{"doi":"10.3390/ph18020236","title":"Cannabinoid-2 Receptor Activation Attenuates Sulfur Mustard Analog 2-Chloroethyl-Ethyl-Sulfide-Induced Acute Lung Injury in Mice","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.","journal":"Pharmaceuticals","year":2025,"id":519028,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9593,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1241451,"name":"Nicholas Richards","orcid":"0009-0008-4832-1651","position":1,"is_corresponding":false},{"id":1387356,"name":"J. Lockett","orcid":null,"position":2,"is_corresponding":false},{"id":1387357,"name":"Man Ly","orcid":null,"position":3,"is_corresponding":false},{"id":558719,"name":"R. Nair","orcid":"0000-0003-3281-014X","position":4,"is_corresponding":false},{"id":363422,"name":"Woong‐Ki Kim","orcid":"0000-0001-9964-185X","position":5,"is_corresponding":false},{"id":654565,"name":"K. Yaragudri Vinod","orcid":null,"position":6,"is_corresponding":false},{"id":510290,"name":"Nagaraja N. Nagre","orcid":"0000-0003-0184-8196","position":7,"is_corresponding":false},{"id":1387355,"name":"G. Nicholson","orcid":null,"position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-19T02:49:14.184995Z","pmid":"40006049","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}