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

Abstract

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.

Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID‐19

“…In respiratory medicine, treatments are often delivered as aerosolized protein therapeutics as diffusion of proteins from the blood to the lungs can be limited. 86 Interestingly, nebulized anticoagulant therapy with antithrombin or heparin has been shown to reduce lung injury without an increase in systemic bleeding in animal models [87][88][89] and ALI patients. 90 However, as discussed, heparin will prevent further fibrin deposition but will be ineffective in the removal of pre-existing fibrin.…”

Nebulised heparin as a treatment for COVID-19: scientific rationale and a call for randomised evidence

“…(48h) AirLife Brand Misty Max 10 ↓ Lung injury, oedema and airways obstruction ↑ PaO2 No side effects Rehberg et al, 2014 [ 112 ] 1000 IU/kg (4h, 12h and 28h after injury) combined with nebulized 500 IU/kg antithrombin (4h and 28h after injury) Rat it. HCl and LPS (30 μg/g) (72h) Aeroneb Pro Nebulizer ↓ Pulmonary coagulation and inflammation No side effects Camprubí-Rimblas et al, 2020 [ 113 ] ↓: reduced, ↑: increased, =: equal, inh inhalation, it. intratracheal, iv.…”

Antithrombin and Its Role in Host Defense and Inflammation

“…Administration of nebulized AT after chemically induced lung injury in rats showed a reduction of edema, downregulation of tissue factor expression, and consequently, lower fibrin deposition in the pulmonary tissue, an effect that was not observed in the group receiving concomitant heparin [79]. Still, more data are needed to assess the effect of AT on extravascular cells and tissues.…”