sr-144528 and Acute-Lung-Injury

Dendritic cells (DCs) play a key role in a variety of inflammatory lung diseases, but their role in sepsis-associated acute lung injury (SA-ALI) is currently not been illuminated. Cannabinoid receptor 2 (CNR2) has been reported to regulate the DCs maturation. However, whether the CNR2 in DCs contributes to therapeutic therapy for SA-ALI remain unclear. In current study, the role of CNR2 on DCs maturation and inflammatory during SA-ALI is to explored.. First, the CNR2 level was analyzed in isolated Peripheral Blood Mononuclear Cells (PBMCs) and Bronchoalveolar Lavage Fluid (BALF) from patient with SA-ALI by qRT-PCR and flow cytometry. Subsequently, HU308, a specific agonist of CNR2, and SR144528, a specific antagonist of CNR2, were introduced to explore the function of CNR2 on DCs maturation and inflammatory during SA-ALI. Finally, CNR2 conditional knockout mice were generated to further confirm the function of DCs maturation and Inflammation during SA-ALI.. First, we found that the expression of CNR2 on DCs was decreased in patient with SA-ALI. Besides, the result showed HU308 could decrease the maturation of DCs and the level of inflammatory cytokines, simultaneously reduce pulmonary pathological injury after LPS-induced sepsis in mice. In contrast of HU308, SR144528 exhibits opposite function of DCs maturate, inflammatory cytokines and lung pathological injury. Furthermore, comparing with SR144528 treatment, similar results were obtained in DCs specific CNR2 knockout mice after LPS treatment.. CNR2 could alleviate SA-ALI by modulating maturation of DCs and inflammatory factors levels. Targeting CNR2 signaling specifically in DCs has therapeutic potential for the treatment of SA-ALI.

Topics: Acute Lung Injury; Animals; Cytokines; Dendritic Cells; Humans; Leukocytes, Mononuclear; Lipopolysaccharides; Lung; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Cannabinoid; Sepsis

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.. 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.. 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.. Our findings indicate that CB2R activation ameliorates PA-induced lung injury and inflammation, thus paving the path for new therapeutic avenues against PA pneumonia.

Topics: Acute Lung Injury; Animals; Cannabinoids; Cytokines; Disease Models, Animal; Inflammasomes; Inflammation; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Pseudomonas aeruginosa; Pseudomonas Infections; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Respiratory Distress Syndrome