Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway

Smooth muscle cell proliferation around small pulmonary vessels is essential to the pathogenesis of pulmonary hypertension. Here we describe a molecular mechanism and animal model for this vascular pathology. Rodents engineered to express angiopoietin 1 (Ang-1) constitutively in the lung develop severe pulmonary hypertension. These animals manifest diffuse medial thickening in small pulmonary vessels, resulting from smooth muscle cell hyperplasia. This pathology is common to all forms of human pulmonary hypertension. We demonstrate that Ang-1 stimulates pulmonary arteriolar endothelial cells through a TIE2 (receptor with tyrosine kinase activity containing IgG-like loops and epidermal growth factor homology domains) pathway to produce and secrete serotonin (5-hydroxytryptamine), a potent smooth muscle mitogen, and find that high levels of serotonin are present both in human and rodent pulmonary hypertensive lung tissue. These results suggest that pulmonary hypertensive vasculopathy occurs through an Ang-1/TIE2/serotonin paracrine pathway and imply that these signaling molecules may be targets for strategies to treat this disease.     

Diagnostic utility of ventilation/perfusion lung scans in acute pulmonary embolism is not diminished by pre-existing cardiac or pulmonary disease

The purpose of this study was to assess the impact of prior cardiac or pulmonary disease upon the utility of ventilation/perfusion (V/Q) scans in the diagnosis of acute pulmonary embolism (PE). Ventilation/perfusion scans were evaluated among 365 patients with no prior cardiac or pulmonary disease and compared to V/Q scans in 526 patients with prior cardiac or pulmonary disease. Among patients with no prior cardiac or pulmonary disease, PE was present in 117 and PE was excluded in 248. Among patients with prior cardiac or pulmonary disease, PE was present in 140 and excluded in 386. The positive predictive value for PE of high probability V/Q scans among patients with prior cardiac or pulmonary disease, 55 of 66 (83 percent), was not significantly lower than among patients without prior cardiac or pulmonary disease, 50 of 54 (93 percent) (NS). The positive predictive value of low probability V/Q scans was similar with prior cardiac or pulmonary disease, 25 of 182 (14 percent), and without prior cardiac or pulmonary disease, 17 of 113 (15 percent) (NS), as was the predictive value of near normal/normal V/Q scans, 2 of 51 (4 percent), vs 3 of 79 (4 percent) (NS). The sensitivity of high probability V/Q scans, with pre-existing cardiac or pulmonary disease and without, 55 of 140 (39 percent) vs 50 of 117 (43 percent), did not differ significantly. The specificity of high probability V/Q scans with prior cardiac or pulmonary disease and without, 375 of 386 (97 percent) vs 244 of 248 (98 percent) was also similar (NS). In conclusion, the diagnostic utility of V/Q scans for acute PE was not impaired by the presence of pre-existing cardiac or pulmonary disease. Fewer patients, however, with no prior cardiac or pulmonary disease, had intermediate (indeterminate) V/Q scans.     

PI3K/Akt/mTOR信号通路与低氧性肺动脉高压研究进展

肺动脉高压是一种预后不良的疾病,在我国因各种肺部慢性疾病引起的低氧性肺动脉高压近年来呈上升发病趋势.磷脂酰肌醇3-激酶(phosphatidylionsitol-3-kinases,PI3K)/蛋白质丝氨酸苏氨酸激酶(protein-serine-threonine kinase,Akt)/哺乳动物雷帕霉素蛋白(mammalian target of rapamycin,mTOR)信号通路作为细胞内重要信号转导通路之一,通过影响细胞的增殖、迁移、凋亡以及蛋白合成、细胞周期等活性参与肺动脉血管重塑以及低氧性肺动脉高压的形成.本文综述了PI3K/Akt/mTOR信号通路在低氧性肺动脉高压中的研究现状,以期为低氧性肺动脉高压的发病机制研究及治疗寻找新的思路.     

Increased alveolar/capillary membrane resistance to gas transfer in patients with chronic heart failure.

