银杏叶提取物对野百合碱所致肺动脉高压保护作用的实验研究

目的：探讨银杏叶提取物对野百合碱所致肺动脉高压（PAH）的早期保护作用。方法：30只雄性 SD大鼠随机分为3组：对照组、PAH 模型组和治疗组,每组10只。PAH 模型组和治疗组大鼠采用脊背部皮下注射1%野百合碱60 mg/kg的方法复制PAH 模型,注射后第2天开始每日予2 ml 0.9%氯化钠注射液（PAH 模型组）或60 mg/kg银杏叶提取物（治疗组）灌胃;对照组脊背部皮下注射等量溶剂,注射后第2天开始每日予2 ml 0.9%氯化钠注射液灌胃。第22天采用颈外静脉右心导管法测定平均肺动脉压（mPAP）、右心室收缩压（RVSP）,测定右心室、左心室、室间隔的重量,计算右心室肥厚指数（RVHI）;采用 HE染色观察肺细小动脉组织结构情况,并计算直径50~150μm的肺小动脉血管管壁厚度占血管厚度百分比（WA%）和血管管壁面积与血管面积比值（WV%）;采用免疫组化方法观察内皮型一氧化氮合成酶（eNOS）及内皮素-1（ET-1）在大鼠肺组织中的表达情况。结果：PAH 模型组、治疗组的 mPAP、RVSP、RVHI、WA%、WV%与对照组比较均明显升高（P〈0.05）,治疗组的 mPAP、RVSP、WA%、WV%较 PAH 模型组均降低（P〈0.05）,而治疗组与 PAH 模型组的RVHI差异无显著性。免疫组化结果显示,3组 eNOS表达,对照组〉治疗组〉PAH 模型组;3组 ET-1的表达, PAH 模型组〉治疗组〉对照组。结论：银杏叶提取物通过抑制 ET-1的合成、减轻内皮细胞损伤、维持 eNOS的表达,达到减缓PAH 进展的作用。     

The effects of single lung transplantation in rats with monocrotaline-induced pulmonary hypertension

Abstract Acute haemodynamic change after single lung transplantation for primary pulmonary hypertension was evaluated using a rat transplantation model. Inbred Fisher 344 rats were administered with 40 mg/kg monocrotaline in order to induce pulmonary hypertension. The rats whose mean pulmonary arterial pressure (PAP) was over 30.0 mmHg received a left lung isograft from a normal donor after right heart catheterization. In the control group, PAP increased after single lung transplantation. On the other hand, in the pulmonary hypertensive group, PAP was significantly decreased 60 min after the transplantation, but 3 and 6 h after the transplantation, the PAP significantly increased again. On the day after the operation, it again decreased significantly. Left-to-right lung blood flow ratio was significantly increased in rats with pulmonary hypertension compared to rats with normal pulmonary pressure on both the 1st and 3rd postoperative days. The oedema of the grafted lung was more severe in the pulmonary hypertensive group than in the control group in the acute phase. In conclusion, single lung transplantation for pulmonary hypertension shifted pulmonary blood perfusion to the grafted lung and this shift made pulmonary oedema of the grafts more severe in the acute phase. These oedematous changes, which were more pronounced in the grafts in the pulmonary hypertensive rats, might have contributed to the transient rise in PAP in those rats after single lung transplanation.     

硝普钠经肺动脉直接输注对肺动脉高压的疗效观察

目的　观察硝普钠对二尖瓣置换术后肺动脉高压的疗效。方法　对二尖瓣置换术后具有肺动脉高压的患者 ,由颈内静脉或锁骨下静脉放置Swan -Ganz导管监测其血液动力学指标 ,采用硝普钠经肺动脉端直接输注进行治疗 ,观察硝普钠治疗前后上述血液动力学指标的变化情况。结果　采用硝普钠进行治疗后 ,患者的平均动脉血压 (MAP)、平均肺动脉压 (MPAP)、外周血管阻力指数 (SVRI)及肺血管阻力指数 (PVRI)较用药前明显下降 (P <0 0 5 ) ,而每搏输出量 (SV)、心输出量(CO)及心脏指数 (CI)较用药前明显增高 (P <0 0 5 )。结论　由肺动脉直接输注硝普钠可有效降低二尖瓣置换术后的肺动脉高压 ,并可提高患者的心输出量     

