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.     

花生四烯酸细胞色素p450表氧化酶基因对野百合碱诱导大鼠肺动脉高压的治疗作用

目的研究过表达花生四烯酸细胞色素p450表氧化酶基因CYP2J2对野百合碱(MCT)诱导的大鼠原发性肺动脉高压的治疗作用,并对其机制进行初步探讨。方法模型组18只雄性大鼠一次性注射MCT(60 mg/kg·w),对照组18只。三周后分六组:MCT 生理盐水(n=6),MCT pCB6(n=6),MCT pCB6-2J2(n=6),生理盐水(n=6),pCB6(n=6),pCB6-2J2(n=6)。两周后,测右室收缩压RVSP和右室肥厚指数RV/(LV s),western blot检测CYP2J2、Smad4蛋白的表达。结果模型组注射生理盐水、pCB6组RVSP分别为(41.48±0.45)和(38.13±3.68)mm Hg,显著高于正常对照组动物(20.89±3.09)mm Hg,(P<0.05)和模型组注射pCB6-2J2组(29.48±5.67)mm Hg,(P<0.05)。模型组注射生理盐水、pCB6组RV/(LV S)分别为(0.425±0.08)和(0.358±0.07)显著高于正常对照组动物(0.24±0.03)(P<0.01)和模型组注射pCB6-2J2组(0.28±0.02) (P<0.05)。Western blots显示模型组注射生理盐水、pCB6组Smad4蛋白表达水平均明显低于注射pCB6-2J2组。结论过表达CYP2J2基因显著缓解野百合碱诱导的大鼠肺动脉高压,降低右室收缩压和减轻右心室肥厚程度,上调了TGFβ信号通道中的Smad4蛋白。     

Cytochrome P450 epoxygenase CYP2J2 and the risk of coronary artery disease

Cytochrome P450 (CYP) enzyme 2J2, an epoxygenase predominantly expressed in the heart, metabolizes arachidonic acid to biologically active eicosanoids. One of the CYP2J2 products, 11,12-epoxyeicosatrienoic acid, has several vasoprotective effects. A frequent promoter polymorphism of CYP2J2 decreases gene expression and is associated with coronary artery disease. This association supports the vascular protective role of CYP-derived eicosanoids in cardiovascular disease.     

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。     

钙库操纵性钙通道特性及其与低氧性肺血管收缩、重构的关系

肺动脉平滑肌细胞内Ca2+浓度增加是导致低氧性肺血管收缩与重构的重要分子基础.由瞬时受体电位蛋白构成的钙库操纵性钙通道(store-operated channels,SOC)是调节细胞内Ca2+浓度的重要机制,并参与了肺动脉高压时血管收缩和重构过程.充分了解SOC通道的特性,对深入认识肺动脉高压发病的病理生理学机制、指导临床治疗策略具有重要意义.     

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.     

Oxygen sensors in hypoxic pulmonary vasoconstriction

Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism adapting lung perfusion to regional ventilation. Perturbations to HPV, such as those occurring in pneumonia, acute respiratory distress syndrome and liver failure, can result in arterial hypoxemia. Under conditions of general hypoxia, HPV increases pulmonary vascular resistance and thus causes acute pulmonary hypertension. Despite intensive research, the underlying mechanisms of HPV have not been fully elucidated. Deciphering signalling pathways that result in HPV could suggest novel approaches to address a failure of HPV, as well as for the treatment of pulmonary hypertension associated with HPV. Within this context, this review focuses on current concepts in the oxygen sensing mechanisms that underlie HPV.     