OBJECTIVE--To investigate pulmonary diffusive resistance to gas exchange in patients with heart failure and healthy volunteers, assessing the relative contributions of the alveolar/capillary membrane and pulmonary capillary blood. SETTING--Hospital outpatient department and pulmonary function laboratory. PATIENTS--38 patients (mean age 60) receiving treatment with loop diuretics and angiotensin converting enzyme inhibitors for stable symptomatic heart failure of > 6 months duration (New York Heart Association (NYHA) classes II and III). Results were compared with those of 17 healthy volunteers (mean age 52). METHODS--The alveolar/capillary membrane diffusive resistance and the pulmonary capillary blood volume available for physiological gas exchange were determined by the Roughton and Forster method, which measures the single breath pulmonary diffusing capacity for carbon monoxide at varying alveolar oxygen concentrations. RESULTS--Total pulmonary diffusive resistance was higher in patients than controls. Alveolar/capillary membrane resistance formed the main component of this increase, accounting for a mean (SD) of 63% (20%) and 86% (8%) of total pulmonary diffusive resistance in patients in NYHA II and III classes respectively, compared with 53% (10%) in controls. The pulmonary capillary blood volume was not significantly different between controls and patients in NYHA class II (66 (18) ml v 61 (18) ml), but was increased in those in NYHA class III (95(46) ml, P < 0.05). CONCLUSION--This study confirmed impairment of pulmonary diffusion at rest in patients with chronic heart failure and identified impaired alveolar/capillary membrane function as the main factor responsible.     

Use of integrated FDG PET/CT imaging in pulmonary carcinoid tumours

BACKGROUND: Integrated positron emission tomography (PET)/computed tomography (CT) scanners have been recently introduced in the diagnostic work-up of suspected pulmonary malignancy and demonstrate encouraging results in the staging of nonsmall-cell lung cancer. OBJECTIVE: To evaluate the usefulness of integrated FDG PET/CT in pulmonary carcinoid tumours. SETTING: University hospital. METHODS: We studied 13 patients (mean age +/- 1 SD, 57 +/- 11 years) with pulmonary carcinoid tumours. All patients demonstrated a single pulmonary lesion. Integrated PET/CT scan and surgical resection were performed in all patients. RESULTS: The pulmonary lesion size ranged from 1.1 to 5.0 cm. Final histological diagnosis confirmed 12 typical and one atypical pulmonary carcinoid. Mean proliferation rate of the typical carcinoids was 1.7 +/- 1.4%. None of the patients had recurrent carcinoid disease or died during follow-up (864 +/- 218 days). Mean standardized uptake value (SUV) of (18)F-fluorodeoxyglucose (FDG) in typical carcinoids was 3.0 +/- 1.5 (range 1.2 - 6.6); SUV in the atypical carcinoid was remarkably high with a value of 8.5. The SUV was lower than 2.5 in 6 of 12 patients (50%). Mediastinal lymph node metastases or extrathoracic metastases were not detected in any patient. CONCLUSIONS: (18)F-fluorodeoxyglucose PET/CT imaging improves accurate localization of metabolic activity and thus the interpretation of pulmonary lesions on CT. FDG uptake in pulmonary carcinoid tumours is often lower than expected for malignant tumours. Therefore, surgical resection or biopsy of lesions suspected to be carcinoids should be mandatory, even if they show no hypermetabolism on FDG PET images.     

Role of echo/Doppler in the diagnosis of pulmonary embolism

Echocardiography supplemented with pulsed and continuous wave Doppler facilities is a potent diagnostic tool in many cardiovascular disorders. Its potential role in the management of patients with suspected pulmonary embolism, though less extensively studied, deserves attention. Benefits of echo/Doppler in these patients are as follows: (1) Echo/Doppler is a noninvasive, relatively inexpensive technique, readily available and repeatable in critically ill patients at the bedside. (2) Echo/Doppler provides a number of independent parameters related to the pulmonary hemodynamics. These parameters include: (a) characteristics of blood flow velocity curves across the right heart valves as well as systolic and diastolic time intervals of the right ventricle (b) motion pattern of the interventricular septum (c) dimensions of the heart chambers and inferior vena cava (d) thickness of the right ventricular free wall (3) Echocardiography allows detection of thrombi within right heart chambers or in major branches of the pulmonary artery in some patients. (4) Echo/Doppler may disclose alternative abnormalities explaining symptoms found in a patient with suspected pulmonary embolism such as pericardial disease, myocardial infarction, aortic dissection, hypovolemic shock, etc.     