Specific inhibition of p38 mitogen-activated protein kinase with FR167653 attenuates vascular proliferation in monocrotaline-induced pulmonary hypertension in rats

OBJECTIVES: p38 mitogen-activated protein kinase is associated with many clinical entities characterized by inflammation. We postulated that inhibition of p38 mitogen-activated protein kinase with FR167653 attenuates inflammation and the development of pulmonary hypertension in monocrotaline-treated rats. METHODS: Rats were divided into 4 groups: (1) the control group (daily 0.9% saline), (2) the FR group (daily FR167653, 2 mg . kg(-1) . d(-1)), (3) the MCT group (daily 0.9% saline the day after a single monocrotaline dose, 60 mg/kg), and (4) the MCT+FR group (daily FR167653, 2 mg . kg(-1) . d(-1), the day after a single MCT dose). Body weight, pulmonary artery pressure, and morphometric changes of the pulmonary artery with the histopathologic method were observed weekly for 4 weeks. Also, p38 mitogen-activated protein kinase activity and inflammatory cytokine expression in the lung were measured. RESULTS: Four weeks after monocrotaline administration, mean pulmonary artery pressure in the MCT+FR group was lower than in the MCT group (MCT+FR vs MCT: 24.7 +/- 1.9 vs 36.5 +/- 2.1 mm Hg; P < .05). In morphometric analysis the percentage of medial wall thickness and the percentage of muscularization in the MCT+FR group were reduced compared with those in the MCT group after 4 weeks (P < .05); however, the number of macrophages was not significantly different. p38 mitogen-activated protein kinase activity was significantly attenuated in the MCT+FR group compared with in the MCT group (7.2 +/- 0.52 vs 2.1 +/- 0.23 fold-increase, P < .05, at 1 week). Although mRNA levels of tumor necrosis factor alpha and interleukin 1beta were reduced in the MCT+FR group compared with in the MCT group (tumor necrosis factor alpha: 1.18 +/- 0.36 vs 3.05 +/- 1.12 fold-increase, P < .05, at 2 weeks; interleukin 1beta: 2.2 +/- 0.34 vs 4.4 +/- 1.09 fold-increase, P < .05, at 1 week), FR167653 did not suppress increased monocyte chemotactic protein 1 mRNA expression induced by monocrotaline (3.2 +/- 0.62 vs 3.1 +/- 0.42 fold-increase, at 1 week). CONCLUSION: FR167653 significantly attenuates the expression of inflammatory cytokines, ultimately preventing the progression of pulmonary hypertension. These results suggest that p38 mitogen-activated protein kinase might play a central role in the molecular events that underlie the development and progression of pulmonary hypertension.     

PEEP对肺高压患儿呼吸功能的影响

目的 观察小儿先心肺高压在心内直视手术麻醉期间,不同通气模式对呼吸功能的影响。方法 将24例中度肺高压（M组）和24例重度肺高压（S组）的先心病患儿随机各分为三组:M1、S1组为PCV通气组;M2、S2组为PCV+PEEP（2cm H2O）通气组;M3、S3组为PCV+PEEP（4cmH2O）通气组。测定各组各时点的呼吸系统总顺应性（Crs）及肺表面活性物质（PS）生化指标。结果与诱导插管后、体外循环（CPB）转流前比较,M1、M2组以及S1、S2组体外循环转流后和术毕的Crs值有显著下降（P<0.01）,而 M3和S3组前后比较则Crs值无明显改变;M1、M2组以及S1、S2组体外循环转流后和术毕的SatPC/TP、SatPC/TPL比值下降显著（M1、S2组,P<0.01;M2、S2组,P<0.05）,而M3和S3组SatPC/TP、SatPC/TPL比值无明显改变。结论 采用4cm H2O的PEEP对于防止术后肺功能的进一步恶化有效。     

