β-肾上腺素能信号传导和 NLRP3 炎性体在慢性间歇性缺氧诱导的小鼠肺癌进展中的作用

IF 5.8 2区 医学 Q1 Medicine
Jianxia Sun, Xinyun Jia, Zhiqiang Zhang, Yang Yang, Chuntao Zhai, Baosheng Zhao, Yuzhen Liu
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引用次数: 0

摘要

背景:以慢性间歇性缺氧(CIH)为特征的阻塞性睡眠呼吸暂停(OSA)是一种普遍存在的疾病,与各种形式的癌症有关。尽管一些临床研究表明 OSA 与肺癌之间存在潜在联系,但这种联系仍不确定,其潜在机制也不完全清楚。本研究探讨了儿茶酚胺-β-肾上腺素能受体(βAR)和NLRP3炎性体在介导CIH对小鼠肺癌进展的影响中的作用:雄性 C57BL/6 N 小鼠接受为期四周的 CIH 治疗,并在皮下播种 Lewis 肺癌细胞。在此期间给予普萘洛尔(一种βAR阻断剂)或奈皮司他(一种儿茶酚胺分泌抑制剂)。监测肿瘤体积和尾动脉血压。免疫组化染色和免疫荧光染色用于评估肿瘤组织中 Ki-67、CD31、VEGFR2、PD-1、PD-L1 和 ASC斑点的蛋白表达。ELISA 检测儿茶酚胺和各种细胞因子,Western 印迹评估细胞周期蛋白 D1、caspase-1 和 IL-1β 的表达。体外血管形成试验研究血管生成。用 NLRP3 基因敲除小鼠来确定 NLRP3 在 CIH 中的作用机制:结果:CIH导致儿茶酚胺增加。结果:CIH导致儿茶酚胺增加,儿茶酚胺-βAR抑制剂药物阻止了CIH引起的血压升高。值得注意的是,这些药物抑制了 CIH 诱导的小鼠肺肿瘤的生长,肿瘤中 Ki-67、细胞周期蛋白 D1、CD31、血管内皮生长因子受体 2、PD-1 和 PD-L1 的表达均有所下降。在体外,普萘洛尔能抑制 CIH 小鼠血清诱导的管形成。此外,CIH导致外周血中TNF-α、IL-6、IL-1β、IFN-γ和sPD-L1水平升高,IL-10水平降低,并伴随着肿瘤中NLRP3炎性体的激活,但这些效应也被药物所阻止。在NLRP3基因敲除的小鼠中,CIH诱导的肿瘤中PD-1/PD-L1的上调受到抑制:我们的研究强调了β肾上腺素能信号传导和NLRP3炎性体对CIH诱导的肺癌进展的重要作用。这些通路是减轻 OSA 对肺癌影响的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Role of β-adrenergic signaling and the NLRP3 inflammasome in chronic intermittent hypoxia-induced murine lung cancer progression.

Background: Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is a prevalent condition that has been associated with various forms of cancer. Although some clinical studies suggest a potential link between OSA and lung cancer, this association remains uncertain, and the underlying mechanisms are not fully understood. This study investigated the role of the catecholamine-β-adrenergic receptor (βAR) and the NLRP3 inflammasome in mediating the effects of CIH on lung cancer progression in mice.

Methods: Male C57BL/6 N mice were subjected to CIH for four weeks, with Lewis lung carcinoma cells seeded subcutaneously. Propranolol (a βAR blocker) or nepicastat (an inhibitor of catecholamine production) was administered during this period. Tumor volume and tail artery blood pressure were monitored. Immunohistochemical staining and immunofluorescence staining were employed to assess protein expression of Ki-67, CD31, VEGFR2, PD-1, PD-L1, and ASC specks in tumor tissues. ELISA was used to detect catecholamine and various cytokines, while western blot assessed the expression of cyclin D1, caspase-1, and IL-1β. In vitro tube formation assay investigated angiogenesis. NLRP3 knockout mice were used to determine the mechanism of NLRP3 in CIH.

Results: CIH led to an increase in catecholamine. Catecholamine-βAR inhibitor drugs prevented the increase in blood pressure caused by CIH. Notably, the drugs inhibited CIH-induced murine lung tumor growth, and the expression of Ki-67, cyclin D1, CD31, VEGFR2, PD-1 and PD-L1 in tumor decreased. In vitro, propranolol inhibits tube formation induced by CIH mouse serum. Moreover, CIH led to an increase in TNF-α, IL-6, IL-1β, IFN-γ and sPD-L1 levels and a decrease in IL-10 in peripheral blood, accompanied by activation of NLRP3 inflammasomes in tumor, but these effects were also stopped by drugs. In NLRP3-knockout mice, CIH-induced upregulation of PD-1/PD-L1 in tumor was inhibited.

Conclusions: Our study underscores the significant contribution of β-adrenergic signaling and the NLRP3 inflammasome to CIH-induced lung cancer progression. These pathways represent potential therapeutic targets for mitigating the impact of OSA on lung cancer.

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来源期刊
Respiratory Research
Respiratory Research RESPIRATORY SYSTEM-
CiteScore
9.70
自引率
1.70%
发文量
314
审稿时长
4-8 weeks
期刊介绍: Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.
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