Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Xinxiang Medical University, 88 Jiankang Road, Weihui, Henan, 453100, Henan, China.
Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, 88 Jiankang Road, Weihui, 453100, Henan, China.
Respir Res. 2024 Sep 28;25(1):347. doi: 10.1186/s12931-024-02969-x.
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.
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.
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.
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.
阻塞性睡眠呼吸暂停（OSA），其特征为慢性间歇性缺氧（CIH），是一种普遍存在的病症，与各种形式的癌症有关。虽然一些临床研究表明 OSA 与肺癌之间存在潜在联系，但这种关联仍不确定，其潜在机制也尚未完全阐明。本研究旨在探究儿茶酚胺-β肾上腺素能受体（βAR）和 NLRP3 炎性小体在介导 CIH 对小鼠肺癌进展中的作用。
雄性 C57BL/6N 小鼠接受四周 CIH 处理，同时皮下接种 Lewis 肺癌细胞。在此期间给予普萘洛尔（βAR 阻滞剂）或奈帕他定（儿茶酚胺产生抑制剂）。监测肿瘤体积和尾动脉血压。免疫组织化学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 用于检测儿茶酚胺和各种细胞因子，而 Western blot 则用于评估细胞周期蛋白 D1、半胱天冬酶-1 和 IL-1β的表达。体外管形成试验用于研究血管生成。使用 NLRP3 基因敲除小鼠来确定 NLRP3 在 CIH 中的作用机制。
CIH 导致儿茶酚胺增加。儿茶酚胺-βAR 抑制剂药物可预防 CIH 引起的血压升高。值得注意的是，这些药物抑制了 CIH 诱导的小鼠肺肿瘤生长，肿瘤中 Ki-67、细胞周期蛋白 D1、CD31、VEGFR2、PD-1 和 PD-L1 的表达降低。体外，普萘洛尔抑制 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，并导致肿瘤中 NLRP3 炎性小体激活，但这些作用也被药物阻断。在 NLRP3 基因敲除小鼠中，CIH 诱导的肿瘤中 PD-1/PD-L1 上调受到抑制。
本研究强调了 β 肾上腺素能信号和 NLRP3 炎性小体在 CIH 诱导的肺癌进展中的重要作用。这些途径为减轻 OSA 对肺癌的影响提供了潜在的治疗靶点。
