A potential role for cannabichromene in modulating TRP channels during acute respiratory distress syndrome.
A potential role for cannabichromene in modulating TRP channels during acute respiratory distress syndrome.
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DOI：
10.1186/s42238-021-00101-0
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发表时间：
2021-10-01
影响因子：
3.7
通讯作者：
Baban B
中科院分区：
文献类型：
--
作者：
Khodadadi H;Salles ÉL;Shin E;Jarrahi A;Costigliola V;Kumar P;Yu JC;Morgan JC;Hess DC;Vaibhav K;Dhandapani KM;Baban B
急性呼吸窘迫综合征（ARDS）是一种危及生命的临床综合征，其可能成为医疗保健系统最严峻的挑战之一，COVID-19大流行证明了这一点。由于目前对ARDS缺乏靶向治疗，因此寻找一种有效的治疗方法来降低ARDS患者的住院率和死亡率，改善患者的生活质量和预后是非常迫切的。ARDS是一种始于肺系统的全身性炎症性疾病，并以病态的双向方式累及所有其他器官。越来越多的证据，包括我们的研究结果，支持大麻素有潜力作为炎症性疾病治疗中的调节治疗方式。因此，这是合理的，以测试他们的能力作为替代疗法治疗ARDS。在这项研究中，我们研究了大麻色烯（CBC）在ARDS实验模型中的潜在保护作用。我们第一次使用吸入CBC治疗作为ARDS样症状小鼠模型的潜在治疗靶点。通过向C57 BL/6小鼠（6-10只雄性小鼠/组，包括假手术、安慰剂和CBC治疗）鼻内给予Poly（I：C）（一种合成的错配双链RNA）诱导ARDS，每日一次给药3次，然后在第二次Poly（I：C）治疗后2小时开始每日吸入CBC或安慰剂，持续8天。我们采用组织学、免疫组化和流式细胞术的方法来评估这些发现。通过使用单因素方差分析（ANOVA），然后使用Newman-Keuls事后检验进行统计分析，以确定所有实验组的平均值之间的差异，并建立所有组之间的显著性（p < 0.05）。我们的数据表明，CBC能够逆转缺氧（使血液O2饱和度增加8%），改善ARDS症状（使肺和血液中的促炎细胞因子减少50%），并保护肺组织免受进一步破坏。进一步的分析表明，CBC可能通过瞬时受体电位（TRP）阳离子通道，TRPA 1和TRPV 1发挥其保护作用，与假手术和未治疗的小鼠相比，其在肺组织中的表达增加了5倍，重建了体内平衡和免疫平衡。我们的研究结果表明，吸入CBC可能是一个有效的替代治疗目标在治疗ARDS。此外，CBC治疗后TRP阳离子通道的表达增加提出了TRP（TRPA 1和TRPV 2）作为新的潜在机制的新作用，以解释CBC以及其他大麻素在治疗ARDS以及其他炎性疾病中的有益作用。重要的是，通过吸入器装置递送CBC是一种转化模型，支持人类受试者试验的可行性，授权进一步研究。
Acute respiratory distress syndrome (ARDS) is a life-threatening clinical syndrome whose potential to become one of the most grievous challenges of the healthcare system evidenced by the COVID-19 pandemic. Considering the lack of target-specific treatment for ARDS, it is absolutely exigent to have an effective therapeutic modality to reduce hospitalization and mortality rate as well as to improve quality of life and outcomes for ARDS patients. ARDS is a systemic inflammatory disease starting with the pulmonary system and involves all other organs in a morbid bidirectional fashion. Mounting evidence including our findings supporting the notion that cannabinoids have potential to be targeted as regulatory therapeutic modalities in the treatment of inflammatory diseases. Therefore, it is plausible to test their capabilities as alternative therapies in the treatment of ARDS. In this study, we investigated the potential protective effects of cannabichromene (CBC) in an experimental model of ARDS. We used, for the first time, an inhalant CBC treatment as a potential therapeutic target in a murine model of ARDS-like symptoms. ARDS was induced by intranasal administration of Poly(I:C), a synthetic mismatched double-stranded RNA, into the C57BL/6 mice (6–10 male mice/group, including sham, placebo, and CBC treated), three once-daily doses followed by a daily dose of inhalant CBC or placebo for the period of 8 days starting the first dose 2 h after the second Poly(I:C) treatment. We employed histologic, immunohistochemistry, and flow cytometry methods to assess the findings. Statistical analysis was performed by using one way analysis of variance (ANOVA) followed by Newman–Keuls post hoc test to determine the differences among the means of all experimental groups and to establish significance (p < 0.05) among all groups. Our data showed that CBC was able to reverse the hypoxia (increasing blood O2 saturation by 8%), ameliorate the symptoms of ARDS (reducing the pro-inflammatory cytokines by 50% in lung and blood), and protect the lung tissues from further destruction. Further analysis showed that CBC may wield its protective effects through transient receptor potential (TRP) cation channels, TRPA1 and TRPV1, increasing their expression by 5-folds in lung tissues compared to sham and untreated mice, re-establishing the homeostasis and immune balance. Our findings suggest that inhalant CBC may be an effective alternative therapeutic target in the treatment of ARDS. In addition, Increased expression of TRPs cation channels after CBC treatment proposes a novel role for TRPs (TRPA1 and TRPV2) as new potential mechanism to interpret the beneficial effects of CBC as well as other cannabinoids in the treatment of ARDS as well as other inflammatory diseases. Importantly, delivering CBC through an inhaler device is a translational model supporting the feasibility of trial with human subjects, authorizing further research.