肿瘤坏死因子α对兔门静脉高压症形成的作用

目的　探讨肿瘤坏死因子α(TNFα)在门静脉高压症(PHT)形成过程中的作用。方法　本实验通过门静脉缩窄法制备兔PHT模型,采用MTT法测定对照组、PHT组门静脉缩窄后1,3,7d以及3周时的外周血TNFα水平,并应用电磁血流量计和多导生理记录仪测定其门静脉血流动力学的变化以及一氧化氮(NO)合成抑制剂对PHT血流动力学的影响。结果　PHT组自由门静脉压(FPP)、门静脉血流量(PVF)、门体分流率(PSSRP)以及外周血TNFα水平显著升高(P<0.01);而平均动脉压(MAP)、向肝门静脉血流量(Qpv)、脏侧闭塞门静脉压(SOPP)明显下降(P<0.01)。应用NO合成抑制剂后PHT组PVF明显降低(P<0.01),MAP明显升高(P<0.01),而FPP无明显变化(P>0.05);对照组除MAP明显升高(P<0.01)外,PVF,FPP均无明显变化(P>0.05)。结论　TNFα对PHT血流动力学改变可能起重要作用,NO是介导此过程的主要介质。     

Oral sildenafil prevents and reverses the development of pulmonary hypertension in monocrotaline-treated rats

The endothelin system plays an important role in the development of pulmonary hypertension. Several studies have suggested that interfering with the function of the endothelin system will be helpful in pulmonary hypertension treatment. In the present study, we investigated the preventive and therapeutic effects of sildenafil on pulmonary hypertension in monocrotaline-treated rats. In the preventive study, the level of mean pulmonary arterial pressure, right ventricular divide, left ventricular and septum, small pulmonary arterial morphologic and elastic fiber changes were highly improved in the treated group (P<0.05). The expressions of endothelin-1 A type receptors on small pulmonary arterial hypertension were significantly reduced in the sildenafil-treated group (P<0.05). The ET-1 level in plasma was increased in the sildenafil-treated group, but did not reach significance. Emphysema, interstitial pneumonia were significantly improved in the sildenafil-treated group. The same findings were also observed in the therapeutic study. The present results suggest that sildenafil can prevent and reverse the development of pulmonary hypertension in monocrotaline-treated rats by improving the function of endothelin system in pulmonary arteries.     

左肺反向循环逆转终末期肺动脉高压

目的 探讨反向肺循环逆转终末期肺动脉高压的机制.方法 选杂种犬30只,随机分成正常对照组(n=10)、肺动脉高压组(n=10)和肺高压反向组(n=10).观察各组的血流动力学参数、动脉血气、外周血一氧化氮(NO)、一氧化氮合酶(eNOS)、内皮素及其肺组织mRNA表达的变化.结果 终末期肺高压模型犬上行左肺反向循环手术后,平均肺动脉压(MPAP)降低[(17.3±3.5)mm Hg,P<0.01],但与正常犬MPAP[(12.6±4.2)mm Hg]相比仍偏高(P<0.05);动脉血氧分压上升到(96.5±6.4)mm Hg(P<0.01),血浆中eNOS升高[(1.53±0.56)μg/ml,P<0.01],NO分泌量增加[(36.25±6.94)μmol/L,P<0.01],ET的含量减少[(21.37±3.82)pg/ml,P<0.01].eNOS-mRNA在术后表达上调,PEET-mRNA在肺高压时表达上调,而在术后表达下调.结论 左肺反向循环具有可行性,可能通过转换血气交换的解剖位置、提高血氧含量、抑制血管收缩因子的产生,增加血管舒张因子的产生降低肺动脉高压.     

Effect of pulmonary hypertension in patients with end-stage lung disease on posttransplantation outcomes

A subgroup of patients with end-stage lung disease develop secondary pulmonary hypertension (PH). PH results in worse prognosis in these patients. However, it is unclear if this effect prevails in the immediate- and long-term outcomes of these patients after lung transplantation (LT). The objective of this study was to evaluate the effect of pretransplantation PH on immediate- or long-term posttransplantation outcomes. A retrospective chart review of post-LT patients at Henry Ford Hospital from January 1995 through January 2008 was done. Patients were grouped by presence or absence of PH and were compared using chi-square or Fisher exact tests for categorical variables and t tests or Wilcoxon rank sum tests for continuous variables. Kaplan-Meier estimation was used to evaluate primary and secondary outcomes. Among the patients included in the study, 25 had PH. This group consisted mostly of females (68%). There was no difference in the indication or type of LT in the 2 groups. There was no statistically significant difference in freedom from bronchiolitis obliterans syndrome (BOS; P = .42), time to onset of BOS (P = .82), grade of BOS (P = .21), or cummulative acute rejection (CAR) score (P = .66). There was no difference in overall mortality at 3 and 5 years (P = .57) or time to death (P = .25). Number of A1 rejection episodes was the only significant predictor for BOS (P = .001). In conclusion, PH due to end-stage lung disease does not have any effect on early or late posttransplantation outcomes. There is predisposition for females with end-stage lung disease to develop secondary PH more so than males. The number of A1 rejections increases the likelihood of development of BOS. A larger multicenter study is needed to confirm the results of this pilot study.     

