Ca2+ and ion channels in hypoxia-mediated pulmonary hypertension

Alveolar hypoxia, a consequence of many lung diseases, can have adverse effects on the pulmonary vasculature. The changes that occur in the pulmonary circulation with exposure to chronic hypoxia include reductions in the diameter of the pulmonary arteries due to structural remodeling of the vasculature. Although the structural and functional changes that occur in the development of pulmonary hypertension have been well investigated, less is known about the cellular and molecular mechanisms of this process. This review will discuss the role of several potassium and calcium channels in hypoxic pulmonary vasoconstriction, both in elevating calcium influx into pulmonary artery smooth muscle cells (PASMCs). In addition to other signal transduction pathways, Ca²⁺ signaling in PASMCs plays an important role in the development and progression of pulmonary hypertension due to its central roles in vasoconstriction and vascular remodeling. This review will focus on the effect of chronic hypoxia on ion channels and the potential pathogenic role of Ca²⁺ signaling and regulation in the progression of pulmonary hypertension.     

POEMS综合征合并肺动脉高压临床分析

目的 分析POEMS综合征合并肺动脉高压患者的临床特点.方法 回顾性分析北京协和医院确诊POEMS综合征患者的临床资料,并将超声心动图证实合并肺动脉高压的患者与肺动脉压正常的患者以及未行超声心动检查的患者的临床表现进行比较,描述合并肺动脉高压的POEMS综合征患者的临床特点.结果 POEMS综合征117例,合并肺动脉高压49例,肺动脉压正常33例,未行超声心动检查35例;肺动脉高压患病率41.9%.肺动脉高压组临床表现主要为胸闷、憋气,发生率42.9%(21/49),显著高于另外两组(P≤0.05),但一半以上患者无明显胸闷、憋气;肺动脉高压组并发胸水、腹水、心包积液发生率较另外两组高(P≤0.01),其他临床表现无显著差异.结论 POEMS综合征超声心动图检测肺动脉高压患病率高达40%以上,但半数以上患者无胸闷、憋气,提示在POEMS综合征诊治过程中应重视肺动脉高压的筛查和早期发现.     

Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia

BACKGROUND: Most patients with familial primary pulmonary hypertension have defects in the gene for bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor beta (TGF-beta) superfamily of receptors. Because patients with hereditary hemorrhagic telangiectasia may have lung disease that is indistinguishable from primary pulmonary hypertension, we investigated the genetic basis of lung disease in these patients. METHODS: We evaluated members of five kindreds plus one individual patient with hereditary hemorrhagic telangiectasia and identified 10 cases of pulmonary hypertension. In the two largest families, we used microsatellite markers to test for linkage to genes encoding TGF-beta-receptor proteins, including endoglin and activin-receptor-like kinase 1 (ALK1), and BMPR2. In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations. RESULTS: We identified suggestive linkage of pulmonary hypertension with hereditary hemorrhagic telangiectasia on chromosome 12q13, a region that includes ALK1. We identified amino acid changes in activin-receptor-like kinase 1 that were inherited in subjects who had a disorder with clinical and histologic features indistinguishable from those of primary pulmonary hypertension. Immunohistochemical analysis in four subjects and one control showed pulmonary vascular endothelial expression of activin-receptor-like kinase 1 in normal and diseased pulmonary arteries. CONCLUSIONS: Pulmonary hypertension in association with hereditary hemorrhagic telangiectasia can involve mutations in ALK1. These mutations are associated with diverse effects, including the vascular dilatation characteristic of hereditary hemorrhagic telangiectasia and the occlusion of small pulmonary arteries that is typical of primary pulmonary hypertension.     

