外泌体介导肺泡上皮细胞在低氧性肺动脉高压中的作用及机制研究

Hypoxic pulmonary hypertension (HPH) can only result from alveolar hypoxia, alveolar epithelial cells were the first to perceive the change of oxygen partial pressure,while the role of alveolar epithelial cells in HPH has not been reported. Our previous research showed that hypoxia promoted promoted the secretion of exosomes from alveolar epithelial cells. Both the co-culture of pulmonary artery smooth muscle cells (PASMCs) and AEC in hypoxia or hypoxic supernatant of alveolar epithelial cells can promote the proliferation of PASMCs. Hypoxic supernatant of alveolar epithelial cells can also promote the contraction of isolated pulmonary vascular ring. Inhibitting exocrine secretion can effectively improve HPH. In addition, it was also found that hypoxia up-regulated the expression of ACE and inhibited the expression of ACE2. Therefore, we hypothesize that hypoxia promoted the imbalance of ACE-AngⅡand ACE2-Ang(l-7) in alveolar epithelial cells, ACE-AngⅡis secreted into the lung interstitial by the form of exocrine, which induced pulmonary vascular remodeling and pulmonary vasoconstriction. Summary, the role and mechanism of exocrine from alveolar epithelial cells in HPH were studied in overall and cellular level. This study provides new targets for intervention against HPH.

只有肺泡缺氧才能引起低氧性肺动脉高压(HPH)，肺泡上皮细胞是最早感知氧分压变化，而肺泡上皮细胞在HPH形成中的作用尚未见报道。我们前期研究发现，低氧促进肺泡上皮细胞外泌体分泌，肺动脉平滑肌细胞(PASMCs)与肺泡上皮细胞低氧条件下共培养，或者PASMCs中加入低氧性肺泡上皮细胞上清液，均能促进PASMCs增殖；另外，低氧性肺泡上皮细胞上清液引起离体肺血管收缩，抑制外泌体分泌能够有效改善HPH。此外，还发现低氧上调肺泡上皮细胞ACE表达，抑制ACE2表达。因此，我们推测，低氧引起肺泡上皮细胞ACE-AngⅡ与ACE2-Ang(1-7) 表达失衡，以外泌体形式将ACE-AngⅡ分泌到肺间质，作用于肺血管，引起肺血管重构和收缩，形成HPH。综上所述，本课题拟在整体和细胞水平，研究肺泡上皮细胞来源外泌体在低氧性肺血管重构和收缩中的作用及机制，为防治HPH提供新的提供新的干预靶点。

早期研究认为只有肺泡缺氧才能引起低氧性肺动脉高压(HPH)，肺泡作为气体交换的首要场所，低氧时肺泡上皮细胞是最早感知肺泡内氧分压变化的细胞，也是遭受的氧分压变化最剧烈的细胞。我们研究发现低氧时肺泡上皮细胞发生改变，并且以外泌体形式分泌出去，改变肺血管微环境，且作用到肺血管，影响肺血管平滑肌细胞的增殖和肺血管的收缩，促进HPH的形成。我们研究证实，低氧导致肺泡上皮细胞ACE-AngⅡ与ACE2-Ang(1-7) 表达失衡，以外泌体形式将ACE-AngⅡ分泌到肺间质，参与肺血管的重构和收缩。抑制外泌体分泌能够有效改善HPH。本研究为明确肺泡上皮细胞在 HPH 发展中的作用提供理论基础，也为临床防治低氧性肺动脉高压提供新的干预靶点。