ORCID
0009-0007-2875-5009 (Nicholson), 0000-0003-3281-014X (Nair), 0000-0003-0184-8196 (Nagre)
Document Type
Article
Publication Date
2025
DOI
10.3390/ph18020236
Publication Title
Pharmaceuticals
Volume
18
Issue
2
Pages
236 (1-15)
Abstract
Background: Exposure to sulfur mustard (SM; 2,2′-dichlorodiethyl sulfide) causes toxicity in the human body, particularly the lungs. The molecular mechanisms of SM-induced lung damage are elusive, and no effective treatments exist. This study explores the anti-inflammatory potential of cannabinoid receptor 2 (CB2R) activation in mitigating acute lung injury (ALI) and inflammation induced by 2-chloroethyl ethyl sulfide (CEES), a structural analog of SM. Methods: C57BL/6J mice were exposed to CEES via intratracheal administration to model ALI. CB2R activation was achieved through the intraperitoneal administration of HU308, a selective synthetic agonist. ALI and inflammation were evaluated at 48 h post-exposure to CEES. Bronchoalveolar lavage fluid (BALF) was collected to measure total cells, protein, and cytokines. Lung injury, inflammatory signaling in alveolar macrophages (AMs), and matrix metalloproteinase-9 (MMP-9) activity were assessed via histological analysis, immunoblotting, and gelatin zymography, respectively. Results: CEES exposure led to an increase in immune cell infiltration, pro-inflammatory cytokines (IL-6 and TNF-α), and pro-MMP9 levels in the BALF, which were significantly decreased by HU308 treatment. The activation of CB2R attenuated CEES-induced NF-κB activation and reduced pro-inflammatory M1 markers (iNOS, and Cox-2) but did not alter the increase in the M2 marker arginase-1. CB2R activation mitigated CEES-induced oxidative stress, as evidenced by lower levels of heme oxygenase-1 (HO-1) and reactive oxygen species (ROS) in mouse AMs. Additionally, 4-hydroxynonenal (4-HNE) levels were reduced in the lungs of HU308-treated mice but were elevated after CEES exposure. Conclusions: These findings suggest that CB2R activation alleviates CEES-induced ALI and inflammation in mice, supporting its potential as a therapeutic approach for vesicant-induced pulmonary injury.
Rights
© 2025 The Authors.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International (CC BY 4.0) License.
Data Availability
Article states: "Data supporting the findings of this study are available from the corresponding author upon request."
Original Publication Citation
Nicholson, G., Richards, N., Lockett, J., Ly, M. B., Nair, R. V., Kim, W.-K., Vinod, K. Y., & Nagre, N. (2025). Cannabinoid-2 receptor activation attenuates sulfur mustard analog 2-chloroethyl-ethyl-sulfide-induced acute lung injury in mice. Pharmaceuticals, 18(2), 1-15, Article 236. https://doi.org/10.3390/ph18020236
Repository Citation
Nicholson, G., Richards, N., Lockett, J., Ly, M. B., Nair, R. V., Kim, W.-K., Vinod, K. Y., & Nagre, N. (2025). Cannabinoid-2 receptor activation attenuates sulfur mustard analog 2-chloroethyl-ethyl-sulfide-induced acute lung injury in mice. Pharmaceuticals, 18(2), 1-15, Article 236. https://doi.org/10.3390/ph18020236
