Effects of nebulized antithrombin and heparin on inflammatory and coagulation alterations in an acute lung injury model in rats

BACKGROUND: During acute respiratory distress syndrome, proinflammatory mediators inhibit natural anticoagulant factors, which alter the normal balance between coagulation and fibrinolysis leading to a procoagulant state. We hypothesize that pulmonary administration of anticoagulants might be beneficial to treat acute respiratory distress syndrome for their anticoagulant and antiinflammatory effects and reduce the risk of systemic bleeding. OBJECTIVES: Our aim is to study the effects of nebulized antithrombin (AT) and combined AT and heparin in an animal model of acute lung injury. METHODS: Acute lung injury was induced in rats by the intratracheal administration of hydrochloric acid and lipopolysaccharide. AT alone (500 IU/kg body weight) or combined with heparin (1000 IU/kg body weight) were nebulized after the injury. Control groups received saline instead. Blood, lung tissue, bronchoalveolar lavage, and alveolar macrophages (AM) isolated from bronchoalveolar lavage were collected after 48 hours and analyzed. RESULTS: Nebulized anticoagulant treatments reduced protein concentration in the lungs and decreased injury‐mediated coagulation factors (tissue factor, plasminogen activator inhibitor‐1, plasminogen, and fibrinogen degradation product) and inflammation (tumor necrosis factor α and interleukin 1β) in the alveolar space without affecting systemic coagulation and no bleeding. AT alone reduced fibrin deposition and edema in the lungs. Heparin did not potentiate AT coagulant effect but promoted the reduction of macrophages infiltration into the alveolar compartment. Anticoagulants reduced nuclear factor‐kB downstream effectors in AM. CONCLUSIONS: Nebulized AT and heparin attenuate lung injury through decreasing coagulation and inflammation without altering systemic coagulation and no bleeding. However, combined AT and heparin did not produce a synergistic effect.