慢性阻塞性肺疾病和低氧性肺动脉高压诊治进展

按照最新的分类诊断标准,临床上将肺动脉高压(PH)分为5类,其中肺部疾病和(或)低氧所致的肺动脉高压属于肺动脉高压的第3类[1],相关的疾病包括慢性阻塞性肺疾病(COPD)、间质性肺疾病、其他伴有限制性和阻塞性混合型通气障碍的肺部疾病、睡眠呼吸暂停、肺泡低通气、慢性高原缺氧和肺发育异常等.我们在此探讨COPD合并肺动脉高压的临床特征及治疗进展.     

蛋白激酶C与低氧性肺动脉高压

蛋白激酶C（PKC）是细胞膜后住处转导通路之一，在细胞的生长、增殖、代谢等各方面发挥重要作用。了解CK信息通道在低氧性肺动脉高压发病中的作用，有助于探索低氧性肺动脉高压新的防治方法。     

p38MAPK在慢性低氧性肺动脉高压中的作用研究进展

肺动脉高压(PH)是一种具有潜在致命性的慢性肺循环疾病,临床表现为右心室后负荷增加,活动耐力下降,严重者可发生循环衰竭而死亡.其病因复杂,可由多种心、肺疾病或肺血管病引起,慢性低氧是PH的一个常见原因.慢性低氧可诱导p38MAPK激活,p38MAPK激活后能增加血管内皮生长因子的表达,血管内皮生长因子能够促进血管内皮细胞迁徙、增殖,从而导致PH的发生.因此,从p38MAPK信号通道角度研究是研究慢性低氧性肺动脉高压发生机制的新方向.     

低氧性肺动脉高压研究进展

低氧性肺动脉高压（hypoxic pulmomary artery hypertension,HPH）是临床常见的病理生理过程,也是慢性阻塞性肺疾病、慢性肺心病、高原肺动脉高压（高原心脏病）等多种心肺疾病发生发展的关键病理环节.HPH的形成包括低氧性肺血管收缩反应（hypoxic pulmonary vasoconstriction,HPV）和低氧性肺血管重塑（hypoxic pulmonary vascularstructure remodeling,HPSR）两个主要发病环节.近年来,国内外对HPH发病机制和治疗的研究取得了较大进步,现就相关方面的研究进展作一综述.     

低氧诱导因子-1在低氧性肺动脉高压中的研究进展

低氧性肺动脉高压(HPH)是由缺氧引起的肺动脉压力进行性升高的肺血管疾病。低氧诱导因子-1(HIF-1)是维持细胞氧稳态的核心转录因子,可促进细胞糖代谢模式的转变、调节细胞膜表面离子通道活性、调节肺血管收缩及舒张因子活性等,在HPH的发生和发展中具有重要作用。现对HIF-1及其下游信号分子在HPH发生和发展中的作用机制进行综述,有助于为HPH的治疗提供新的理论依据和治疗靶点。     

肺血管重塑与低氧性肺动脉高压

肺血管重塑和肺动脉高压密切相关,慢性缺氧是肺血管重塑和肺动脉高压的一个常见原因.肺血管重塑以纤维母细胞、平滑肌细胞和内皮细胞增殖为最大特征,并导致管腔闭塞.了解肺血管重塑特征和机制对于预防或者逆转肺动脉高压具有重要的意义.     

卡托普利治疗低氧性肺动脉高压的研究进展

卡托普利治疗低氧性肺动脉高压的研究进展中山医科大学附属第一医院呼吸内科吴为群综述容中生审校卡托普利（ｃａｐｔｏｐｒｉｌ）是临床广泛使用的血管紧张素转化酶（ＡＣＥ）抑制剂，主要用来治疗高血压和心力衰竭。近年来，有人将其应用于低氧性肺动脉高压的治疗。本文...     

