Abstract
Introduction
Nitrogen mustard (NM) is a potent cytotoxic vesicant and alkylating agent that can cause acute lung injury and progress to chronic pulmonary complications, including fibrosis, emphysema, and bronchiolitis obliterans. Although NM has not been used in warfare, its ease of synthesis and potential for weaponization make it a significant chemical threat. Myeloid cells play a critical role in NM-induced pathogenic responses. Previous studies have shown that inhibition of monoacylglycerol lipase (MAGL or MgII), a key enzyme of the endocannabinoid system, exerts anti-inflammatory effects. However, the role of myeloid MAGL in chemically induced lung injury remains unknown. Here, we used conditional deletion of MAGL in myeloid cells to test the hypothesis that myeloid MAGL deficiency protects against NM-induced acute lung injury.
Methods
MAGLfl/fl, and myeloid-specific MAGL-deficient mice (MyeMAGL) were exposed to NM (0.125 mg/kg) via intratracheal administration. At 72 h post-exposure, pulmonary mechanics were assessed using FlexiVent rodent ventilator system. Bronchoalveolar lavage fluid (BALF) was collected to determine total cell counts and IL-1β concentrations by ELISA. Stat3 activation was evaluated by immunoblot analysis of phosphorylated Stat3 (P-Stat3) and total Stat3 expression in lung tissue. Lung injury was assessed by histological analysis.
Results
Conditional deletion of MAGL in myeloid cells significantly attenuated NM-induced decline in lung function. Myeloid MAGL deficiency reduced BALF total cell counts, and IL-1β which were elevated following NM exposure. Immunoblot analysis showed reduced Stat3 activation in MyeMAGL lungs. Histological analysis revealed reduced lung injury in myeloid MAGL-deficient mice.
Conclusion
These findings demonstrate that myeloid MAGL contributes to NM-induced acute lung injury and inflammation. Targeting myeloid MAGL may represent a promising therapeutic strategy for mitigating acute pulmonary injury following NM exposure