Activation of cannabinoid-2 receptor protects against Pseudomonas aeruginosa induced acute lung injury and inflammation.
Activation of cannabinoid-2 receptor protects against Pseudomonas aeruginosa induced acute lung injury and inflammation.
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DOI：
10.1186/s12931-022-02253-w
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发表时间：
2022-12-03
影响因子：
5.8
通讯作者：
Catravas, John D.
中科院分区：
文献类型：
--
作者：
Nagre, Nagaraja;Nicholson, Gregory;Cong, Xiaofei;Lockett, Janette;Pearson, Andrew C.;Chan, Vincent;Kim, Woong-Ki;Vinod, K. Yaragudri;Catravas, John D.
关键词：
细菌性肺炎是急性肺损伤(ALI)和急性呼吸窘迫综合征(ARDS)的主要危险因素。铜绿假单胞菌(PA)是一种对多种药物耐药的条件致病菌，是各种临床环境下ALI和ARDS的主要病原体之一。鉴于大麻素2受体(CB2R)的抗炎作用，在小鼠模型上测试了CB2R激活在调节PA诱导的ALI和炎症中的作用，作为传统抗生素治疗的替代。为激活CB2R，经腹腔注射选择性合成激动剂JWH133。对C57BL/6J小鼠。此外，选择性CB2R拮抗剂SR144528与JWH133联合应用，以检测CB2R介导的效应的特异性。PA经气管内给药(I.T.)用于诱导小鼠肺炎。在PA暴露后24小时，用FlexiVent系统测量肺力学。测定支气管肺泡灌洗液(BALF)中细胞总数、蛋白质含量和中性粒细胞数。同时测定全肺细菌载量。通过组织学检查评价肺损伤程度，通过测定BALF细胞因子和趋化因子水平评价PA诱导的炎症反应。中性粒细胞激活(免疫荧光和免疫印迹检测)和PA诱导的炎症信号(免疫印迹分析)也进行了研究。JWH133激活CB2R可显著降低PA诱导的ALI和细菌负荷。CB2R的激活也抑制了PA诱导的免疫细胞浸润、中性粒细胞数量和炎性细胞因子的增加。这些效应被CB2R拮抗剂SR144528取消，进一步证实了CB2R介导的效应的特异性。与WT小鼠相比，CB2R基因敲除(CB2RKO)小鼠的PA诱导的炎症水平显著升高。CB2R的激活减少了中性粒细胞的过度激活，而缺乏CB2R的小鼠的中性粒细胞活性升高。CB2R的药理活性显著降低PA诱导的NF-κB和NLRP3炎性小体的激活，而CB2KO小鼠则升高NLRP3炎性小体的激活。我们的研究结果表明，CB2R的激活可以减轻PA引起的肺损伤和炎症，从而为治疗PA肺炎的新途径铺平道路。
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.
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影响因子：
5.5
作者：
Fukumoto, Jutaro;Fukumoto, Itsuko;Kolliputi, Narasaiah
通讯作者：
Kolliputi, Narasaiah
影响因子：
81.5
作者：
Matthay, Michael A.;Zemans, Rachel L.;Calfee, Carolyn S.
通讯作者：
Calfee, Carolyn S.
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
15.9
作者：
Cohen, Taylor S.;Prince, Alice S.
通讯作者：
Prince, Alice S.
通过减少自噬和增强吞噬作用，NLRP3的缺失增强了多数型败血症期间的存活。
DOI：
10.4049/jimmunol.1601745
发表时间：
2017-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Jin L;Batra S;Jeyaseelan S
通讯作者：
Jeyaseelan S