血管紧张素转换酶2的研究进展

血管紧张素转换酶2(ACE2)是新近发现的ACE的同源物,两者由共同的祖先基因演变而来,蛋白和催化特性亦有诸多相似之处,但催化产物的作用却大不相同.ACE2的主要产物是与血管紧张素(Ang)Ⅱ作用相反的Ang 1-7,两者共同调节肾素-血管紧张素系统(RAS)的稳态.ACE2可能在RAS中扮演与ACE相反的角色,此外还与糖尿病早期的肾脏保护及严重急性呼吸综合征(SARS)的发生有关.     

ACE2可作为预防肺动脉高压的靶点

活化的肾素血管紧张素系统（RAS）会导致血管收缩和血管扩张途径的失衡,从而会导致肺动脉高压的形成。最近的研究表明,血管紧张素转换酶2（ACE2）——RAS血管保护轴的一个成员,对肺的病理生理具有调节作用,包括肺纤维化和急性肺部疾病。鉴于此,本研究假设内源性ACE2的活化能够改变RAS的平衡,从而预防肺动脉高压的发生。     

新型冠状病毒肺炎临床治疗药物最新研究进展

新型冠状病毒肺炎(coronavirus disease 2019,COVID-19)正在世界范围内流行.作为冠状病毒,新型冠状病毒(SARS-CoV-2)和严重急性呼吸综合征冠状病毒(SARS-CoV)都通过人血管紧张素转化酶2(ACE2)受体侵入宿主细胞.面对疫情异常严峻的现状,目前尚缺乏疫苗和尚无特异性针对该病毒...     

新型冠状病毒肺炎与血管紧张素转化酶2的研究现状

自2019年底起，新型冠状病毒肺炎（Coronavirus disease 2019，COVID-19）病例席卷全球。该病毒为β属冠状病毒，基因特征与严重急性呼吸综合征冠状病毒（Severe Acute Respiratory Syndrome Coronavirus，SARS-CoV）有较高相似性，被命名为2019新型冠状病毒（2019 Novel Coronavirus，2019-nCoV）或严重急性呼吸综合征冠状病毒-2（SARS-CoV-2），主要通过棘突蛋白介导与宿主血管紧张素转化酶2（angiotensin-converting enzyme 2，ACE2）受体结合侵犯人体。ACE2与COVID-19感染密切相关，既是SARS-CoV-2感染人体的关键靶点，ACE2表达多寡也是影响COVID-19患者疾病严重程度和死亡率的重要因素。因此靶向ACE2和肾素-血管紧张素系统（renin-angiotensin system，RAS）的诸多上市药物和在研药物，如血管紧张素转化酶抑制剂（angiotensin-converting enzyme inhibitor，ACEI）、血管紧张素受体拮抗剂（angiotensin receptor blocker，ARB）、重组人ACE2、Ⅱ型跨膜丝氨酸蛋白酶（type II transmembrane serine proteases，TMSPSS2）抑制剂、特异性中和抗体等都有可能成为治疗COVID-19的可行策略。此外，依据现有证据并不建议合并高血压的轻症COVID-19确诊病例或疑似病例轻易停用ACEI/ARB，以免造成血压波动。     

肾素-血管紧张素系统在COVID-19中作用及药物干预

COVID-19的发病特征为发热、干咳、乏力,严重者可进展为急性呼吸窘迫综合征(ARDS)等,甚至危及生命。SARS-CoV-2可通过血管紧张素转化酶2(ACE2)入侵细胞并导致ACE2表达下调。ACE2表达下调会导致肾素-血管紧张素系统(RAS)的失衡,从而引起后续病理状态发生,RAS在ARDS中也发挥重要的作用。本文总结了RAS系统在COVID-19发病过程中可能存在的作用,以及基于RAS对于COVID-19的治疗可能,为优化治疗及后续研究提供参考。     

感染2019新型冠状病毒的高血压病患者不建议停用血管紧张素转换酶抑制剂及血管紧张素Ⅱ受体阻滞剂

对于感染2019新型冠状病毒(2019-nCoV)的高血压病患者,是否应该停用血管紧张素转换酶抑制剂/血管紧张素Ⅱ受体阻滞剂(ACEI/ARB)类药物,存在两种相反观点。血管紧张素转换酶2(ACE2)已经被证实是肾素-血管紧张素系统(RAS)负向调控的关键酶,激活ACE2/Ang(1-7)/Mas轴后可以拮抗血管紧张素Ⅱ对RAS激活后的有害作用。ACE2也是SARS病毒和2019-nCoV感染细胞的功能性受体,ACE2在2019-nCoV感染中的作用及对新型冠状病毒肺炎病情的影响,目前尚不明确。目前尚没有ACEI/ARB增加2019-nCoV感染风险和加重病情的证据。对感染2019-nCoV的高血压病患者不建议停用ACEI/ARB类药物。     

