Chronic model of sulfur mustard‐induced lung injury in Fischer 344 rats

Abstract

Recent chemical attacks in Syria demonstrate the nondiscriminatory threat that chemical agents pose to both military personnel and civilians alike. Sulfur mustard (SM)is a highly reactive and toxic chemical agent that poses such a threat and is considered a potential weapon that could be employed in acts of terror. SM reacts with epithelial tissue of the respiratory tract, causing a progressive, debilitating injury that currently has no FDA‐approved medical therapeutic countermeasure. This study aimed to develop a chronic model of SM‐induced pulmonary morbidities in inbred Fischer 344 rats with the overall goal of evaluating mesenchymal stem cell therapy as a proof‐of‐concept study. Fifty‐one (n=15 per SM group, n=6vehicle group) male rats were anesthetized, underwent tracheal intubation and were exposed to one of three concentrations of sulfur mustard vapor (0.7, 1.0, and1.4 mg/kg) or vehicle (ethanol) via inhalation for 50 min. At euthanasia (21–28days PE), respiratory mechanics and lung pathology, on the left and accessory lobes, were assessed. Forced oscillation parameters of SM‐exposed animals showed similar significant reductions, despite the SM dose, in inspiratory capacity (IC), compliance of the entire respiratory system (Crs), and significant increases in the respiratory system elastance(Ers) and resistance (Rrs) in comparison to control (ethanol) animals. Pressure‐volume (PV) loop parameters showed that all three SM doses caused similar significant reductions in static compliance (Cst), forced vital capacity FVC, inspiratory capacity (A), K, forced expiratory volume at 200ms (FEV200) and peak inspiratory flow (PEF) in comparison to control animals. However, SM‐induced reductions in these parameters were non‐distinguishable between doses. Animals that received SM had pathology findings of proteinaceous edema fluid in the bronchial, bronchiolar, and alveolar regions of the lungs with mild to severe perivascular edema, hemorrhage and inflammation. Multifocal bronchiolar mucous cell hyperplasia was prominent after SM exposure with partial to extensive fibrosis of the bronchial wall and variable epithelial loss occurring. Although variable in severity and not widespread, alveolar fibrosis also occurred multifocally. In conclusion, a reduction in Crs and an increase in Ers of the forced oscillation measures, in animals that received SM, indicate an increased lung stiffness and elasticrecoil of the lung. PV‐loop analysis presented with a restrictive and obstructive pulmonary function pattern with an increase in Rrs and decreases in inspiratory capacity, FEV200 and PEF along with flattening (reduction) of the downward curvature of the deflating limb of the PV loop. Pathology results are consistent with the respiratory mechanics findings.Support or Funding InformationThe research described was supported by an interagency agreement (AOD18014‐001‐00000) between the NIH office of the Directory and the USAMRICD under the oversight of the Chemical Countermeasures Research Program within the Office of Biodefense Research at the National Institute of Allergy and Infectious Diseases. The views expressed are solely those of the authors and do not necessarily represent the official views of the CCRP, NIAID, NIH, HHS, USAMRICD or DOD.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.