Enhanced hypoxic pulmonary vasoconstriction in hypertension

In this study, we tested the hypothesis that hypoxic pulmonary vasoconstriction may be enhanced in systemic hypertension. The hypothesis took origin from the following two considerations: alveolar hypoxia constricts the pulmonary vessels by enhancing the Ca2+ penetration across sarcolemma of the smooth muscle cells and systemic high blood pressure is associated with an elevation of tone and reactivity of the lung vessels, which seems to depend on an excessive cytosol free Ca2+ concentration due to alterations in sodium handling and in the Na+-Ca2+ exchange system. These considerations suggest the possibility that the disorders in the biochemistry of smooth muscle contraction in hypertension facilitate the rise of cytosol Ca2+ concentration during alveolar hypoxia, thus resulting in a potentiation of the vasoconstrictor properties of this stimulus. In 43 hypertensive and 17 normotensive men, pulmonary arteriolar resistance has been evaluated during air respiration and after 15 minutes of breathing 17%, 15%, and 12% oxygen in nitrogen. Curves relating changes in pulmonary arteriolar resistance to oxygen breathing contents had similar configuration in the two populations but in hypertension were steeper and significantly shifted to the left, reflecting a lower threshold and an enhanced reactivity. This pattern was not related to differences in severity of the hypoxic stimulus, plasma catecholamine concentration, or hypocapnia and respiratory alkalosis induced by hypoxia and probably was not mediated through alpha-receptor activation. Calcium channel blockade with nifedipine was able to almost abolish both the normotensive and the hypertensive pulmonary vasoconstriction reaction. These findings support the hypothesis that hypoxic pulmonary vasoconstriction may be enhanced in systemic hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanisms of hypoxic pulmonary vasoconstriction

During the last 4 decades hypoxic vasoconstriction has been acknowledged as an important pulmonary control mechanism that via matching ventilation and perfusion regulates one of the important physiologic parameters--PaO2. Whether the hypoxic vasoconstriction occurs directly in a localized vascular site with distinct biochemistry or whether it is mediated by a local hormone has not been resolved. Progress has been made because of the introduction of micropuncture techniques that allow direct pressure measurements in small segments of the lung vascular tree. Measurements of the force of contraction and membrane potential (118) and manipulation of the environment of pulmonary microvessels are the most recent progress in the elucidation of the mechanism of hypoxic vasoconstriction. Elements of energy, oxygen, and lipid metabolism appear to contribute to the biochemistry of this elusive response.     

Low-molecular-weight heparin inhibits hypoxic pulmonary hypertension and vascular remodeling in guinea pigs

RATIONALE: We have shown previously that antiproliferative unfractionated heparins block hypoxia-induced pulmonary arterial hypertension (PAH) and vascular remodeling, and hypothesized that low-molecular-weight heparins (LMWHs) would too. OBJECTIVES: To determine the potential role and mechanisms of dalteparin and enoxaparin (two LMWHs) in inhibiting hypoxic PAH and vascular remodeling. METHODS: Male Hartley guinea pigs were exposed for 10 days to normobaric 10% oxygen with dalteparin (5 mg/kg), enoxaparin (5 mg/kg), or with an equivalent volume of normal saline solution. Normoxic control animals (n = 5) received room air for 10 days. Bovine pulmonary artery smooth-muscle cells (PASMCs) were grown in 10% fetal bovine serum without heparin, with dalteparin (1 microg/mL) or with enoxaparin (1 microg/mL). MEASUREMENTS: Pulmonary arterial pressure (PAP), cardiac index, right ventricular heart weight divided by left ventricular plus septum weight (RV/LV+S), hematocrit, percentage of wall thickness of intraacinar vessels (%WT-IA), percentage of wall thickness of terminal bronchiole vessels (%WT-TA), and the percentage of thick-walled vessels (%Thick) were determined. In PASMCs, expression of p27 and cell growth were compared because in mice whole heparin depends on p27 for its antiproliferative action. MAIN RESULTS: In hypoxic animals, hematocrit, PAP, total pulmonary vascular resistance index, RV/LV+S, %WT-IA, %WT-TA, and %Thick all rose significantly vs normoxic control animals (p < 0.05); cardiac index was unchanged. Dalteparin but not enoxaparin significantly reduced PAP, total pulmonary vascular resistance index, and RV/LV + S (p < 0.05 vs hypoxia alone); inhibited PASMC growth; and upregulated p27 expression. Enoxaparin moderately reduced vascular remodeling, which did not translate into less pulmonary hypertension. CONCLUSIONS: Not all LMWHs are the same. Dalteparin was more effective than enoxaparin in inhibiting pulmonary hypertension and vascular remodeling in hypoxic guinea pigs.     

