−1), different doses of heparin/NAH (2.5, 5, 10, 20 mg/kg, ip) were injected, twice a day, for 3 days. Heparin/NAH improved blood gas (4A), lung edema (4B), MPO activity of lung tissue (4C) and pathological changes (4D, 4E). In Figure 4E: (a) control group, (b) acid aspiration group, (c, d, e, f) groups treated by heparin, (g, h, i, j) groups treated by NAH. Data are presented as mean±SD (n = 6). The hematoxylin and eosin (HE) stained lung sections are representative of 3 similar samples. Original magnification×200. *p<0.05 vs. the control group, **p<0.01 vs. the control group; #p<0.05 vs. the injury group, ##p<0.01 vs. the injury group.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0097074-g004: Effect of heparin/NAH on degree of acid aspiration caused ALI in mice.After acid aspiration (0.1 mol/l, 2 µl g−1), different doses of heparin/NAH (2.5, 5, 10, 20 mg/kg, ip) were injected, twice a day, for 3 days. Heparin/NAH improved blood gas (4A), lung edema (4B), MPO activity of lung tissue (4C) and pathological changes (4D, 4E). In Figure 4E: (a) control group, (b) acid aspiration group, (c, d, e, f) groups treated by heparin, (g, h, i, j) groups treated by NAH. Data are presented as mean±SD (n = 6). The hematoxylin and eosin (HE) stained lung sections are representative of 3 similar samples. Original magnification×200. *p<0.05 vs. the control group, **p<0.01 vs. the control group; #p<0.05 vs. the injury group, ##p<0.01 vs. the injury group.
Mentions: Mice were ip injected with heparin/NAH, twice a day, for 3 days after acid aspiration (0.1 mol/l, 2 µl g−1). The degree of ALI was evaluated by blood gas, MPO activity, lung edema and pathological changes. As shown in Figure 4A, hypoxemia was much more evident in the injury group than in the control group. Heparin/NAH improved the blood gas. The dose of 5 mg/kg slightly relieved the decrease in PaO2, while 10 mg/kg dramatically improved PaO2. At 20 mg/kg, NAH provided better protection than 10 mg/kg, whereas the protection provided by heparin nearly disappeared. The change in PaCO2 and pH was not evident among different groups at predetermined time points (data not shown).

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