Effectiveness of deferiprone in transfusion-independent beta-thalassemia/HbE patients

Beta-thalassemia/HbE (beta-thal/HbE) is a thalassemia intermedia (TI) which encompasses a broad spectrum of severity. Here, we used deferiprone (DFP) as an iron chelating agent in TI patients receiving intermittent blood transfusion who are asymptomatic for cardiovascular disease in order to evaluate the effectiveness in iron overload and reduce the possibility of cardiovascular complications. Thirty transfusion-independent beta-thal/HbE patients with iron overload were treated with DFP for 1?year. Hematological, biochemical, oxidative stress and echocardiographic parameters were determined. Serum ferritin, non-transferrin-bound iron, and malondialdehyde decreased significantly (P<0·05) after 1-year treatment with DFP. For echocardiographic results, mean pulmonary arterial pressure and pulmonary vascular resistance were diminished significantly (P<0·05). All those parameters were still improved after subgroup analysis was done for the high ferritin group (>2500 ng/ml). DFP therapy alone improved iron overload and oxidative stress and compliance was good. We propose that prevention of pulmonary hypertension is also possible for TI undergoing intermittent blood transfusion.     

Regression in thromboembolic type of primary pulmonary hypertension during 2 1/2 years of antithrombotic therapy

Primary pulmonary hypertension carries a poor prognosis, with a 5 year survival rate of less than 25%. However, a previous study of more than 100 patients with tissue-proved primary pulmonary hypertension suggested that antithrombotic therapy may have a beneficial effect on survival, especially in patients with the thromboembolic type of primary pulmonary hypertension. This report describes a 54 year old white man with primary pulmonary hypertension of the thromboembolic type (proved by right upper lobe lung biopsy) who, after long-term antithrombotic therapy, showed resolution of symptoms of dyspnea and fatigue, regression of electrocardiographic signs of right ventricular hypertrophy and regression of elevated pulmonary artery pressure. Base-line cardiac catheterization in January 1982 revealed elevated pulmonary artery pressure (104/37 mm Hg) and pulmonary vascular resistance (14.6 units/m2) that did not decrease with 100% oxygen or intravenous hydralazine (12 mg). The patient was treated with warfarin and dipyridamole, 100 mg four times daily. The most recent cardiac catheterization in January 1984 revealed a pulmonary artery pressure of 50/15 mm Hg and a pulmonary vascular resistance of 8.7 units/m2. It is believed that this is the first report of regression of the symptoms and signs of biopsy-proved primary pulmonary hypertension. In view of the lack of a response to vasodilators in 1982, it is suggested that antithrombotic therapy is partially responsible for the improvement of this patient.     

Application value of GeneXpert MTB/RIF system in diagnosis of pulmonary tuberculosis

