Activation of cannabinoid-2 receptor protects against Pseudomonas aeruginosa induced acute lung injury and inflammation
Abstract Background Bacterial pneumonia is a major risk factor for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Pseudomonas aeruginosa (PA), an opportunistic pathogen with an increasing resistance acquired against multiple drugs, is one of the main causative agents of ALI...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-12-01
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| Series: | Respiratory Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12931-022-02253-w |
| _version_ | 1811207978753196032 |
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| author | Nagaraja Nagre Gregory Nicholson Xiaofei Cong Janette Lockett Andrew C. Pearson Vincent Chan Woong-Ki Kim K. Yaragudri Vinod John D. Catravas |
| author_facet | Nagaraja Nagre Gregory Nicholson Xiaofei Cong Janette Lockett Andrew C. Pearson Vincent Chan Woong-Ki Kim K. Yaragudri Vinod John D. Catravas |
| author_sort | Nagaraja Nagre |
| collection | DOAJ |
| description | Abstract Background Bacterial pneumonia is a major risk factor for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Pseudomonas aeruginosa (PA), an opportunistic pathogen with an increasing resistance acquired against multiple drugs, is one of the main causative agents of ALI and ARDS in diverse clinical settings. Given the anti-inflammatory role of the cannabinoid-2 receptor (CB2R), the effect of CB2R activation in the regulation of PA-induced ALI and inflammation was tested in a mouse model as an alternative to conventional antibiotic therapy. Methods In order to activate CB2R, a selective synthetic agonist, JWH133, was administered intraperitoneally (i.p.) to C57BL/6J mice. Furthermore, SR144528 (a selective CB2R antagonist) was administered in combination with JWH133 to test the specificity of the CB2R-mediated effect. PA was administered intratracheally (i.t.) for induction of pneumonia in mice. At 24 h after PA exposure, lung mechanics were measured using the FlexiVent system. The total cell number, protein content, and neutrophil population in the bronchoalveolar lavage fluid (BALF) were determined. The bacterial load in the whole lung was also measured. Lung injury was evaluated by histological examination and PA-induced inflammation was assessed by measuring the levels of BALF cytokines and chemokines. Neutrophil activation (examined by immunofluorescence and immunoblot) and PA-induced inflammatory signaling (analyzed by immunoblot) were also studied. Results CB2R activation by JWH133 was found to significantly reduce PA-induced ALI and the bacterial burden. CB2R activation also suppressed the PA-induced increase in immune cell infiltration, neutrophil population, and inflammatory cytokines. These effects were abrogated by a CB2R antagonist, SR144528, further confirming the specificity of the CB2R-mediated effects. CB2R-knock out (CB2RKO) mice had a significantly higher level of PA-induced inflammation as compared to that in WT mice. CB2R activation diminished the excess activation of neutrophils, whereas mice lacking CB2R had elevated neutrophil activation. Pharmacological activation of CB2R significantly reduced the PA-induced NF-κB and NLRP3 inflammasome activation, whereas CB2KO mice had elevated NLRP3 inflammasome. Conclusion Our findings indicate that CB2R activation ameliorates PA-induced lung injury and inflammation, thus paving the path for new therapeutic avenues against PA pneumonia. |
| first_indexed | 2024-04-12T04:12:46Z |
| format | Article |
| id | doaj.art-3891e0604def4564b92c7e1a16061160 |
| institution | Directory Open Access Journal |
| issn | 1465-993X |
| language | English |
| last_indexed | 2024-04-12T04:12:46Z |
| publishDate | 2022-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj.art-3891e0604def4564b92c7e1a160611602022-12-22T03:48:27ZengBMCRespiratory Research1465-993X2022-12-0123111310.1186/s12931-022-02253-wActivation of cannabinoid-2 receptor protects against Pseudomonas aeruginosa induced acute lung injury and inflammationNagaraja Nagre0Gregory Nicholson1Xiaofei Cong2Janette Lockett3Andrew C. Pearson4Vincent Chan5Woong-Ki Kim6K. Yaragudri Vinod7John D. Catravas8Department of Physiological Sciences, Eastern Virginia Medical SchoolDepartment of Physiological Sciences, Eastern Virginia Medical SchoolDepartment of Physiological Sciences, Eastern Virginia Medical SchoolDepartment