ATP钾通道开放剂对大鼠慢性低氧性肺动脉高压的作用

目的：研究ATP敏感性钾通道开放剂左旋克罗卡琳（levcromakalim)和克罗卡啉（cromakalim)对慢性低氧大鼠肺动脉平滑肌细胞钾通道（KATP)和低氧性肺动脉高压的作用。方法：90只Wistar大鼠随机分为正常对照组（15只）和低氧组（75只）。应用膜片钳技术，在对称性高钾溶液中，将急性分离的大鼠肺动脉平滑肌细胞的内面向外式膜片上，分离出ATP敏感性KATP电流。应用右心插管技术，测定给药前、后大鼠平均肺动脉压（mPAP)。结果：慢性低氧3周大鼠肺动脉平滑肌细胞KATP通道活性与正常组大鼠比较无明显变化。但钾通道开放剂levcromakalim和cromakalim可明显激活慢性低氧大鼠肺动脉平滑肌细胞KATP电流。给低氧大鼠静脉注射levcromakalim和cromakalim，可对其mPAP产生剂量依赖性的降压作用，而对平均体动脉压也有一定的降低作用。结论：虽然KATP可能没有直接参与大鼠慢性低氧性肺动脉高压的产生，但levcromakalim和cromakalim可通过激活KATP通道而拮抗低氧对其它钾通道的抑制作用，levcromakalim和cromakalim可降低慢性缺氧大鼠低氧性肺动脉高压。     

葛根素对低氧性肺动脉高压大鼠肺动脉压力及结构的影响

目的观察大鼠在低氧状态下出现的肺动脉高压和肺小动脉结构的重构，以及葛根素对这两个病理变化的干预效应。方法雄性SD大鼠24只，随机分为对照组、低氧组和葛根素干预组。低氧组和葛根素干预组在常压低氧舱内建立肺动脉高压模型，葛根素干预组大鼠每天腹腔注射葛根素500mg／kg，测定各组平均肺动脉压，并取大鼠左肺沿肺门横断取材，石蜡包埋切片，进行苏木素伊红（HE）染色，观察肺小动脉形态学变化。结果①对照组和葛根素干预组大鼠平均肺动脉压均明显低于低氧组[（15．01±1．47）mmHg、（20．43±2．86）mmHg、（29．74±2．32）mmHg，P〈0．01]。②对照组大鼠肺小血管管壁较薄、管腔较大，低氧组大鼠肺小动脉普遍增厚，管腔狭窄，葛根素干预组的肺小动脉管壁及血管管腔狭窄程度较低氧组显著减轻。结论慢性缺氧可导致肺动脉壁增厚、管腔狭窄等血管重构病理改变；葛根素能在一定程度上抑制低氧肺动脉高压的形成和发展及肺血管结构的重构。     

Bone morphogenetic protein 4 promotes pulmonary vascular remodeling in hypoxic pulmonary hypertension

We show that 1 of the type II bone morphogenetic protein (BMP) receptor ligands, BMP4, is widely expressed in the adult mouse lung and is upregulated in hypoxia-induced pulmonary hypertension (PH). Furthermore, heterozygous null Bmp4(lacZ/+) mice are protected from the development of hypoxia-induced PH, vascular smooth muscle cell proliferation, and vascular remodeling. This is associated with a reduction in hypoxia-induced Smad1/5/8 phosphorylation and Id1 expression in the pulmonary vasculature. In addition, pulmonary microvascular endothelial cells secrete BMP4 in response to hypoxia and promote proliferation and migration of vascular smooth muscle cells in a BMP4-dependent fashion. These findings indicate that BMP4 plays a dominant role in regulating BMP signaling in the hypoxic pulmonary vasculature and suggest that endothelium-derived BMP4 plays a direct, paracrine role in promoting smooth muscle proliferation and remodeling in hypoxic PH.     

