Modeling resolution of direct acute lung injury

Translational animal models allowing the study of both inflammatory and resolution phases of acute lung injury (ALI) are lacking. Widely used models including intratracheal endotoxin or bleomycin are difficult to translate. Here we developed and optimized a reproducible model of resolving aspiration pneumonitis that mimics human ALI. C57Bl6 mice were instilled intratracheally with 75μl of 0.1M hydrochloric acid by direct laryngoscopy under anesthesia. At specified timepoints up to 10 days after instillation, respiratory mechanics, arterial blood gases, soluble mediators in bronchoalveolar lavage fluid (BALF), and alveolar fluid clearance (AFC) using an in situ preparation were measured. Acid instillation produced significant increases in BALF protein levels and respiratory elastance. BALF levels of TNF and soluble RAGE, a marker of epithelial damage, both increased, while AFC deteriorated. All of these injury parameters peaked at days 1-3 post-acid, but resolved by days 5-10. These results indicate that the model replicates major hallmarks of ALI, i.e. changes in respiratory mechanics, gas exchange, lung permeability, inflammation and AFC, but shows full resolution. This model will allow future investigation of novel resolving pathways. Supported by the Wellcome Trust.