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.
Highlights
Acute lung injury (ALI) is characterized by refractory hypoxemia, increased alveolar–capillary permeability and uncontrolled overwhelming inflammatory responses
The high mortality associated with ALI/Acute respiratory distress syndrome (ARDS) indicates that the key mechanism of pathogenesis is unclear
The lung injury was induced by intratracheal instillation of hydrochloric acid (HCl) via the tracheostomy
Summary
Acute lung injury (ALI) is characterized by refractory hypoxemia, increased alveolar–capillary permeability and uncontrolled overwhelming inflammatory responses. Acute respiratory distress syndrome (ARDS) is the final stage of ALI with a mortality rate of ,40% or more, and is the leading cause of death in intensive care units [1,2]. Aspiration pneumonia is a main risk factor for ALI/ARDS. A recent prospective cohort study showed that more than 10% of ALI/ARDS cases are associated with a witnessed aspiration [5,6,7]. The high mortality associated with ALI/ARDS indicates that the key mechanism of pathogenesis is unclear. With the exception of protective ventilation strategies for the lungs, interventions for ALI/ARDS are less purposeful [8,9]. A better understanding of the pathogenic mechanism of ALI/ARDS may help in the development of potentially effective therapies
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
