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Pulmonary Veno-occlusive Disease and Pulmonary Capillary Hemangiomatosis 肺静脉闭塞性疾病和肺毛细血管瘤病
Pub Date : 2020-01-01 DOI: 10.1007/978-3-030-52787-7_6
B. Levarge, D. Montani, M. Humbert
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引用次数: 0
Sarcoidosis-Associated Pulmonary Hypertension 结节病相关性肺动脉高压
Pub Date : 2020-01-01 DOI: 10.1007/978-3-030-52787-7_9
H. Ford, Ahmed Sesay, E. Sonntag, S. Krishnan
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引用次数: 0
Caspase-1 triggers smooth muscle cell proliferation in hypoxic pulmonary hypertension Caspase-1触发缺氧肺动脉高压平滑肌细胞增殖
Pub Date : 2019-09-28 DOI: 10.1183/13993003.congress-2019.pa5049
Camilla Udjus, B. Halvorsen, P. Aukrust, G. Christensen, O. Skjønsberg, K. Larsen
Background: Pulmonary hypertension is a serious complication to chronic lung diseases, often with alveolar hypoxia. Mechanisms for hypoxia-induced pulmonary hypertension are suggested to be initial vasoconstriction, followed by inflammation, proliferation of smooth muscle cells (SMCs) and fibrosis in pulmonary arteries. Elevated levels of Interleukin (IL)-18, IL-1β and IL-6 are found in patients with pulmonary hypertension. IL-18 and IL-1β are proinflammatory cytokines activated by the enzyme caspase-1. We have documented that caspase-1 deficient mice have reduced hypoxia-induced pulmonary hypertension and reduced muscularization in pulmonary arteries compared to wild-type (WT) mice. Objective: To study mechanisms of SMC proliferation in hypoxic pulmonary hypertension initiated by the enzyme caspase-1. Methods: Pulmonary arteries from WT and caspase-1-/- mice were harvested and grown “ex vivo”. Human SMCs were exposed to hypoxia and treated with caspase-1 inhibitor. Proliferation of SMCs was measured by cell count, BrdU incorporation, Ki67 and cyclin D1 mRNA. Results: Caspase-1 abrogated arteries showed reduced SMC proliferation, together with lowered levels of IL-18, IL-1β and IL-6. Supply of IL-18 or IL-1β rescued SMC proliferation in caspase-1 deficient arteries, and the level of IL-6 protein was restored. Hypoxic stimulation of human SMCs showed increased BrdU incorporation and Ki67 protein levels, indicating hypoxia-induced cell proliferation. Cell count, BrdU incorporation and cyclin D1 mRNA levels were reduced by adding a caspase-1 inhibitor. Conclusions: The enzyme caspase-1 regulates smooth muscle cell proliferation through IL-18/IL-1β and IL-6, being novel targets in pulmonary hypertension.
背景:肺动脉高压是慢性肺部疾病的严重并发症,常伴有肺泡缺氧。缺氧引起肺动脉高压的机制可能是最初的血管收缩,随后是炎症、平滑肌细胞(SMCs)增殖和肺动脉纤维化。肺动脉高压患者白细胞介素(IL)-18、IL-1β和IL-6水平升高。IL-18和IL-1β是由caspase-1酶激活的促炎细胞因子。我们已经证明,与野生型(WT)小鼠相比,caspase-1缺陷小鼠缺氧诱导的肺动脉高压和肺动脉肌肉化减少。目的:探讨caspase-1诱导低氧肺动脉高压细胞SMC增殖的机制。方法:取WT和caspase-1-/-小鼠肺动脉,体外培养。人类SMCs暴露于缺氧和caspase-1抑制剂处理。通过细胞计数、BrdU掺入、Ki67和cyclin D1 mRNA检测SMCs的增殖情况。结果:Caspase-1去除动脉后,SMC增殖减少,IL-18、IL-1β、IL-6水平降低。提供IL-18或IL-1β可恢复caspase-1缺陷动脉中SMC的增殖,并恢复IL-6蛋白水平。缺氧刺激的人SMCs显示BrdU掺入和Ki67蛋白水平增加,表明缺氧诱导细胞增殖。添加caspase-1抑制剂可降低细胞计数、BrdU掺入和cyclin D1 mRNA水平。结论:caspase-1酶通过IL-18/IL-1β和IL-6调控平滑肌细胞增殖,是肺动脉高压的新靶点。
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引用次数: 0
A phase 1, single-center, open-label, dose-rising clinical trial to evaluate the pharmacokinetics, safety and tolerability of treprostinil inhalation powder (TreT) in healthy normal volunteers 一项1期、单中心、开放标签、剂量递增的临床试验,旨在评估TreT在健康正常志愿者体内的药代动力学、安全性和耐受性
Pub Date : 2019-09-28 DOI: 10.1183/13993003.congress-2019.pa4749
Peter Smith, C. Watkins, K. Kraft, M. Grant
