Recapitulation of Human Pathophysiology and Identification of Forensic Biomarkers in a Translational Swine Model of Chlorine Inhalation Injury

Abstract

RationaleChlorine gas (Cl2) has been repeatedly used as a chemical weapon, first in World War I and most recently in Syria. Life-threatening Cl2 exposures frequently occur in domestic and occupational environments, and in transportation accidents. There is a knowledge gap in large animal models of Cl2-induced acute lung injury (ALI) required to accurately model human etiology and for the development of targeted countermeasures ObjectiveTo develop a translational model of Cl2-induced ALI in swine to study toxico-pathophysiology and identify biomarkers useful for forensic analysis. MethodsSpecific pathogen-free Yorkshire swine (30-40 kg) of either sex were exposed to Cl2 gas ([≤] 240 ppm for 1 h) or filtered air under anesthesia and controlled mechanical ventilation. ResultsExposure to Cl2 resulted in severe hypoxia and hypoxemia, increased airway resistance and peak inspiratory pressure, and decreased dynamic lung compliance. Chlorine exposure resulted in increased total BALF and neutrophil counts, vascular leakage, and edema compared to the control group. The model recapitulated all three key histopathological features of human ALI, such as neutrophilic alveolitis, deposition of hyaline membranes, and formation of microthrombi. Free and lipid-bound 2-chlorofatty acids and chlorotyrosine-modified proteins (3-chloro-L-tyrosine and 3,5-dichloro-L-tyrosine) were detected in plasma and lung after Cl2-exposure. ConclusionsThe translational model developed in this study replicates key features of humans exposed to Cl2 and is suitable to test medical countermeasures. Specific biomarkers of Cl2 exposure have been identified in plasma and lung tissue samples. Take home messageWe developed a swine model of chlorine gas-induced acute lung injury that exhibits several features of human acute respiratory distress syndrome. We validated chlorinated fatty acids and protein adducts in plasma and lung samples as forensic biomarkers.