Effect of renal denervation on the development of hypertension in Dahl-Iwai salt-sensitive rats.

Renal denervation has been shown to delay the onset of hypertension in spontaneously hypertensive rats and DOCA-salt sensitive rats. We investigated the contribution of the renal nerves to the development of hypertension in Dahl-Iwai salt-sensitive (DS) rats. Bilateral renal denervation or sham-operation was carried out in DS rats, and animals were then kept on a high salt diet (study I) or on a normal salt diet (study II). DS rats became severely hypertensive (207 +/- 8 mmHg) after 4 weeks on a high salt diet. They became mildly hypertensive (156 +/- 3 mmHg) after 4 weeks on a normal salt diet. In both studies, renal denervation exerted no effect on the development of hypertension in the DS rats. The urinary sodium excretion, urinary volume, heart rate and body weight were unaltered by renal denervation. These results indicate that the renal nerves do not make a major contribution to the development of hypertension in DS rats.     

Observations on the pathogenesis and management of pulmonary hypertension

Experimental subclavian-pulmonary and aorta-pulmonary anastomoses were performed in attempts to produce progressively increasing pulmonary vascular changes and to observe their sequential development. At six weeks after anastomosis there was medial hypertrophy, at eight weeks total involvement of the artery, and at eleven weeks severe pulmonary vascular disease, total decrease in the number of capillaries, and complete obstruction of the lumen. These pathologic changes are compared with the normal course of events in the fetal and postnatal lung. A series of patients with patent ductus arteriosus, single ventricle, and a large ventricular septal defect were studied and categorized into three phases according to the severity of their clinical symptoms. A method for producing pulmonary artery stenosis in the laboratory as applied to a three month old infant is discussed.     

Pulmonary vasodilator effects of norepinephrine during the development of chronic pulmonary hypertension in neonatal lambs

Background. This experimental study was performed to determinethe effects of norepinephrine on: (i) the pulmonary vasculartone during the development of pulmonary hypertension (PH) inthe fetus and (ii) the circulatory adaptation at birth afterchronic intrauterine PH. Methods. Chronically instrumented fetal lambs were randomizedinto two groups: (i) a group with PH obtained by antenatal partialligation of the ductus arteriosus (DA) (n=9) and (ii) a controlgroup without DA ligation (n=6). Pulmonary vascular responsesto norepinephrine (1.5 µg min^–1) were measured inutero 7 days after surgery. At day 8 post-surgery, after delivery,animals were ventilated for 3 h with oxygen 100%. The groupwith PH was randomly assigned to receive norepinephrine or saline. Results. Mean pulmonary artery pressure (PAP) and pulmonaryvascular resistance (PVR) were higher in the PH group (P<0.01).Norepinephrine-induced decrease in PVR was more pronounced inthe PH group than in the control group (63 vs 35%, respectively;P<0.01). In the PH group, the decrease in PVR during mechanicalventilation was greater in the animals receiving norepinephrinethan in the animal receiving saline (from 1.05 (0.12) to 0.1(0.02) vs from 1.04 (0.1) to 0.2 (0.04) mm Hg ml^–1 min^–1,respectively; P<0.01). After 3 h of ventilation, mean PVRin the PH lambs treated by norepinephrine was similar to thosemeasured in the control lambs. Aortic pressure was higher inthe group treated with norepinephrine. Conclusion. The data suggest that norepinephrine may improvepost-natal pulmonary adaptation in the newborn with persistentPH both by increasing systemic vascular pressure and by increasingpulmonary blood flow.