NIH grant: 2-Arachidonoylglycerol signaling in nitrogen mustard-induced lung injury (1R21ES037516-01A1)

retained text

NIH grant 1R21ES037516-01A1: 2-Arachidonoylglycerol signaling in nitrogen mustard-induced lung injury
Institute: {'code': 'ES', 'abbreviation': 'NIEHS', 'name': 'National Institute of Environmental Health Sciences', 'admin_org_id': '12500022', 'admin_funding_url': ''}. PI: Nagaraja  Nagre. Award: $458144.
Start: 2026-06-23T00:00:00.
Summary:
Nitrogen mustard (NM), a potent cytotoxic vesicant, can cause acute lung injury and potentially lead to chronic
conditions like fibrosis, emphysema, and bronchiolitis obliterans. NM remains a significant chemical threat due
to its ease of synthesis and weaponization. Currently, there are no effective medical countermeasures to mitigate
NM-induced lung damage, therefore, the search for an effective therapeutic or prophylactic treatment persists.
The endocannabinoids and their lipid-related mediators contribute to the modulation of oxidative stress and lipid
peroxidation and 2- Arachidonoylglycerol (2-AG), is the most abundant endocannabinoid. 2-AG is produced ‘on
demand’ and rapidly degraded, and monoacylglycerol lipase (MAGL or MgII) is the main enzyme responsible for
2-AG catabolism. The hydrolysis of 2-AG by MAGL terminates the activation of CB receptors, releasing free AA
that serves as a precursor for the synthesis of pro-inflammatory eicosanoids. Enhancing the 2-AG signaling
displays an anti-inflammatory response to proinflammatory and mechanical insults. Our preliminary findings
indicated that acute exposure to NM resulted in a significant increase in MAGL in mouse lung tissues, immune
cells, and human alveolar macrophages. Furthermore, our pilot study showed that the administration of JZL184,
a potent inhibitor of MAGL resulted in a significant reduction in NM-induced acute lung injury and immune cell
infiltration in mice. Given these promising indications, this project aims to further investigate how augmenting the
2-AG signaling by inactivation of MAGL could confer protection against NM-induced lung injury. Aim 1: To assess
the efficacy of MAGL inhibition/inactivation in protection against NM-induced acute lung injury, inflammatory
response, and oxidative stress. Aim 2: To delineate the mechanism of protection by MAGL inhibition/inactivation
in NM-induced acute lung injury, inflammatory response, and oxidative stress. These efforts would assist in
translational strategies for the development of therapeutic agents against NM-induced lung damage.

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