Clinical and immunoserological characteristics of mixed connective tissue disease associated with pulmonary arterial hypertension

We investigated the clinical characteristics and immunoserological alterations in patients with mixed connective tissue disease (MCTD) associated with pulmonary arterial hypertension (PAH). Anti-U1RNP autoantibodies, anti-endothelial cell antibodies (AECA) and serum thrombomodulin (TM) as well as von Willebrand factor antigen (vWFAg) concentrations were measured in 25 patients with MCTD associated with PAH and in 154 MCTD patients without PAH. The results showed that the probability of survival was lower in MCTD patients with PAH than in the 154 MCTD-non-PAH patients (5-year survival rate in MCTD with PAH: 73%, versus 96% in MCTD-non-PAH; P < 0.01). AECA were more frequently present in the sera of MCTD patients with PAH than in MCTD-non-PAH (P < 0.001). Serum TM and vWFAg levels were higher in MCTD-PAH patients than in MCTD-non-PAH patients (TM: P < 0.001; vWFAg: P < 0.001). Significant correlation was noticed between the quantity of AECA and TM level (r = 0.466) as well as the quantity of AECA and vWFAg level (r = 0.550). In conclusion, our results suggest that in MCTD the presence of AECA and endothelial cell activation may play a role in the development of PAH and in the maintenance of obliterative vascular processes.     

Clinical response to inhaled nitric oxide in persistent pulmonary hypertension of the newborn.

We observed clinical response to inhaled nitric oxide (iNO) in 12 neonates with persistent pulmonary hypertension of the newborn (PPHN). Clinical response was defined as a decrease in oxygenation index (OI) by 40%. Ten of 12 neonates had response to iNO showing decrease OI from 46.1+/-7.6 to 14.4+/-6.8 at 1 hour after inhalation. Sustained improvement of OI was achieved in 8 neonates and two neonates were relapsed. In the group of neonates who had OI above 40 (n=7), 6 of them showed the decrease of OI from 66.1+/-4.8 to 18.3+/-8.0 at 1 hour. In two groups, one had OI of 40 or greater, and the other OI of 40 or less, there were no differences in pattern of response and early death rate. The response rates according to underlying diseases were as follows; idiopathic PPHN 100%, respiratory distress syndrome 100%, and diaphragmatic hernia 66.7%. Relapse was observed in one neonate with sepsis caused by pneumonia and in one infant with meconium aspiration syndrome. Two infants showed no response to iNO (one diaphragmatic hernia and one suspected pulmonary hypoplasia). We conclude that iNO therapy could improve oxygenation in high percentage of newborn infants with severe PPHN of various underlying conditions except pulmonary hypoplasia.     

低氧性肺动脉高压和慢性支气管炎、肺气肿并肺动脉高压动物模型的异同

目的 比较低氧性肺动脉高压与慢性支气管炎、肺气肿并肺动脉高压动物模型的异同,为研究慢性阻塞性肺疾病中肺动脉高压形成机制提供良好的实验模型.方法 24只雄性SD大鼠随机纳入10%低氧组(A组)、慢性支气管炎、肺气肿并肺动脉高压组(B组)及正常对照组(C组),8只/组.吸入10%氧2周制作A组,气管内注入脂多糖和每天烟熏混合刺激加18%低氧制作B组模型.各组测定血气分析、肺血流动力学并对肺泡灌洗液行白细胞计数、分类.肺组织HE染色或三联染色后观测气道炎症和肺血管重构的病理形态学改变.结果 (1)与C组比较,A、B组右心室收缩压、平均肺动脉压、右心室与左心室+室间隔重量比升高,腺泡内肌化型动脉增多、管壁增厚(P＜0.05).(2)BALF分析A组白细胞总数与C组差异无显著性(P＞0.05);B组白细胞总数及中性粒细胞增多(P＜0.05).(3) A组气道炎症以上皮细胞变性坏死、黏液杯状细胞增生为主,炎细胞浸润不明显.B组气道炎症符合慢性支气管炎、肺气肿改变,管壁呈现以淋巴细胞为主的多种炎细胞浸润.结论 B组同时体现了慢性气道炎症、肺气肿改变和肺血管重构的特征,更适合用于慢性阻塞性肺疾病中肺动脉高压形成机制的研究.