Jiang Pan, Huang Huai, Liu Zilong, Xiang Guiling, Wu Xiaodan, Hao Shengyu, Li Shanqun
Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
The Nutrition Department at Zhongshan Hospital, Fudan University, Shanghai, China.
Respir Res. 2025 Jan 13;26(1):13. doi: 10.1186/s12931-024-03062-z.
Obstructive sleep apnea (OSA) is frequently associated with increased incidence and mortality of pulmonary hypertension (PH). The immune response contributes to pulmonary artery remodeling and OSA-related diseases. The immunologic factors linked to OSA-induced PH are not well understood. STAT6 is crucial in the signaling pathway that modulates immune response. However, the status of phosphorylated STAT6 (p-STAT6) in an OSA-induced PH mouse model remains largely unexplored.
Chronic intermittent hypoxia (CIH) plays a crucial role in the progression of OSA. This study utilized a in vivo CIH model to examine the role of STAT6 in CIH-induced PH.
CIH mice exhibited pulmonary artery remodeling and pulmonary hypertension, indicated by increased right ventricular systolic pressure (RVSP), higher right ventricular to left ventricular plus septum (RV/LV + S) ratios, and significant morphological alterations compared to normoxic (Nor) mice. Increased p-STAT6 in the lungs and elevated p-STAT6 + IL-4 + producing T cells in CIH mice. STAT6 deficiency (STAT6-/-) improved PH and PA remodeling in CIH-induced PH mouse models.STAT6 deficiency impaired the T helper 2 (Th2) immune response, affecting IL-4 and IL-13 secretion. IL-4, rather than IL-13, activated STAT6 in human pulmonary artery smooth muscle cells (hPASMCs). STAT6 knockdown decreased the proliferation in IL-4 treated hPASMCs.
These findings exhibit the critical role of STAT6 in the pathogenesis of CIH induced PH by regulating Th2 immune response.STAT6 could be a significant therapeutic target for OSA-related PH.
阻塞性睡眠呼吸暂停（OSA）常与肺动脉高压（PH）的发病率和死亡率增加相关。免疫反应有助于肺动脉重塑和OSA相关疾病。与OSA诱导的PH相关的免疫因素尚不完全清楚。信号转导和转录激活因子6（STAT6）在调节免疫反应的信号通路中起关键作用。然而，在OSA诱导的PH小鼠模型中，磷酸化STAT6（p-STAT6）的状态在很大程度上仍未被探索。
慢性间歇性缺氧（CIH）在OSA的进展中起关键作用。本研究利用体内CIH模型来研究STAT6在CIH诱导的PH中的作用。
与常氧（Nor）小鼠相比，CIH小鼠表现出肺动脉重塑和肺动脉高压，表现为右心室收缩压（RVSP）升高、右心室与左心室加室间隔（RV/LV + S）比值升高以及明显的形态学改变。CIH小鼠肺中p-STAT6增加，产生p-STAT6 + IL-4 +的T细胞增多。STAT6缺陷（STAT6-/-）改善了CIH诱导的PH小鼠模型中的PH和PA重塑。STAT6缺陷损害了辅助性T细胞2（Th2）免疫反应，影响IL-4和IL-13的分泌。IL-4而非IL-13激活人肺动脉平滑肌细胞（hPASMCs）中的STAT6。敲低STAT6可降低IL-4处理的hPASMCs的增殖。
这些发现表明STAT6通过调节Th2免疫反应在CIH诱导的PH发病机制中起关键作用。STAT6可能是OSA相关PH的重要治疗靶点。