为了解利福平耐药实时荧光定量核酸扩增检测技术(GeneXpert MTB/RIF)在初诊肺结核患者诊断中的应用价值,作者收集了2015年1月至2016年12月浙江省嘉兴市第一医院就诊的初诊疑似肺结核患者361例,留取痰液标本分别进行涂片荧光金胺O染色镜检(简称“涂片镜检”)、结核分枝杆菌MGIT 320液体培养(简称“液体培养”)、GeneXpert MTB/RIF检测(简称“Xpert检测”)和固体比例法药物敏感性试验。最终临床诊断为:肺结核184例(50.97%),肺部感染162例(44.88%),非典型分枝杆菌肺部感染15例(4.15%)。361例疑似肺结核患者中,Xpert 检测的阳性率[32.41%(117/361)]明显高于涂片镜检[22.71%(82/361)](χ ²=8.49,P<0.05),与液体培养[26.32%(95/361)]比较不存在明显差异(χ ²=3.23,P=0.072),涂片镜检法与液体培养法比较差异无统计学意义(χ ²=1.26,P=0.261)。184例肺结核患者中,Xpert 检测的阳性率[63.59%(117/184)]高于涂片镜检[36.41%(67/184)]和液体培养[48.91%(90/184)](χ ²=27.17,P<0.01;χ ²=8.05,P<0.05);117例涂阴肺结核患者的Xpert检测阳性率[42.74%(50/117)]高于液体培养[24.79%(29/117)](χ ²=8.43,P=0.004)。以临床诊断为标准,Xpert检测初诊疑似肺结核患者的敏感度为63.59%(117/184),特异度为100.00%(177/177),正确指数为0.64。以固体比例法药物敏感性试验结果为金标准,Xpert 检测利福平耐药的敏感度为4/5,特异度为97.70%(85/87),正确指数为0.97。说明GeneXpert MTB/RIF在初诊疑似肺结核患者,尤其是涂阴肺结核患者中,检测结核分枝杆菌感染及对利福平耐药具有较高的效能。     

Methylprednisolone-pulse therapy in a patient with rheumatoid arthritis and diffuse interstitial pneumonia/pulmonary fibrosis

A forty-eight year-old female with rheumatoid arthritis developed cough, sputum and dyspnea. Chest X-ray film demonstrated bilateral diffuse interstitial pneumonia and pulmonary fibrosis. Laboratory findings were as follows: ESR 29 mm/h, CRP 3.86 mg/dl, RA test (+), RAHA (-) and WBC 7200/mm3. Marked hypoxemia (po(2)45 Torr) was demonstrated by blood gas analysis. Asymptomatic pulmonary fibrotic lesions which preceded articular symptoms were identified on her previous chest X-ray films. Methylprednisolone-pulse therapy (1g/day, for 3 days) was repeated three times with a 2-week interval. The treatment rapidly improved both pulmonary symptoms and chest X-ray findings. Although the fibrotic shadows on chest X-ray did not completely disappear, her conditions have been maintained well under the treatment with prednisolone (10mg/day) plus D-penicillamine (200mg/day).     

Vasa vasorum neovascularization and lesion distribution among different vascular beds in ApoE-/-/LDL-/- double knockout mice

OBJECTIVE: To increase understanding of the substantial variation in the incidence and distribution of atherosclerotic lesions among different vascular beds. In view of some evidence that there are different distributions of adventitial vasa vasorum (VV) in different vascular beds, and that this correlates with lesion formation, we explored this possible linkage in apoE-/-/LDL-/- double knockout mice, which develop VV at age beyond 16 weeks. METHODS AND RESULTS: Samples from the aorta, coronary, pulmonary, carotid, and cerebral arteries in apoE-/-/LDL-/- double knockout mice at the age of 16-80 weeks (n=24) were scanned by micro-CT. Using those 3D images, we characterized plaque volume, vessel luminal diameter and VV luminal volume along the vessels. Results were complemented by histology. Advanced atherosclerotic lesions were found in the aorta, pulmonary artery and carotid artery. Occluded intramyocardial vessels (vessel diameter approximately 0.1mm) with concomitant myocardial infarctions were found without any evidence of adventitial VV neovascularization. VV luminal volume follows the order: aorta>pulmonary arteries>carotid arteries. VV were only observed in atherosclerotic diseased vessels with a lumen diameter>0.4mm. No atherosclerotic lesions, and no VV, were observed in cerebral arteries. CONCLUSION: The spatial heterogeneity in the development of atherosclerotic lesions among different vascular beds is linked to appearance of VV and to vessel lumen diameter.     