of Physiological Sciences, Eastern Virginia Medical SchoolDepartment of Physiological Sciences, Eastern Virginia Medical SchoolDepartment of Physiological Sciences, Eastern Virginia Medical SchoolDepartment of Microbiology and Molecular Cell Biology, Eastern Virginia Medical SchoolEmotional Brain Institute, Nathan Kline Institute for Psychiatric ResearchFrank Reidy Research Center for Bioelectrics, Old Dominion UniversityAbstract Background Bacterial pneumonia is a major risk factor for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Pseudomonas aeruginosa (PA), an opportunistic pathogen with an increasing resistance acquired against multiple drugs, is one of the main causative agents of ALI and ARDS in diverse clinical settings. Given the anti-inflammatory role of the cannabinoid-2 receptor (CB2R), the effect of CB2R activation in the regulation of PA-induced ALI and inflammation was tested in a mouse model as an alternative to conventional antibiotic therapy. Methods In order to activate CB2R, a selective synthetic agonist, JWH133, was administered intraperitoneally (i.p.) to C57BL/6J mice. Furthermore, SR144528 (a selective CB2R antagonist) was administered in combination with JWH133 to test the specificity of the CB2R-mediated effect. PA was administered intratracheally (i.t.) for induction of pneumonia in mice. At 24 h after PA exposure, lung mechanics were measured using the FlexiVent system. The total cell number, protein content, and neutrophil population in the bronchoalveolar lavage fluid (BALF) were determined. The bacterial load in the whole lung was also measured. Lung injury was evaluated by histological examination and PA-induced inflammation was assessed by measuring the levels of BALF cytokines and chemokines. Neutrophil activation (examined by immunofluorescence and immunoblot) and PA-induced inflammatory signaling (analyzed by immunoblot) were also studied. Results CB2R activation by JWH133 was found to significantly reduce PA-induced ALI and the bacterial burden. CB2R activation also suppressed the PA-induced increase in immune cell infiltration, neutrophil population, and inflammatory cytokines. These effects were abrogated by a CB2R antagonist, SR144528, further confirming the specificity of the CB2R-mediated effects. CB2R-knock out (CB2RKO) mice had a significantly higher level of PA-induced inflammation as compared to that in WT mice. CB2R activation diminished the excess activation of neutrophils, whereas mice lacking CB2R had elevated neutrophil activation. Pharmacological activation of CB2R significantly reduced the PA-induced NF-κB and NLRP3 inflammasome activation, whereas CB2KO mice had elevated NLRP3 inflammasome. Conclusion Our findings indicate that CB2R activation ameliorates PA-induced lung injury and inflammation, thus paving the path for new therapeutic avenues against PA pneumonia.https://doi.org/10.1186/s12931-022-02253-wBacterial pneumoniaPseudomonas aeruginosaAcute lung injury and inflammationCannabinoid-2 receptor |
| spellingShingle | Nagaraja Nagre Gregory Nicholson Xiaofei Cong Janette Lockett Andrew C. Pearson Vincent Chan Woong-Ki Kim K. Yaragudri Vinod John D. Catravas Activation of cannabinoid-2 receptor protects against Pseudomonas aeruginosa induced acute lung injury and inflammation Respiratory Research Bacterial pneumonia Pseudomonas aeruginosa Acute lung injury and inflammation Cannabinoid-2 receptor |
| title | Activation of cannabinoid-2 receptor protects against Pseudomonas aeruginosa induced acute lung injury and inflammation |
| title_full | Activation of cannabinoid-2 receptor protects against Pseudomonas aeruginosa induced acute lung injury and inflammation |
| title_fullStr | Activation of cannabinoid-2 receptor protects against Pseudomonas aeruginosa induced acute lung injury and inflammation |
| title_full_unstemmed | Activation of cannabinoid-2 receptor protects against Pseudomonas aeruginosa induced acute lung injury and inflammation |
| title_short | Activation of cannabinoid-2 receptor protects against Pseudomonas aeruginosa induced acute lung injury and inflammation |
| title_sort | activation of cannabinoid 2 receptor protects against pseudomonas aeruginosa induced acute lung injury and inflammation |
| topic | Bacterial pneumonia Pseudomonas aeruginosa Acute lung injury and inflammation Cannabinoid-2 receptor |
| url | https://doi.org/10.1186/s12931-022-02253-w |
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