Isoforskolin, an adenylyl cyclase activator, attenuates cigarette smoke-induced COPD in rats,Phytomedicine

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Isoforskolin, an adenylyl cyclase activator, attenuates cigarette smoke-induced COPD in rats
Phytomedicine ( IF 6.7 ) Pub Date : 2021-08-08 , DOI: 10.1016/j.phymed.2021.153701
Chuang Xiao ₁ , Sha Cheng ₁ , Haochang Lin ₁ , Zhiying Weng ₁ , Peihua Peng ₁ , Deyou Zeng ₁ , Xiaohua Du ₁ , Xiujuan Zhang ₁ , Yaqing Yang ₁ , Yaping Liang ₁ , Rong Huang ₁ , Chen Chen ₁ , Lueli Wang ₁ , Hongxiang Wu ₁ , Runfeng Li ₂ , Xinhua Wang ₂ , Rongping Zhang ₁ , Zifeng Yang ₂ , Xian Li ₁ , Xue Cao ₃ , Weimin Yang ₁

Affiliation

Background

Chronic obstructive pulmonary disease (COPD) is characterized by limited airflow due to pulmonary and alveolar abnormalities from exposure to cigarette smoke (CS). Current therapeutic drugs are limited and the development of novel treatments to prevent disease progression is challenging. Isoforskolin (ISOF) from the plant Coleus forskohlii is an effective activator of adenylyl cyclase (AC) isoforms. Previously we found ISOF could attenuate acute lung injury in animal models, while the effect of ISOF on COPD has not been elucidated.

Purpose

In this study, we aimed to evaluate the efficacy of ISOF on COPD and reveal its potential mechanisms.

Methods

A rat model of COPD was established by long-term exposure to CS, then the rats were orally administered with ISOF (0.5, 1 and 2 mg/kg). The pulmonary function, lung morphology, inflammatory cells and cytokines in serum or bronchoalveolar lavage fluid (BALF) were evaluated. Transcriptomics, proteomics and network pharmacology analysis were utilized to identify potential mechanisms of ISOF. Droplet digital PCR was used to detect the mRNA expression of AC1-10 in donor lung tissues. AC activation was determined in recombinant human embryonic kidney 293 (HEK293) cells stably expressing human AC isoforms. In addition, ISOF caused trachea relaxation ex vivo were assessed in isolated trachea rings from guinea pigs.

Results

ISOF significantly ameliorated pathological damage of lung tissue and improved pulmonary function in COPD rats. ISOF treatment decreased the number of inflammatory cells in peripheral blood, and also the levels of pro-inflammatory cytokines in serum and BALF. Consistent with omics-based analyses, ISOF markedly downregulated the mTOR level in lung tissue. Flow cytometry analysis revealed that ISOF treatment reduced the ratio of Th17/Treg cells in peripheral blood. Furthermore, the expression levels of AC1 and AC2 are relatively higher than other AC isoforms in normal lung tissues, and ISOF could potently activate AC1 and AC2 in vitro and significantly relax isolated guinea pig trachea.

Conclusion

Collectively, our studies suggest that ISOF exerts its anti-COPD effect by improving lung function, anti-inflammation and trachea relaxation, which may be related to AC activation, mTOR signaling and Th17/Treg balance.

中文翻译：

Isoforskolin 是一种腺苷酸环化酶激活剂，可减轻大鼠吸烟引起的 COPD

背景

慢性阻塞性肺疾病 (COPD) 的特征是由于暴露于香烟烟雾 (CS) 导致的肺和肺泡异常导致气流受限。目前的治疗药物是有限的，开发新的预防疾病进展的治疗方法具有挑战性。来自毛喉锦紫苏植物的异福司可林 (ISOF)是腺苷酸环化酶 (AC) 异构体的有效激活剂。以前我们发现 ISOF 可以减轻动物模型中的急性肺损伤，而 ISOF 对 COPD 的影响尚未阐明。

目的

在本研究中，我们旨在评估 ISOF 对 COPD 的疗效并揭示其潜在机制。

方法

通过长期暴露于CS建立COPD大鼠模型，然后给大鼠口服ISOF（0.5、1和2mg/kg）。评估血清或支气管肺泡灌洗液 (BALF) 中的肺功能、肺形态、炎症细胞和细胞因子。利用转录组学、蛋白质组学和网络药理学分析来确定 ISOF 的潜在机制。采用液滴数字PCR检测供体肺组织中AC1-10的mRNA表达。在稳定表达人 AC 同种型的重组人胚胎肾 293 (HEK293) 细胞中确定 AC 激活。此外，在离体的豚鼠气管环中评估了ISOF 引起的离体气管松弛。

结果

ISOF显着改善COPD大鼠肺组织病理损伤，改善肺功能。ISOF 治疗降低了外周血中炎性细胞的数量，以及血清和 BALF 中促炎细胞因子的水平。与基于组学的分析一致，ISOF 显着下调了肺组织中的 mTOR 水平。流式细胞术分析显示，ISOF 治疗降低了外周血中 Th17/Treg 细胞的比例。此外，AC1和AC2在正常肺组织中的表达水平相对高于其他AC亚型，并且ISOF可以在体外有效激活AC1和AC2并显着松弛离体豚鼠气管。