Electrophilic Fatty Acids Reduce Chlorine-Lung Toxicity via Inhibition of Macrophage Activation

Rutgers Biomedical And Health Sciences, Newark NJ

Investigators

Abstract

ABSTRACT Chlorine (Cl2) is a reactive gas that can cause severe lung damage. It has been used as a chemical warfare agent since World War I and recently has been used on a large scale in the Syrian civil war. It matches the criteria of a chemical of concern as defined by the countermeasures research program. In addition to its importance as a chemical warfare agent Cl2 injury is often seen in accidental exposures. The major route of Cl2 exposure is through inhalation and thus, most of the morbidity and mortality that results is due to respiratory complications. Signs and symptoms of Cl2 exposure include cough, choking, irritation and burning in the throat and upper airway, and general difficulty breathing. These symptoms typically display within the first 24 hr following exposure. In the long term, Cl2-mediated lung injury can result in a range of pathologies. The early initiation of injury and the varied long-term sequelae indicate that it is important to intervene within the first 24 hr. Therefore, we have developed a mouse model of inhaled Cl2 exposure that focuses on the first 24 hr for the purposes of testing medical countermeasures. Upon inhalation, Cl2 partitions into the lung lining fluid where it forms hydrochloric and hypochlorous acids and can react with the respiratory mucosa leading to lipid oxidation, DNA damage and cytotoxicity within both pulmonary epithelial and endothelial cells. These reactions result in surfactant dysfunction, loss of epithelial barrier integrity and consequent inflammatory activation. A key step in the inflammatory process is the recruitment of pro-inflammatory activated macrophages. We propose that inhibiting the recruitment and activation of pro-inflammatory macrophages will mitigate Cl2 toxicity in the lung. Electrophilic fatty acids (EFAs) are a class of compounds that have been found to inhibit inflammation in a variety of circumstances. Previously, we have found that the naturally occurring EFA nitro-oleic acid (OA-NO2) inhibits macrophage activation and recruitment in bleomycin-mediated lung injury. In preliminary studies, we have seen this effect in Cl2 injury. It is our contention that by limiting macrophage activation, one can reduce the consequent inflammatory activation and its associated injury. It is our hypothesis that systemic delivery of EFAs post Cl2 inhalation will reduce macrophage recruitment and activation leading to mitigation of lung injury. There are a wide variety of substitutions that can be made upon EFAs that will alter their target specificity and pharmacokinetics. Within the first aim of this study, we will pre-screen up to 55 EFAs for their ability to inhibit macrophage activation in vitro with a view to identifying the most effective potential treatments of Cl2 toxicity in the lung. In our second aim we will examine how i.p. administration of five lead compound EFAs each with a different structural alteration can lead to pro-inflammatory macrophage inhibition and alleviation of injury. These studies will yield mechanistic information as to the role of macrophage recruitment in Cl2-induced lung injury and how EFAs can alter pro-inflammatory activation. As well as assessing the potential of EFAs as medical countermeasures for Cl2 induced lung injury.