Chronic pelvic pain syndrome and voiding dysfunction

Chronic prostatitis/chronic pelvic pain syndrome is a disease that is mainly characterized by three parameters: pain in the suprapubic and pelvic area, presence or absence of white blood cells in expressed prostatic secretions, and voiding disorders of various degrees. The causative factors underlying this very common condition are poorly understood. Therapeutic options (ie, antimicrobial treatment) often are based on the presence of an inflammatory reaction in the expressed prostatic secretions, but the benefit of recurring or prolonged courses of antimicrobial agents is highly variable. Observations have been made regarding functional and structural changes in the lower urinary tract that are suggestive to have an impact on the pathogenesis of chronic pelvic pain syndrome.     

Chronic propranolol attenuates hypoxic pulmonary vasoconstriction in conscious rats

Experiments were performed on conscious, chronically instrumented rats to assess the effect of chronic propranolol treatment on basal pulmonary hemodynamics and on hypoxic pulmonary vasoconstriction. Rats received either propranolol (4 mg/day) or vehicle for 31 days via implanted osmotic mini-pumps. Animals were then acutely exposed to 8% and 10% O2. Pulmonary arterial pressure (PAP), mean arterial blood pressure (MABP) and heart rate (HR) were monitored via chronically implanted catheters, and cardiac output (CO) was measured by thermodilution. Chronic administration o propranolol was associated with minimal changes in MABP, PAP and total pulmonary resistance (TPuR). However, HR and CO decreased and total systemic resistance (TSR) increased in propranolol treated rats. The acute hypoxic pulmonary vasoconstrictor response of propranolol treated rats was significantly less than that of untreated control animals. Systemic hemodynamic responses to acute hypoxia did not differ between the groups. These data indicate that chronic propranolol administration reduces the acute hypoxic pulmonary vasoconstrictor response in conscious rats, but does not alter basal pulmonary hemodynamics.     

成纤维细胞活化在低氧性肺血管重构中的作用

以往在低氧性肺血管重构机制的研究中,外膜的作用往往被忽略。新近的研究表明,血管外膜特别是其中的成纤维细胞在调节血管功能中发挥着重要的作用。外膜中的成纤维细胞是低氧刺激的首要“损伤感受细胞”,低氧可以激活血管外膜成纤维细胞,活化的成纤维细胞既可以合成分泌细胞生长因子、炎症因子,进而促进中膜血管平滑肌细胞增殖,又可以转分化为平滑肌样细胞（肌纤维母细胞）、分泌胶原蛋白,导致血管重构。因此,低氧导致的成纤维细胞活化及表型转换在肺血管重构中起重要作用,贯穿着低氧性肺血管重构的整个病理过程。     

Endothelial dysfunction in the pulmonary vascular bed

The pulmonary endothelium modulates vascular tone by the release of endothelium-derived constricting (EDCF) and relaxing (EDRF) factors, among them endothelin-1, nitric oxide, prostacyclin, and putative endothelium-derived hyperpolarizing factors. Abnormalities in EDCF and EDRF generation have been demonstrated in a number of cardiopulmonary disease states, such as primary and secondary pulmonary hypertension, chronic obstructive lung disease, cardiopulmonary bypass, and congestive heart failure. An imbalance between EDCF and EDRF, termed "pulmonary endothelial dysfunction," may contribute to the alteration in vascular tone characteristic of pulmonary disease. The following review summarizes the present knowledge of the role of EDCF and EDRF in such processes with major focus on pulmonary endothelial dysfunction in hypoxia-induced pulmonary hypertension.     

肺血管内皮细胞功能障碍与肺动脉高压

肺动脉高压的发病机制是一个复杂的、多因素参与的过程.近年来,逐步形成内皮功能紊乱学说,认为肺血管内皮是引起血管收缩和特征性病理改变的首要因素.本文就肺血管内皮细胞功能障碍和肺动脉高压的研究进展作一综述.     

