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: Yanlin Zhang, Zanmei Zhao, Li Guan, Lijun Mao, Shuqiang Li, Xiaoxu Guan, Ming Chen, Lixia Guo, Lihua Ding, Cuicui Cong, Tao Wen, Jinyuan Zhao
• Journal: PloS one (PLoS One) Vol. 9 Issue 5 Pg. e97074 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24816808 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Histones
• Nucleosomes
• N-acetylheparin
• Heparin
• Peroxidase
• Hydrochloric Acid

Topics

• Acute Lung Injury (chemically induced, drug therapy, pathology)
• Analysis of Variance
• Animals
• Blood Gas Analysis
• Blotting, Western
• Heparin (administration & dosage, analogs & derivatives, pharmacology, therapeutic use)
• Histological Techniques
• Histones (antagonists & inhibitors, blood, drug effects)
• Hydrochloric Acid (adverse effects)
• Mice
• Mice, Inbred C57BL
• Nucleosomes (metabolism)
• Peroxidase (metabolism)
• Pneumonia, Aspiration (drug therapy, pathology)
• Survival Rate
• Treatment Outcome