Medicine, University of California, San Diego, La Jolla, California, USA.
VA San Diego Healthcare System, La Jolla, California, USA.
Physiol Rep. 2022 Feb;10(3):e15185. doi: 10.14814/phy2.15185.
Pulmonary arterial hypertension (PAH) is associated with significant morbidity and mortality. PAH is characterized by pulmonary artery remodeling, elevated right ventricular pressure (RVP) and, ultimately, cardiac failure. Pulmonary endothelial cells can sense danger or damage caused by mechanical injury or pathogens through alarmin cytokines. These cytokines can signal proliferation to restore barrier integrity or aberrant hyperproliferation and remodeling. We hypothesized that IL-33 signals pulmonary artery endothelial cells to proliferate under hypertensive conditions during the remodeling response and rise in RVP. To test this hypothesis, pulmonary hypertension (PH) was induced in C57Bl/6J, IL-33 receptor gene deleted (ST2 ) and MYD88 gene deleted (MYD88 ) mice by exposure to 10% O and SU5416 injections (SUHX). RVP, arterial wall thickness, endothelial cell proliferation and IL-33 levels and signaling were evaluated. In response to SUHX. RVP increased in C57Bl/6J mice in response to SUHX (49% male and 70% female; p < 0.0001) and this SUHX response was attenuated in ST2 mice (29% male p = 0.003; 30% female p = 0.001) and absent in MYD88 mice. Wall thickness was increased in SUHX C57Bl/6J mice (p = 0.005), but not in ST2 or MYD88 mice. Proliferating cells were detected in C57Bl/6J mice by flow cytometry (CD31 /BrDU ; p = 0.02) and immunofluorescence methods (Ki-67+). IL-33 was increased by SUHX (p = 0.03) but a genotype effect was not observed (p = 0.76). We observed that in hPAECs, IL-33 expression is regulated by both IL-33 and DLL4. These data suggest IL-33/ST2 signaling is essential for the endothelial cell proliferative response in PH.
肺动脉高压（PAH）与显著的发病率和死亡率相关。PAH 的特征在于肺动脉重塑、右心室压力（RVP）升高，最终导致心力衰竭。肺内皮细胞可以通过警报细胞因子感知机械损伤或病原体引起的危险或损伤。这些细胞因子可以发出信号促进增殖以恢复屏障完整性或异常的过度增殖和重塑。我们假设，在重塑反应和 RVP 升高期间，IL-33 在高血压条件下信号传递给肺动脉内皮细胞以增殖。为了验证这一假设，我们通过暴露于 10% O 和 SU5416 注射（SUHX）在 C57Bl/6J、IL-33 受体基因缺失（ST2）和 MYD88 基因缺失（MYD88）小鼠中诱导肺动脉高压（PH）。评估了 RVP、动脉壁厚度、内皮细胞增殖以及 IL-33 水平和信号传递。在 SUHX 作用下，C57Bl/6J 小鼠的 RVP 增加（雄性 49%，雌性 70%；p<0.0001），而在 ST2 小鼠中，这种 SUHX 反应减弱（雄性 29%，p=0.003；雌性 30%，p=0.001），在 MYD88 小鼠中则不存在。SUHX C57Bl/6J 小鼠的壁厚度增加（p=0.005），但在 ST2 或 MYD88 小鼠中则没有。通过流式细胞术（CD31/BrDU；p=0.02）和免疫荧光方法（Ki-67+）检测到 C57Bl/6J 小鼠中的增殖细胞。SUHX 增加了 IL-33（p=0.03），但未观察到基因型效应（p=0.76）。我们观察到，在 hPAECs 中，IL-33 的表达受 IL-33 和 DLL4 的调节。这些数据表明，IL-33/ST2 信号在 PH 中的内皮细胞增殖反应中是必不可少的。