Intermedin modulates hypoxic pulmonary vascular remodeling by inhibiting pulmonary artery smooth muscle cell proliferation

BackgroundHypoxic pulmonary arterial hypertension (PAH) is a disabling disease with limited treatment options. Hypoxic pulmonary vascular remodeling is a major cause of hypoxic PAH. Pharmacological agents that can inhibit the remodeling process may have great therapeutic value.ObjectiveTo examine the effect of intermedin (IMD), a new calcitonin gene-related peptide family of peptide, on hypoxic pulmonary vascular remodeling.MethodsRats were exposed to normoxia or hypoxia (∼10% O₂), or exposed to hypoxia and treated with IMD, administered by an implanted mini-osmotic pump (6.5 μg/rat/day), for 4 weeks. The effects of IMD infusion on the development of hypoxic PAH and right ventricle (RV) hypertrophy, on pulmonary vascular remodeling, on pulmonary artery smooth muscle cell (PASMC) proliferation and apoptosis, and on the activations of l-arginine nitric oxide (NO) pathway and endoplasmic reticulum stress apoptotic pathway were examined.ResultsRats exposed to hypoxia developed PAH and RV hypertrophy. IMD treatment alleviated PAH and prevented RV hypertrophy. IMD inhibited hypoxic pulmonary vascular remodeling as indicated by reduced wall thickness and increased lumen diameter of pulmonary arterioles, and decreased muscularization of distal pulmonary vasculature in hypoxia-exposed rats. IMD treatment inhibited PASMC proliferation and promoted PASMC apoptosis. IMD treatment increased tissue level of constitutive NO synthase activity and tissue NO content in lungs, and enhanced l-arginine uptake into pulmonary vascular tissues. IMD treatment increased cellular levels of glucose-regulated protein (GRP) 78 and GRP94, two major markers of endoplasmic reticulum (ER) stress, and increased caspase-12 expression, the ER stress-specific caspase, in lungs and cultured PASMCs.ConclusionsThese results demonstrate that IMD treatment attenuates hypoxic pulmonary vascular remodeling, and thereby hypoxic PAH mainly by inhibiting PASMC proliferation. Promotion of PASMC apoptosis may also contribute to the inhibitory effect of IMD. Activations l-arginine–NO pathway and of ER stress-specific apoptosis pathway could be the mechanisms mediating the anti-proliferative and pro-apoptotic effects of IMD.     

Alteration of pulmonary vascular resistance and pulmonary cyclic nucleotide metabolism in the hypoxic pig

Summary Hypoxia leads to an elevation of the pulmonary vascular resistance (pvR) in pigs. This alteration of the hemodynamic was accompanied by a slight increase of intraparenchymatous concentrations of cyclic GMP (cGMP) while cycle AMP (cAMP) levels were not different from values, measured during normoxia. -adrenergic agents are potent inhibitors of the hypoxia induced vasoconstriction. This effect was associated with an increase of intraparenchymatous cAMP-concentrations and a decrease of cGMP-levels. The regression analysis between pvR versus the ratio cGMP/cAMP revealed a significant linears correlation. These data may indicate, that cAMP and cGMP are involved in hypoxia induced vasoconstriction and its pharmacological inhibition.

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Veränderungen des pulmonal-vaskulären Widerstandes und Metabolismus der cyclischen Nukleotide beim hypoxischen Schwein

Zusammenfassung Hypoxie führt beim Schwein zur Erhöhung des pulmonal-vaskulären Widerstandes (pvR). Diese hämodynamische Veränderung ist von einem Anstieg des intraparenchymatösen Spiegels von cyclischem GMP (cGMP) begleitet, während die Konzentrationen des cyclischen AMP (cAMP) im Vergleich zu Werten unter Normoxie unverändert sind. -Sympathikomimetika sind potente Inhibitoren dieser hypoxie-induzierten Vasokonstriktion. Dieser Effekt ist mit einem Anstieg des intraparenchymatösen Spiegels von cAMP und einem Abfall des cGMP-Spiegels assoziiert. Die Regressionsanalyse zwischen dem pvR und dem Quotienten cGMP/cAMP erbrachte eine signifikante lineare Korrelation. Dieses läßt vermuten, daß cAMP und cGMP bei der hypoxie-induzierten pulmonalen Visokonstriktion und deren Aufhebung durch -Sympathikomimetika kausal beteiligt sind.

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