From the Stanford University School of Medicine, Department of Medicine, CA (R.T., P.M., T.S., J.Q., M.S., L.P.N., A.L., M.R., A.H., L.A., M.R.N.).
VA Palo Alto Health Care System, CA (O.M., Y.-C.L., A.L., A.B.T., J.M.S., M.R.N.).
Circ Res. 2018 Jun 8;122(12):1689-1702. doi: 10.1161/CIRCRESAHA.117.312058. Epub 2018 Mar 15.
Pulmonary arterial hypertension (PH) is a life-threatening condition associated with immune dysregulation and abnormal regulatory T cell (Treg) activity, but it is currently unknown whether and how abnormal Treg function differentially affects males and females.
To evaluate whether and how Treg deficiency differentially affects male and female rats in experimental PH.
Male and female athymic rats, lacking Tregs, were treated with the VEGFR2 (vascular endothelial growth factor receptor 2) inhibitor SU5416 or chronic hypoxia and evaluated for PH; some animals underwent Treg immune reconstitution before SU5416 administration. Plasma PGI (prostacyclin) levels were measured. Lung and right ventricles were assessed for the expression of the vasoprotective proteins COX-2 (cyclooxygenase 2), PTGIS (prostacyclin synthase), PDL-1 (programmed death ligand 1), and HO-1 (heme oxygenase 1). Inhibitors of these pathways were administered to athymic rats undergoing Treg immune reconstitution. Finally, human cardiac microvascular endothelial cells cocultured with Tregs were evaluated for COX-2, PDL-1, HO-1, and ER (estrogen receptor) expression, and culture supernatants were assayed for PGI and IL (interleukin)-10. SU5416-treatment and chronic hypoxia produced more severe PH in female than male athymic rats. Females were distinguished by greater pulmonary inflammation, augmented right ventricular fibrosis, lower plasma PGI levels, decreased lung COX-2, PTGIS, HO-1, and PDL-1 expression and reduced right ventricular PDL-1 levels. In both sexes, Treg immune reconstitution protected against PH development and raised levels of plasma PGI and cardiopulmonary COX-2, PTGIS, PDL-1, and HO-1. Inhibiting COX-2, HO-1, and PD-1 (programmed death 1)/PDL-1 pathways abrogated Treg protection. In vitro, human Tregs directly upregulated endothelial COX-2, PDL-1, HO-1, ERs and increased supernatant levels of PGI and IL-10.
In 2 animal models of PH based on Treg deficiency, females developed more severe PH than males. The data suggest that females are especially reliant on the normal Treg function to counteract the effects of pulmonary vascular injury leading to PH.
肺动脉高压（PH）是一种危及生命的疾病，与免疫失调和调节性 T 细胞（Treg）活性异常有关，但目前尚不清楚 Treg 功能的异常是否以及如何对男性和女性产生不同的影响。
评估 Treg 缺乏症在实验性 PH 中对雄性和雌性大鼠的影响是否存在差异以及如何产生差异。
采用 VEGFR2（血管内皮生长因子受体 2）抑制剂 SU5416 或慢性低氧处理缺乏 Treg 的雄性和雌性无胸腺大鼠，并评估 PH 情况；部分动物在给予 SU5416 前进行 Treg 免疫重建。测量血浆 PGI（前列环素）水平。评估肺和右心室中血管保护蛋白 COX-2（环氧化酶 2）、PTGIS（前列环素合酶）、PDL-1（程序性死亡配体 1）和 HO-1（血红素加氧酶 1）的表达。向接受 Treg 免疫重建的无胸腺大鼠给予这些途径的抑制剂。最后，共培养 Treg 的人心脏微血管内皮细胞评估 COX-2、PDL-1、HO-1 和 ER（雌激素受体）的表达，并检测培养上清液中的 PGI 和 IL（白细胞介素）-10。SU5416 处理和慢性低氧导致雌性无胸腺大鼠比雄性大鼠产生更严重的 PH。雌性大鼠表现出更严重的肺部炎症、右心室纤维化增加、血浆 PGI 水平降低、肺 COX-2、PTGIS、HO-1 和 PDL-1 表达减少以及右心室 PDL-1 水平降低。在两性中，Treg 免疫重建均能预防 PH 的发生，并提高血浆 PGI 和心肺 COX-2、PTGIS、PDL-1 和 HO-1 的水平。抑制 COX-2、HO-1 和 PD-1（程序性死亡 1）/PDL-1 途径会消除 Treg 的保护作用。在体外，人 Treg 直接上调内皮细胞 COX-2、PDL-1、HO-1、ER，并增加上清液中 PGI 和 IL-10 的水平。
在基于 Treg 缺乏症的 2 种 PH 动物模型中，雌性大鼠比雄性大鼠发生更严重的 PH。数据表明，女性尤其依赖正常的 Treg 功能来对抗导致 PH 的肺血管损伤的影响。