病原生物学中细胞色素P450的重要意义

细胞色素Ｐ4 50单加氧酶系在药物、杀虫剂、植物毒素等外源化合物的解毒及内源化合物的代谢中所起的重要作用 ,已引起越来越多研究者的重视。细胞色素Ｐ4 50 (ＣＹＰ4 50 )作为该酶系的末端氧化酶 ,可与底物结合并将电子从ＮＡＤＰＨ传递至ＮＡＤＰＨ细胞色素Ｐ4 50还原酶。细胞色素Ｐ4 50的重要特征是还原型Ｐ4 50与ＣＯ结合形成的复合体 ,在波长 4 50ｎｍ处有最大的吸收峰 (γ峰 )。目前ＣＯ差光谱检测仍是检测细胞色素Ｐ4 50的主要手段之一。Ｋｌｉｎｇｅｎｂｅｒ在鼠肝脏微粒体中首次发现了这种具有特殊光谱学特征的色素蛋白 ,但其极不…     

安立生坦与波生坦对低氧性肺动脉高压大鼠肺血管重构的比较研究

目的:比较安立生坦和波生坦对低氧性肺动脉高压(hypoxic pulmonary hypertension,HPH)大鼠肺血管重构治疗效果的比较。方法:40只SD大鼠随机分成5组:对照组、模型组、波生坦组、安立生坦组和安慰剂组,每组8只。对照组于自然环境中饲养4周,其他组置于低压低氧舱中低氧(8 h/d)饲养4周。从低氧开始第3周起,安立生坦组、波生坦组和安慰剂组大鼠每天进舱前依次分别给予安立生坦(5 mg/kg)、波生坦组(125 mg/kg)和生理盐水(2 ml)灌胃,共两周。实验结束后,测定所有大鼠平均肺动脉压力(mPAP)、右心室收缩末压(RVSP)和右心室压力最大上升速率(dP/dtmax)。各组大鼠肺组织以HE染色后,观察中小动脉形态的变化。应用图像分析系统检测管壁厚度占外径的百分比[WT(%)]和管壁面积占总面积的百分比[WA(%)]。应用免疫组化染色法检测肺血管平滑肌肌动蛋白(α-SMA)的表达。结果:HE染色切片显示,模型组和安慰剂组大鼠的肺小动脉管壁增厚、管腔狭窄,安立生坦组和波生坦组可基本恢复至对照组状态。与对照组相比,模型组和安慰剂组mPAP、WT(%)、WA(%)和α-SMA蛋白的表达均显著升高(P<0.05),安立生坦组和波生坦组上述各项指标差异均无统计学意义。结论:安立生坦与波生坦均能显著降低HPH大鼠的肺动脉压力,逆转肺血管重构。安立生坦组与波生坦组的治疗效果无统计学差异。     

CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction

Hypoxic pulmonary vasoconstriction (HPV) optimizes pulmonary ventilation-perfusion matching in regional hypoxia, but promotes pulmonary hypertension in global hypoxia. Ventilation-perfusion mismatch is a major cause of hypoxemia in cystic fibrosis. We hypothesized that cystic fibrosis transmembrane conductance regulator (CFTR) may be critical in HPV, potentially by modulating the response to sphingolipids as mediators of HPV. HPV and ventilation-perfusion mismatch were analyzed in isolated mouse lungs or in vivo. Ca²⁺ mobilization and transient receptor potential canonical 6 (TRPC6) translocation were studied in human pulmonary (PASMCs) or coronary (CASMCs) artery smooth muscle cells. CFTR inhibition or deficiency diminished HPV and aggravated ventilation-perfusion mismatch. In PASMCs, hypoxia caused CFTR to interact with TRPC6, whereas CFTR inhibition attenuated hypoxia-induced TRPC6 translocation to caveolae and Ca²⁺ mobilization. Ca²⁺ mobilization by sphingosine-1-phosphate (S1P) was also attenuated by CFTR inhibition in PASMCs, but amplified in CASMCs. Inhibition of neutral sphingomyelinase (nSMase) blocked HPV, whereas exogenous nSMase caused TRPC6 translocation and vasoconstriction that were blocked by CFTR inhibition. nSMase- and hypoxia-induced vasoconstriction, yet not TRPC6 translocation, were blocked by inhibition or deficiency of sphingosine kinase 1 (SphK1) or antagonism of S1P receptors 2 and 4 (S1P_2/4). S1P and nSMase had synergistic effects on pulmonary vasoconstriction that involved TRPC6, phospholipase C, and rho kinase. Our findings demonstrate a central role of CFTR and sphingolipids in HPV. Upon hypoxia, nSMase triggers TRPC6 translocation, which requires its interaction with CFTR. Concomitant SphK1-dependent formation of S1P and activation of S1P_2/4 result in phospholipase C-mediated TRPC6 and rho kinase activation, which conjointly trigger vasoconstriction.In regional hypoventilation of the lung, hypoxic pulmonary vasoconstriction (HPV) protects against systemic hypoxemia by redistributing blood flow from poorly to better ventilated areas of the lung, thereby minimizing ventilation-perfusion (V_A/Q) mismatch (1). In chronic hypoxemia-associated lung disease, however, HPV contributes to pulmonary hypertension (PH), characterized by increased resistance and progressive remodeling of the pulmonary arteries, eventually leading to right ventricular hypertrophy and, ultimately, right heart failure.In the lung, hypoxia is initially sensed at the alveolocapillary level (2). The signal is then propagated retrogradely via gap junctions to upstream arterioles, where it is transmitted to adjacent pulmonary arterial smooth muscle cells (PASMCs) for initiation of HPV (2). Contraction of PASMCs is ultimately triggered by RhoA/rho kinase (RhoK)-mediated Ca²⁺ sensitization and concomitant cytosolic Ca²⁺ increase (1), for which transient receptor potential canonical 6 (TRPC6) plays a predominant role (3). TRPC6 is a nonselective cation channel (4) that is highly expressed in PASMCs (3) and colocalizes with caveolin-1 (5). Upon hypoxia, TRPC6 translocates to caveolin- and sphingolipid-rich lipid rafts (6), where it is activated by diacylglycerol (DAG) via phospholipase C (PLC) (4, 7). However, the signaling pathways that translocate TRPC6 to caveolae and activate PLC and RhoA in response to hypoxia remain obscure. Here, we provide evidence for a previously unrecognized role of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) in HPV and mechanistically link this finding to a newly identified, dual role of sphingolipids in both the activation of PLC and RhoA and the translocation of TRPC6.Gene mutations in CFTR cause CF, an autosomal recessive genetic disorder leading to viscous mucus secretion and recurring lung infections. CF is typically associated with profound pulmonary V_A/Q mismatches (8) and intrapulmonary shunts (9), which led us to hypothesize that HPV may be impaired in this condition. Indeed, arterial hypoxemia in CF patients can be accounted for by V_A/Q inequalities and shunts, yet not by impaired O₂ diffusion (10). Intriguingly, HPV is also abrogated in pneumonia (11) or sepsis (12) caused by Pseudomonas aeruginosa, which phenocopy CF disease via secretion of the virulence factor CFTR inhibitory factor (Cif) (13). Robert et al. reported the expression of CFTR in PASMCs and demonstrated its involvement in the modulation of pulmonary arterial tone (14). In the systemic circulation, CFTR-F508del, the most common mutation underlying human CF disease, has recently been associated with diminished Ca²⁺ release in vascular smooth muscle cells, decreased aortic tone, and responsiveness (15). Of specific relevance for HPV, CFTR was recently shown to directly interact with TRPC6, thus regulating TRPC6-dependent Ca²⁺ influx (16). Based on these considerations, we postulated that CFTR may play a crucial, yet so far unrecognized, role in hypoxia-induced Ca²⁺ mobilization underlying PASMC contraction and HPV.Interestingly, CFTR is considered to regulate homeostasis and lipid raft concentrations of sphingolipids (17, 18), which have recently become implicated in HPV in that HPV is blocked by inhibition of neutral sphingomyelinase (nSMase), which releases ceramide from sphingomyelin (19). nSMase is activated upon oxidative stress (20), possibly via arachidonic acid liberation by phospholipase A₂ (21), which all have been linked to HPV (1). In addition, ceramide accumulates in PASMCs upon hypoxia (22), mediates caveolar TRPC6 translocation in lung endothelial cells (23), and contributes to constriction of pulmonary artery rings (19, 24). Although ceramide may thus potentially act as a direct mediator of HPV, it may also serve as substrate for the formation of other, bioactive sphingolipids, most notably sphingosine-1-phosphate (S1P). S1P is generated by conversion of ceramide to sphingosine and its subsequent phosphorylation by sphingosine kinase (SphK) (25), which is known to be up-regulated upon hypoxia (26). In the lung, SphK1 is the predominant SphK isoform (27) and has been shown to modulate pulmonary vascular responsiveness and remodeling (28). S1P acts intracellularly as a second messenger or extracellularly via activation of five G protein-coupled receptors (GPCRs) termed S1P_1–5 (25), of which S1P₂ (29) and S1P₄ (30) mediate pulmonary vasoconstriction. Because S1P₂ (29, 31) and S1P₄ (32) receptor engagement activates PLC and RhoK, and S1P is a known activator of TRPC5 (33), we hypothesized that S1P may trigger both central pathways of HPV, DAG formation and consecutive TRPC6-induced Ca²⁺ mobilization, as well as RhoK-mediated Ca²⁺ sensitization (1). A potential role of S1P in HPV is particularly intriguing in consideration of its potential tie to CFTR, in that CFTR is one of only two transporters shown to translocate S1P across biological membranes (17). In the present study, we hence probed for the functional role of CFTR and its mechanistic link to sphingolipid signaling in HPV.     