Rationale: United Therapeutics is developing a new drug-device product comprising a dry powder formulation of treprostinil inhalation powder (TreT) and a small, portable, dry powder inhaler, to treat pulmonary arterial hypertension (PAH). Objectives: The primary objective was to evaluate the pharmacokinetics (PK), safety and tolerability of TreT in healthy normal volunteers (HNVs). Methods: This was an open-label, single ascending dose study in 36 HNVs, assigned to 6 single dose cohorts of TreT (30, 60, 90, 120, 150, and 180 µg). Safety and tolerability of TreT was evaluated in each cohort prior to escalating the dose for the next cohort. Blood samples were obtained before TreT administration and at selected times through 480 minutes post‑dose. Blood samples were analyzed for treprostinil using a validated analytical method and PK parameters were calculated using noncompartmental methods. Results: A total of 36 HNVs were randomized and dosed. There were no severe adverse events (AEs), serious AEs, or deaths during the study. No AEs led to a subject’s early termination. The most frequently reported AEs were cough (n=11, 30.6%) and headache (n=8, 22.2%). Bioanalysis confirmed that the treprostinil plasma concentrations and exposure for TreT, achieved clinically relevant concentrations comparable to those observed in historical Tyvaso single dose clinical studies. Cmax and AUC for treprostinil, increased in a linear manner with increasing dose. Conclusion: Overall, TreT was safe and well-tolerated and produced clinically relevant concentrations of treprostinil when inhaled as a dry powder.
理由:联合治疗公司正在开发一种新的药物装置产品,包括一种干粉状制剂的曲前列地尼吸入粉(TreT)和一种小型便携式干粉吸入器,用于治疗肺动脉高压(PAH)。目的:主要目的是评估TreT在健康正常志愿者(hnv)体内的药代动力学(PK)、安全性和耐受性。方法:这是一项开放标签、单次递增剂量的研究,36名hnv被分配到6个TreT单剂量队列(30、60、90、120、150和180µg)。在下一个队列增加剂量之前,对每个队列进行TreT的安全性和耐受性评估。在TreT给药前和给药后480分钟的特定时间采集血液样本。采用经验证的分析方法分析血液样本中的曲前列汀,并采用非室室法计算PK参数。结果:共36例hnv被随机分配并给药。研究期间未发生严重不良事件(ae)、严重ae或死亡。没有ae导致受试者提前死亡。最常见的ae是咳嗽(n=11, 30.6%)和头痛(n=8, 22.2%)。生物分析证实,TreT的treprostiil血浆浓度和暴露达到临床相关浓度,与历史上Tyvaso单剂量临床研究中观察到的浓度相当。treprostiil的Cmax和AUC随剂量的增加呈线性增加。结论:总的来说,TreT是安全且耐受性良好的,并且当作为干粉吸入时产生临床相关浓度的曲前列氨酯。
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引用次数: 2
A prospective study comparing the repeatability and sensitivity to change of non-invasive endpoints in pulmonary arterial hypertension: the RESPIRE study 一项前瞻性研究比较肺动脉高压无创终点变化的可重复性和敏感性:呼吸研究
Pub Date : 2019-09-28 DOI: 10.1183/13993003.congress-2019.oa496
D. Kiely, A. Swift, Marcella Cogliano, L. Kendall, C. Oram, D. Capener, A. Rothman, P. Garg, C. Johns, M. Austin, J. Pickworth, P. Hickey, Tony Kahn, A. Lawrie, R. Condliffe, Fred Wilson, J. Wild
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引用次数: 2
Right ventricular-arterial coupling in chronic thromboembolic pulmonary hypertension patients during exercise 慢性血栓栓塞性肺动脉高压患者运动时的右心室-动脉耦合
Pub Date : 2019-09-28 DOI: 10.1183/13993003.congress-2019.pa1436
N. Braams, O. Spruijt, F. Oosterveer, B. Westerhof, A. Noordegraaf, L. Meijboom, F. S. D. Man, H. Bogaard
{"title":"Right ventricular-arterial coupling in chronic thromboembolic pulmonary hypertension patients during exercise","authors":"N. Braams, O. Spruijt, F. Oosterveer, B. Westerhof, A. Noordegraaf, L. Meijboom, F. S. D. Man, H. Bogaard","doi":"10.1183/13993003.congress-2019.pa1436","DOIUrl":"https://doi.org/10.1183/13993003.congress-2019.pa1436","url":null,"abstract":"","PeriodicalId":20724,"journal":{"name":"Pulmonary hypertension","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77994561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
Role of vasoactive mediators on cigarette smoke extract (CSE)-induced proliferation in human pulmonary artery smooth muscle cells (hPASMCs) 血管活性介质对香烟提取物诱导的人肺动脉平滑肌细胞增殖的影响
Pub Date : 2019-09-28 DOI: 10.1183/13993003.congress-2019.pa1423
