Suppression of Lung Oxidative Stress, Inflammation, and Fibrosis following Nitrogen Mustard Exposure by the Selective Farnesoid X Receptor Agonist Obeticholic Acid

Abstract

Nitrogen mustard (NM) is a cytotoxic vesicant known that causes pulmonary injury that can progress to fibrosis. NM toxicity is associated with an influx of inflammatory macrophages in the lung. Farnesoid X Receptor (FXR) is a nuclear receptor involved in bile acid and lipid homeostasis that has anti-inflammatory activity. In these studies, we analyzed the effects of FXR activation on lung injury, oxidative stress and fibrosis induced by NM. Male Wistar rats were exposed to phosphate buffered saline (CTL) or NM (0.125mg/kg) by i.t. Penn-Century MicroSprayer®™ aerosolization; this was followed by treatment with the FXR synthetic agonist, obeticholic acid (OCA, 15mg/kg) or vehicle control (0.13-0.18g peanut butter), 2hr later, and then once/day, 5 days/week thereafter for 28d. NM caused histopathological changes in the lung including epithelial thickening, alveolar circularization, and pulmonary edema. Picrosirius Red staining and lung hydroxyproline content were increased indicative of fibrosis; foamy lipid laden macrophages were also identified in the lung. This was associated with aberrations in pulmonary function including increases in resistance and hysteresis. Following NM exposure, lung expression of HO-1 and iNOS, and the ratio of nitrate/nitrites in bronchoalveolar lavage fluid (BAL), markers of oxidative stress increased, along with BAL levels of inflammatory proteins, fibrinogen and sRAGE. Administration of OCA attenuated NM-induced histopathology, oxidative stress, inflammation and altered lung function. These findings demonstrate that FXR plays a role in limiting NM-induced lung injury and chronic disease, suggesting that activating FXR may represent an effective approach to limiting NM-induced toxicity.

Progress and Challenges in Developing Medical Countermeasures for Chemical, Biological, Radiological, and Nuclear Threat Agents

“…Mesna demonstrated significant survival benefits, improved cardiopulmonary function, and reduced airway fibrin cast formation in a rat model of SM inhalation, suggesting its potential as an inexpensive and readily available therapeutic option for real-world SM exposure situations. In a rigorous pharmacology study, Laskin and team investigated the impact of farnesoid X receptor (FXR) activation on lung injury, oxidative stress, and fibrosis induced by the cytotoxic vesicant NM ( Meshanni et al, 2024 ). The mustard-induced histopathological changes, fibrosis, aberrations in pulmonary function, and increased oxidative stress and inflammation markers were effectively attenuated by the administration of the FXR synthetic agonist obeticholic acid, indicating the potential therapeutic role of FXR activation in limiting NM-induced lung injury and chronic disease and thereby confirming it as a viable approach for intervention.…”

Special Section on Medical Countermeasures, From Bench to Battlefield: Translating Experimental Therapies for Effective Combat Against Chemical Threats–Editorial

“…The second paper establishes a robust animal model for investigating lung injury resulting from cutaneous exposure to Lewisite (Zafar et al, 2024). The third paper demonstrates Mesna's effectiveness as an antidote for SM exposure (Nick et al, 2024), while the final paper explores FXR activation as a therapeutic approach for NM-induced lung injury (Meshanni et al, 2024). Furthermore, two papers describe progress in developing antidotes for cyanide and arsenical agents.…”