Endocannabinoid anandamide mediates hypoxic pulmonary vasoconstriction

Endocannabinoids are important regulators of organ homeostasis. Although their role in systemic vasculature has been extensively studied, their impact on pulmonary vessels remains less clear. Herein, we show that the endocannabinoid anandamide (AEA) is a key mediator of hypoxic pulmonary vasoconstriction (HPV) via fatty acid amide hydrolase (FAAH)-dependent metabolites. This is underscored by the prominent vasoconstrictive effect of AEA on pulmonary arteries and strongly reduced HPV in FAAH^−/− mice and wild-type mice upon pharmacological treatment with FAAH inhibitor URB597. In addition, mass spectrometry measurements revealed a clear increase of AEA and the FAAH-dependent metabolite arachidonic acid in hypoxic lungs of wild-type mice. We have identified pulmonary vascular smooth muscle cells as the source responsible for hypoxia-induced AEA generation. Moreover, either FAAH^−/− mice or wild-type mice treated with FAAH inhibitor URB597 are protected against hypoxia-induced pulmonary hypertension and the concomitant vascular remodeling in the lung. Thus, the AEA/FAAH pathway is an important mediator of HPV and is involved in the generation of pulmonary hypertension.Endocannabinoids have been shown to induce vasorelaxation in systemic vessels which is primarily mediated by the specific cannabinoid 1 and 2 (CB1/CB2) and also other G protein-coupled receptors (e.g., non-CB1/CB2 receptors) (1, 2). Based on these results, especially CB1 receptors have been proposed as promising therapeutic targets for the treatment of arterial hypertension (2). Endocannabinoids are also known to potentially act via their intracellular enzymatic metabolization by the fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL) to (vaso)active intermediates (3, 4), but these pathways are considered less important for the regulation of vascular tone in systemic vessels.Pulmonary arteries are unique because of their prominent vasoconstriction in response to hypoxia. Hypoxic vasoconstriction is responsible for adapting perfusion to ventilation in the lungs and therefore also plays an important role in pathophysiological situations characterized by a high ventilation/perfusion mismatch such as acute lung injury or liver cirrhosis (5, 6). In addition, this mechanism potentially contributes to the onset of pulmonary hypertension in response to hypoxia occurring in high altitude or in various respiratory diseases such as chronic obstructive pulmonary disease or fibrosis (7–9). Pulmonary arterial smooth muscle cells are suggested to play a major role in hypoxic vasoconstriction (10), but the precise mechanisms and the underlying signals are still not well understood. Earlier experimental evidence suggested that the endocannabinoid anandamide (AEA) can either enhance (11) or reduce (12) pulmonary arterial tone, and this prompted us to reexplore the role of endocannabinoids in basic physiological and pathophysiological responses of pulmonary arteries using experimental in vitro, ex vivo, and in vivo approaches.     

