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.