Presentations

Abstract

Introduction:

Sulfur mustard (SM) and nitrogen mustard (NM) are cytotoxic vesicants developed as chemical warfare agents, causing severe respiratory damage with significant morbidity and mortality. The known stockpiles of these vesicants, along with its familiar simplicity of synthesis raises concerns over its intentional misuse and accidental exposure. NM-induced acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) can lead to fibrosis with pathological changes including inflammatory cell accumulation, epithelial and endothelial cell damage. Despite advances in understanding the biological effects, effective therapies are still needed. The endocannabinoid system is known to play diverse physiological functions, one of them being its natural mechanism to control aberrant inflammatory responses. Our preliminary study showed that acute exposure of mice lungs to NM resulted in an increased expression of monoacylglycerol lipase (MAGL), a component of the endocannabinoid system. In this study, we aimed to examine the effect of MAGL inhibition on NM- induced acute lung injury and inflammation via a selective MAGL inhibitor, JZL184.

Methods:

We administered NM via the intratracheal route into the lungs of mice. JZL184 (10mg/kg) was administered via the intraperitoneal route 1h prior to NM exposure and every 24h thereafter. At 72h of post-NM exposure, we collected Bronchoalveolar lavage fluid (BALF) and lung tissues. The MAGL enzyme activity was measured in the lung. We measured the amount of the immune cells, and cytokine levels in the BALF was measured by using ELISA. NM-induced lung injury was examined by lung histology, and the inflammatory signaling was examined by immunohistochemistry.

Results:

Acute exposure of mice lungs to NM resulted in an increase in MAGL activity. Inhibition of MAGL by JZL184 significantly reduced the immune cell infiltration into the lung that was elevated in response to NM exposure. JZL184-treated mice had lower BALF levels of IL-6 and CXCL1/KC. Lung histologic analysis revealed lowered immune cell infiltration and injury in JZL184-treated mice. MAGL inhibition resulted in reduced iNOS expression as revealed by immunofluorescence.

Conclusion:

Inhibition of MAGL by JZL184 ameliorated the NM-induced ALI and inflammation in mice. Inhibition of endocannabinoid metabolism could promote anti-inflammatory effects in protection against NM-induced lung injury.