花生四烯酸细胞色素p450表氧化酶基因对肺动脉高压大鼠血浆和组织中ET-1、NO、TXA2和PGI2变化的影响

目的观察野百合碱(MCT)诱导的肺动脉高压大鼠中花生四烯酸色素p450表氧化酶CYP2J2基因过表达时血浆和肺组织中内皮素-l(ET-1)、一氧化氮(NO)血栓素A2(TXA2)和前列腺素I2(PGI2)的水平及肺组织中一氧化氮合酶(NOS)活性的变化。方法成年雄性SD大鼠60只随机分为正常对照组(n=30)和MCT模型组(n=30),皮下注射MCT(60mg/kg)建立肺动脉高压模型。三周后尾静脉分别注射生理盐水和质粒分为6组:NS组,pCDNA3.1(n=10),pcDNA3.1-CYP2J2(n=10),MCT+NS(n=10),MCT+pCDNA3.1(n=10),MCT+pCDNA3.1-CYP2J2(n=10)。三周后,检测大鼠肺动脉压(mPAP),测定血浆和肺组织中ET-1和NO水平,检测肺组织中NOS和eNOS的活性,检测血浆和肺组织TXA2代谢产物TXB2和PGI2代谢产物6-酮-前列腺素1α(6-keto-PGF1α)水平及TXB2/6-keto-PGF1α的比值。结果 MCT模型组mPAP,血浆和肺组织中ET-1水平和TXB2含量和TXB2/6-keto-PGF1α比值均明显高于正常对照组(P<0.05),而pCDNA3.1-CYP2J2治疗组与MCT模型组比均显著降低(P<0.05),但仍高于正常对照组(P<0.05);MCT模型组血浆和肺组织中NO和6-keto-PGF1α含量,肺组织eNOS和NOS活性,TXB2/6-keto-PGF1α比值均明显低于正常对照组(P<0.05),而pCDNA3.1-CYP2J2治疗组均明显增高(P<0.05),但仍低于正常对照组(P<0.05)。结论花生四烯酸色素p450表氧化酶基因CYP2J2可逆转MCT诱导的肺动脉高压,其机制可能与降低肺组织和血浆中的ET-1和TXA2含量,升高PGI2含量,上调TXA2/PGI2比值,上调机体内eNOS和总NOS活性,增加体内NO水平有关。CYP2J2基因治疗对肺动脉高压有积极的治疗作用。     

The effects of agents that bind to cytochrome P-450 on hypoxic pulmonary vasoconstriction

The relationship between pulmonary arterial pressure (Ppa) and blood (Q) was determined during normoxia and hypoxia in ventilated pig lungs perfused in situ with the animal's own blood. Hypoxia shifted the Ppa-Q relationship to the right and decreased its slope, indicating pulmonary vasoconstriction. Carbon monoxide (11.5% in the inspired gas) and metyrapone ditartrate (10 mg/min into the perfusate) caused vasodilation when oxygenation was normal and reduced the vasoconstriction caused by hypoxia. Since the only pharmacological property CO and metyrapone are thought to have in common at the concentrations employed is the ability to bind to the heme iron of cytochrome P-450, these results are consistent with the hypothesis that desaturation of this cytochrome leads to pulmonary vasoconstriction. Prostaglandin F2alpha, infused into the pulmonary artery at 0.01 mg/min, when oxygenation was normal, had effects on the Ppa-Q relationship similar to those of hypoxia. The F2alpha response was also reduced by CO and metyrapone, suggesting either that P-450 was involved in the F2alpha response or that CO and metyrapone were toxic to pulmonary vascular smooth muscle. Proadifen hydrochloride (1 mg/min), which is thought to bind to the protein moiety of P-450 also reduced the hypoxic response, but was a vasoconstrictor during normoxia and did not affect the F2alpha response.