实验性肺纤维化细胞凋亡及Fas/FasL基因变化

目的　检测肺纤维化时细胞凋亡及Fas/FasL基因的变化,探讨细胞凋亡和基因变化在肺间质纤维化中的意义。方法　将 40只大鼠分为肺纤维化组及正常对照组,每组 20只,应用末端原位杂交(TUNEL)、原位杂交、免疫组化技术检测博莱霉素致肺间质纤维化大鼠肺组织细胞凋亡、Fas/FasLmRNA水平及蛋白表达的变化。结果　肺纤维化组大鼠肺组织中细胞凋亡指数为 55.3±12.2,对照组为 4 7±1 0,两组比较差异有统计学意义(t=13.06,P<0 .01),Fas及FasLmRNA肺纤维化组为(175.8±21.6, 5.2±1.6),正常对照组为 (26.6±1.9, 0.5±0.4),两组比较差异有统计学意义 (t分别为 21.7, 8.79;P均<0.01),肺纤维化组Fas、FasL蛋白表达分别为 956±96, 285±76,正常对照组分别为 491±96, 100±18,两组比较差异有统计学意义 (t=5.03, 12.81;P<0.01)。结论　肺间质纤维化时肺组织细胞凋亡上调,Fas/FasL基因上调蛋白表达增强,在肺纤维化发生、发展中起到重要的作用。     

基质金属蛋白酶9与急性肺损伤/急性呼吸窘迫综合征

急性呼吸窘迫综合征的本质是弥漫性肺泡毛细血管膜损伤、血管通透性增加所致的通透性肺水肿.基质金属蛋白酶可以降解细胞外基质蛋白,使肺毛细血管通透性增加,引发肺水肿,导致急性肺损伤和(或)急性呼吸窘迫综合征.本文就基质金属蛋白酶9在急性肺损伤/急性呼吸窘迫综合征中的作用及研究进展进行综述.     

D-二聚体/hs-CRP比值在社区获得性肺炎合并肺栓塞中的诊断价值初探

目的:初探D-二聚体/超敏C反应蛋白(hs-CRP)比值在社区获得性肺炎(CAP)合并肺栓塞中的诊断价值。方法:本研究为病例对照研究。采用非随机抽样方法收集并分析2018年8月至2021年7月深圳市第二人民医院就诊的CAP患者115例,根据肺血管造影结果分为CAP合并肺栓塞组( n＝48)和单纯CAP组( ...     

Tuberculosis in HIV/AIDS patients: a Malaysian experience

This retrospective study was conducted at the National Tuberculosis Center (NTBC) where 252 HIV-positive patients coexisting with tuberculosis (TB/HIV) were examined. We found that patients with pulmonary (PTB) and extrapulmonary tuberculosis (EPT) had similar mean age. A higher sex ratio between male to female (10.7:1) was observed in patients with PTB. The other characteristics of patients with pulmonary and extrapulmonary tuberculosis were not statistically different from each other. Cough (88%) and hemoptysis were the most common presenting symptoms, significantly related to patients with PTB. Lymphadenopathy (33.5%) was the most common sign in patients with EPT. The majority of patients with pulmonary and extrapulmonary tuberculosis had CD4 cell counts of less than 200 cells/mm3 (range 0-1,179 with a median of 57 cells/mm3). Lung (89%) and miliary (55.6%) forms were the most frequent disease locations in patients with PTB and EPT, respectively. A higher percentage of patients with PTB (42%) were treated successfully with short-course (6 months) therapy, whereas in patients with EPT (43%) needed a longer period (9 months) for successful treatment. Of the patients who defaulted treatment, a higher proportion (87%) had PTB. No MDR-TB or relapse cases were found in this study.     