A. Alqarni, O. Brand, A. Pasini, Abdulrhman Alghamdi, Wael Alshehri, Mushabbab A Alahmari, L. Pang
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引用次数: 1
Outcome of pulmonary thromboendarterectomy in chronic thromboembolic disease with normal hemodynamic: is it time to change the definition of CTEPH 正常血流动力学的慢性血栓栓塞性疾病肺血栓动脉内膜切除术的结果:是时候改变CTEPH的定义了吗
Pub Date : 2019-09-28 DOI: 10.1183/13993003.congress-2019.pa1439
F. Rashidi, R. Parvizi, Eisa Bilejani, Ata Koohi
{"title":"Outcome of pulmonary thromboendarterectomy in chronic thromboembolic disease with normal hemodynamic: is it time to change the definition of CTEPH","authors":"F. Rashidi, R. Parvizi, Eisa Bilejani, Ata Koohi","doi":"10.1183/13993003.congress-2019.pa1439","DOIUrl":"https://doi.org/10.1183/13993003.congress-2019.pa1439","url":null,"abstract":"","PeriodicalId":20724,"journal":{"name":"Pulmonary hypertension","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86285108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Risk assessment and prognosis in patients with pulmonary arterial hypertension receiving intravenous treprostinil 静脉注射曲前列地尼肺动脉高压患者的风险评估及预后
Pub Date : 2019-09-28 DOI: 10.1183/13993003.congress-2019.oa499
K. Olsson, M. Richter, J. Kamp, H. Gall, A. Heine, H. Ghofrani, J. Fuge, R. Ewert, M. Hoeper
{"title":"Risk assessment and prognosis in patients with pulmonary arterial hypertension receiving intravenous treprostinil","authors":"K. Olsson, M. Richter, J. Kamp, H. Gall, A. Heine, H. Ghofrani, J. Fuge, R. Ewert, M. Hoeper","doi":"10.1183/13993003.congress-2019.oa499","DOIUrl":"https://doi.org/10.1183/13993003.congress-2019.oa499","url":null,"abstract":"","PeriodicalId":20724,"journal":{"name":"Pulmonary hypertension","volume":"2016 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86468631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Therapeutic limitations of oral medications to normalize hemodynamics in patients with pulmonary artery hypertension 口服药物使肺动脉高压患者血流动力学正常化的治疗局限性
Pub Date : 2019-09-28 DOI: 10.1183/13993003.congress-2019.pa5467
H. Shimokawahara, H. Matsubara, K. Hayashi, T. Nishihara, M. Tsuji, T. Naito, M. Shigetoshi, I. Tabuchi, M. Munemasa
Background: Pulmonary arterial hypertension (PAH) has a poor prognosis despite the available therapeutic options. Normalization of hemodynamics would be needed to obtain the good prognosis. Aims and Objectives: We aimed to investigate the determinants in PAH patients for normalization of hemodynamics only with oral drugs. Methods: We retrospectively reviewed 190 patients with PAH treated at a single referral center. Hemodynamic parameters were investigated before and after treatments. All the patients were divided into a good control group with mean pulmonary arterial pressure (mPAP)<30mmHg and a poor control group with mPAP≧30mmHg at follow-up. Results: Eighty-two patients were idiopathic/heritable, 65 patients were connective tissue disease, 22 patients congenital heart disease and 21 patients were portal hypertension. mPAP decreased significantly from baseline to follow-up (51±18.7 mmHg to 34.1±15.2 mmHg, p Conclusions: To achieve normalization of hemodynamics in PAH, parenteral prostanoid should be used in cases with baseline mPAP exceeding 40mmHg.
背景:肺动脉高压(PAH)的预后较差,尽管现有的治疗方案。血流动力学的正常化将需要获得良好的预后。目的和目的:我们的目的是研究PAH患者仅通过口服药物使血流动力学正常化的决定因素。方法:我们回顾性分析了在单一转诊中心治疗的190例PAH患者。观察治疗前后血流动力学参数。随访时将患者分为平均肺动脉压(mPAP)<30mmHg的良好对照组和平均肺动脉压≧30mmHg的不良对照组。结果:特发性/遗传性82例,结缔组织病65例,先天性心脏病22例,门静脉高压症21例。从基线到随访,mPAP明显下降(51±18.7 mmHg至34.1±15.2 mmHg), p结论:为了使PAH血流动力学正常化,对于基线mPAP超过40mmHg的病例,应采用前列腺素外注射。
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引用次数: 0
期刊
Pulmonary hypertension
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