title: N-acetyl-heparin attenuates acute lung injury caused by acid aspiration mainly by antagonizing histones in mice.
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.
authors.affiliation: Research Center of Occupational Medicine, Third Hospital of Peking University, Beijing, China.
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Research Center of Occupational Medicine, Third Hospital of Peking University, Beijing, China.
authors.forename: Zanmei
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Research Center of Occupational Medicine, Third Hospital of Peking University, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Guan
authors.affiliation: Research Center of Occupational Medicine, Third Hospital of Peking University, Beijing, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Mao
authors.affiliation: Research Center of Occupational Medicine, Third Hospital of Peking University, Beijing, China.
authors.forename: Shuqiang
authors.initials: S
authors.lastname: Li
authors.affiliation: Research Center of Occupational Medicine, Third Hospital of Peking University, Beijing, China.
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Guan
authors.affiliation: Research Center of Occupational Medicine, Third Hospital of Peking University, Beijing, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.affiliation: Research Center of Occupational Medicine, Third Hospital of Peking University, Beijing, China.
authors.forename: Lixia
authors.initials: L
authors.lastname: Guo
authors.affiliation: Research Center of Occupational Medicine, Third Hospital of Peking University, Beijing, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Ding
authors.affiliation: Research Center of Occupational Medicine, Third Hospital of Peking University, Beijing, China.
authors.forename: Cuicui
authors.initials: C
authors.lastname: Cong
authors.affiliation: Beijing Institute of Hepatology, Beijing You'an Hospital affiliated with Capital Medical University, Beijing, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wen
authors.affiliation: Research Center of Occupational Medicine, Third Hospital of Peking University, Beijing, China.
authors.forename: Jinyuan
authors.initials: J
authors.lastname: Zhao
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D000704:Analysis of Variance; D000818:Animals; D001784:Blood Gas Analysis; D015153:Blotting, Western; D006493:Heparin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006652:Histological Techniques; D006657:Histones / Q000037:antagonists & inhibitors / Q000097:blood / Q000187:drug effects*; D006851:Hydrochloric Acid / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009707:Nucleosomes / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011015:Pneumonia, Aspiration / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D006657:Histones; D009707:Nucleosomes; C089591:N-acetylheparin; D006493:Heparin; D009195:Peroxidase; D006851:Hydrochloric Acid