Usefulness of the MSG/IFICG/EORTC diagnostic criteria of invasive pulmonary aspergillosis in the clinical management of patients with acute leukaemia developing pulmonary infiltrates

Invasive pulmonary aspergillosis (IPA) is a frequently fatal complication in patients with acute leukaemia. Because diagnosis is still difficult, non-invasive diagnostic criteria were recently proposed by MSG/IFICG/EORTC for study purposes. We have analysed their usefulness in the clinical management of acute leukaemic patients with pulmonary infiltrates. Twenty-seven infiltrates developed during 174 chemotherapy cycles given to 50 consecutive patients. According to diagnostic criteria, IPA was diagnosed in 42% of patients and 77.8% of pulmonary infiltrates. AML diagnosis and the first induction cycle were significant risk factors. “Proven” IPA was rare, occurring in one patient (2%). The diagnosis of “probable” IPA was made in seven patients (14%) and was strongly supported by the significant association of characteristic radiological lesions (“major” clinical criterion) with the positivity of one microbiological criterion (P = 0.026). Conversely, “possible” IPA was frequent (26%) because its pertinent diagnostic criteria were fulfilled in 48.1% of pulmonary infiltrates. However, in 84.6% of cases, the diagnosis of “possible IPA” aspecifically derived from the association of two conditions, a new pulmonary infiltrate with symptoms of lower respiratory tract infection (“minor clinical criterion”), together with the definition of “susceptible” host, which applied to 100% of our leukaemic patients. We conclude that, according to MSG/IFICG/EORTC criteria, a high number of pulmonary infiltrates would be diagnosed as IPA, but only a diagnosis of “proven/probable” IPA should be considered reliable in the clinical management of suspected IPA.     

FIZZ1/RELMalpha,a novel hypoxia-induced mitogenic factor in lung with vasoconstrictive and angiogenic properties

In a mouse chronic hypoxia model of pulmonary hypertension, we discovered a novel hypoxia-inducible gene in lung, FIZZ1/RELMalpha, first through a cDNA array analysis and then confirmed by RT-PCR. Western blot and immunohistochemistry revealed that its expression was induced by hypoxia only in lung. The hypoxia-upregulated gene expression was located in the pulmonary vasculature, bronchial epithelial cells, and type II pneumocytes. 3H-thymidine incorporation demonstrated that the recombinant protein stimulated rat pulmonary microvascular smooth muscle cell (RPSM) proliferation dose-dependently ranging from 3.3x10(-9) to 3.3x10(-8) mol/L. Therefore, we renamed this gene as hypoxia-induced mitogenic factor (HIMF). HIMF strongly activated Akt phosphorylation. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 (10 micromol/L) inhibited HIMF-activated Akt phosphorylation. It also inhibited HIMF-stimulated RPSM proliferation. Thus, the PI3K/Akt pathway, at least in part, mediates the proliferative effect of HIMF. Further studies showed that HIMF had angiogenic and vasoconstrictive properties. HIMF increased pulmonary arterial pressure and vascular resistance more potently than either endothelin-1 or angiotensin II.     

螺旋CT肺动脉造影联合核素肺通气/灌注扫描在急性肺动脉血栓栓塞中的应用研究

目的探讨螺旋CT肺血管成像(SCTPA)联合核素肺通气/灌注(V/Q)扫描检查在急性肺动脉血栓栓塞(PTE)诊断中的应用价值。方法对2003年1月至2006年12月青岛市立医院呼吸科92例疑似急性PTE患者进行SCTPA、核素肺V/Q扫描以及相关检查,评价SCTPA、肺V/Q扫描以及联合检查对PTE的诊断价值。结果92例疑似PTE患者中,确诊肺栓塞者35例。SCTPA的受试者工作特征(ROC)曲线下面积为0.922,肺V/Q扫描的ROC曲线下面积为0.824,联合检查的ROC曲线下面积为0.933,明显高于肺V/Q扫描(Z=2.05,P<0.05)。结论SCTPA联合肺V/Q扫描可提高对急性PTE的诊断效率。     

Pulmonary hyalinizing granuloma in HIV/AIDS

A 55-year-old man who was recently diagnosed with HIV/AIDS developed multiple bilateral pulmonary nodules after starting highly active antiretroviral therapy. Workup confirmed the diagnosis of pulmonary hyalinizing granuloma. This is the first described case of pulmonary hyalinizing granuloma in HIV/AIDS, and may represent a rare form of immune reconstitution inflammatory syndrome.