肺动脉高压病理生理学 遗传学和分子生物学.pptVIP

血管增殖性肺动脉高压病人的丛状病变 Courtesy of Norbert Voelkel (VEGF) 从状病变的免疫染色 严重肺动脉高压的血管增殖紊乱 正常人 内皮细胞 IPAH患者 内皮细胞 三维血管造影术揭示广泛的血管重构和无序血管网络的发展 White et al Am J Physiol Lung Cell Mol Physiol 293: L583-L590, 2007 三维血管造影术揭示广泛的血管重构和无序血管网络的发展 21 days after 60 mg/kg MCT Before early capillary loss 7 days after MCT 21-day rat 对照 肺切除大鼠 RA PA 肺动脉高压: 微血管缺乏的疾病？ Courtesy of Dr. Michelakis, University of Alberta 酪氨酸激酶 (PDGF, VEGF) Apoptosis Proliferation Ghofrani et al NEJM 2005 0 0 10 -8 10 -7 10 -6 5-HT (10-6 M) 5-HT (M) 1000 2000 500 1500 2500 Ketanserin GR127935 Fluoxetine Citalopram SB20665 [3H]Thymidine incorporation (cpm / well) 5-HT2A, 5-HT2B 5-HT1B, 1D 5-HT 5-HT transporter 5-HT Na+ 5-HT 平滑肌细胞 Eddahibi S et al, Circ Res, 1999 人肺动脉血管平滑肌细胞中5-HT促有丝分裂活性 剪切力 血流量增加 ? 肺动脉压力 ?内皮的损伤 ? 细胞外基质的降解 ?内源性血管弹性酶 基质金属蛋白酶的激活 ? FGF ? TGF-? ? 凝血 ? 炎症 内皮细胞损伤 剪切力 炎症的影响 遗传学 家族型肺动脉高压-A是一种复杂孟德尔(氏)病: 常染色体显性遗传 ?基因外显率 0.2 骨形成蛋白受体（BMPR)2 突变见于： 50% 的 家族性肺动脉高压 30% 的 散发性肺动脉高压 8% 的 食欲抑制药物相关性肺动脉高压 未受影响 携带者 受累 15 19 45 UK family 04 19 58 53 20 Courtesy of Richard C. Trembath * * Metabolic Functions of the Pulmonary Circulation Cells comprising the the lung vasculature, particularly endothelial cells that line the vessel lumen, are involved in the uptake or metabolic conversion of several vasoactive substances in the circulation. Lung vascular cells also release biologically active compounds into the circulation that act either locally or in other organs. Some of the substances metabolized by the lung from mixed venous blood are listed in the table. The lung may also synthesize and/or release substances such as histamine, prostaglandins, leukotrienes, platelet activating factor, serotonin and nitric oxide in response to certain conditions, such as pulmonary emboli or shock (anaphylaxis). * Plexiform lesion from a patient with severe angioproliferative pulmonary hypertension. The nuclei of the phenotypically altered cells in the plexiform lesion demonstrate punctuate, brow