Cannabinoid-2 Receptor Activation Attenuates Sulfur Mustard Analog 2-Chloroethyl-Ethyl-Sulfide-Induced Acute Lung Injury in Mice
<b>Background:</b> 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 potenti...
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MDPI AG
2025-02-01
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| Online Access: | https://www.mdpi.com/1424-8247/18/2/236 |
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| author | Gregory Nicholson Nicholas Richards Janette Lockett My Boi Ly Raj V. Nair Woong-Ki Kim K. Yaragudri Vinod Nagaraja Nagre |
| author_facet | Gregory Nicholson Nicholas Richards Janette Lockett My Boi Ly Raj V. Nair Woong-Ki Kim K. Yaragudri Vinod Nagaraja Nagre |
| author_sort | Gregory Nicholson |
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| description | <b>Background:</b> 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. <b>Methods:</b> 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. <b>Results:</b> 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. <b>Conclusions:</b> 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. |
| format | Article |
| id | doaj-art-ea1e8b67ff784adab9ae2e939ad7ea38 |
| institution | DOAJ |
| issn | 1424-8247 |
| language | English |
| publishDate | 2025-02-01 |
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| spelling | doaj-art-ea1e8b67ff784adab9ae2e939ad7ea382025-08-20T03:12:12ZengMDPI AGPharmaceuticals1424-82472025-02-0118223610.3390/ph18020236Cannabinoid-2 Receptor Activation Attenuates Sulfur Mustard Analog 2-Chloroethyl-Ethyl-Sulfide-Induced Acute Lung Injury in MiceGregory Nicholson0Nicholas Richards1Janette Lockett2My Boi Ly3Raj V. Nair4Woong-Ki Kim5K. Yaragudri Vinod6Nagaraja Nagre7Department of Biomedical and Translational Sciences, Macon & Joan Brock Virginia Health Sciences, Eastern Virginia Medical School at Old Dominion University Norfolk, Old Dominion University, Norfolk, VA 23507, USADepartment of Biomedical and Translational Sciences, Macon & Joan Brock Virginia Health Sciences, Eastern Virginia Medical School at Old Dominion University Norfolk, Old Dominion University, Norfolk, VA 23507, USADepartment of Biomedical and Translational Sciences, Macon & Joan Brock Virginia Health Sciences, Eastern Virginia Medical School at Old Dominion University Norfolk, Old Dominion University, Norfolk, VA 23507, USADepartment of Biomedical and Translational Sciences, Macon & Joan Brock Virginia Health Sciences, Eastern Virginia Medical School at Old Dominion University Norfolk, Old Dominion University, Norfolk, VA 23507, USADepartment of Biomedical and Translational Sciences, Macon & Joan Brock Virginia Health Sciences, Eastern Virginia Medical School at Old Dominion University Norfolk, Old Dominion University, Norfolk, VA 23507, USADepartment of Microbiology & Immunology, Tulane University School of Medicine, Tulane University, New Orleans, LA 70112, USAEmotional Brain Institute, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USADepartment of Biomedical and Translational Sciences, Macon & Joan Brock Virginia Health Sciences, Eastern Virginia Medical School at Old Dominion University Norfolk, Old Dominion University, Norfolk, VA 23507, USA<b>Background:</b> 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. <b>Methods:</b> 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. <b>Results:</b> 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. <b>Conclusions:</b> 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.https://www.mdpi.com/1424-8247/18/2/236cannabinoidscannabinoid receptor-22-chloroethyl ethyl sulfideacute lung injuryC57BL/6 J mice |
| spellingShingle | Gregory Nicholson Nicholas Richards Janette Lockett My Boi Ly Raj V. Nair Woong-Ki Kim K. Yaragudri Vinod Nagaraja Nagre Cannabinoid-2 Receptor Activation Attenuates Sulfur Mustard Analog 2-Chloroethyl-Ethyl-Sulfide-Induced Acute Lung Injury in Mice Pharmaceuticals cannabinoids cannabinoid receptor-2 2-chloroethyl ethyl sulfide acute lung injury C57BL/6 J mice |
| title | Cannabinoid-2 Receptor Activation Attenuates Sulfur Mustard Analog 2-Chloroethyl-Ethyl-Sulfide-Induced Acute Lung Injury in Mice |
| title_full | Cannabinoid-2 Receptor Activation Attenuates Sulfur Mustard Analog 2-Chloroethyl-Ethyl-Sulfide-Induced Acute Lung Injury in Mice |
| title_fullStr | Cannabinoid-2 Receptor Activation Attenuates Sulfur Mustard Analog 2-Chloroethyl-Ethyl-Sulfide-Induced Acute Lung Injury in Mice |
| title_full_unstemmed | Cannabinoid-2 Receptor Activation Attenuates Sulfur Mustard Analog 2-Chloroethyl-Ethyl-Sulfide-Induced Acute Lung Injury in Mice |
| title_short | Cannabinoid-2 Receptor Activation Attenuates Sulfur Mustard Analog 2-Chloroethyl-Ethyl-Sulfide-Induced Acute Lung Injury in Mice |
| title_sort | cannabinoid 2 receptor activation attenuates sulfur mustard analog 2 chloroethyl ethyl sulfide induced acute lung injury in mice |
| topic | cannabinoids cannabinoid receptor-2 2-chloroethyl ethyl sulfide acute lung injury C57BL/6 J mice |
| url | https://www.mdpi.com/1424-8247/18/2/236 |
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