胸部疾病血清血管紧张素转化酶活性测定初探

血管紧张素转化酶(ACE)存在于肺,肾、脑、眼球、小肠、胎盘等组织的血管内皮细胞或上皮细胞,也存在于血浆、尿等体液中,在正常情况以肺组织含量最高。因此,ACE 可能成为肺损伤的酶学检查指标而用于临床实践。我院自1982～1983年,对天津市60例健康成人及几组不同肺部疾病患者进行了血清血管紧张素转化酶测定,以求其正常值并了解某些肺部疾病的血清、血管紧张素转化酶(SACE)活性的变化。     

线粒体与急性肺损伤

急性肺损伤(acute lung injury,ALI)是指严重感染、创伤、休克后,出现以肺泡毛细血管损伤导致的肺水肿和肺不张为病理特征的一种肺部炎症与通透性增加综合征,临床表现为呼吸窘迫和顽固性低氧血症[1].     

血管紧张素转换酶2抗新冠病毒药理作用机制的研究进展

血管紧张素转换酶2（ACE2）是肾素-血管紧张素系统负向调节血压的关键因子，主要分布在心脏、肾脏和胃肠等部位。最新研究发现ACE2是新型冠状病毒（SARS-CoV-2）入侵的功能性受体。新型冠状病毒和SARS相关冠状病毒（SARS-CoV）都能利用宿主细胞表面ACE2作为受体，与病毒刺突糖蛋白（Spike）受体结合结构域（RBD）结合发生相互作用，介导病毒入侵宿主细胞。回顾性分析ACE2在抗SARS-CoV中的研究进展，结合目前对新型冠状病毒肺炎（COVID-19）疫情防治的认识及Spike-ACE2蛋白相互作用的最新研究成果，对ACE2抗新型冠状病毒的药理作用机制研究进行简要综述，以期为新冠肺炎抗病毒特效药的研发提供参考。     

严重急性呼吸综合征可能的发病机制及西维来司钠的治疗潜力

严重急性呼吸综合征是一种由冠状病毒变种引起的呼吸道传染病,其肺部病理表现为急性肺损伤.中性粒细胞在肺部的聚集与活化,从而释放大量弹性蛋白酶,损伤肺部微血管和表面活性物质,可能是冠状病毒感染后引起急性肺损伤的重要病理生理机制.弹性蛋白酶抑制剂西维来司钠治疗全身性炎症反应综合征引起的急性肺损伤有很好的疗效,因而也可能是治疗严重急性呼吸综合征安全有效的药物.     

Angiotensin-converting enzyme 2 in lung diseases

The renin-angiotensin system (RAS) plays a key role in maintaining blood pressure homeostasis, as well as fluid and salt balance. Angiotensin II, a key effector peptide of the system, causes vasoconstriction and exerts multiple biological functions. Angiotensin-converting enzyme (ACE) plays a central role in generating angiotensin II from angiotensin I, and capillary blood vessels in the lung are one of the major sites of ACE expression and angiotensin II production in the human body. The RAS has been implicated in the pathogenesis of pulmonary hypertension and pulmonary fibrosis, both commonly seen in chronic lung diseases such as chronic obstructive lung disease. Recent studies indicate that the RAS also plays a critical role in acute lung diseases, especially acute respiratory distress syndrome (ARDS). ACE2, a close homologue of ACE, functions as a negative regulator of the angiotensin system and was identified as a key receptor for SARS (severe acute respiratory syndrome) coronavirus infections. In the lung, ACE2 protects against acute lung injury in several animal models of ARDS. Thus, the RAS appears to play a critical role in the pathogenesis of acute lung injury. Indeed, increasing ACE2 activity might be a novel approach for the treatment of acute lung failure in several diseases.     

药物保护肺毛细血管内皮细胞 降低SARS发病率

急性呼吸窘迫综合征(ARDS)的致病因素很多，但最终均形成急性肺损伤(ALI)，主要由肺毛细血管内皮细胞损害所介导，虽采用医疗措施，包括吸氧及气管插管进行呼吸机呼吸等，病人死亡率仍高。传染性非典型肺炎(SARS)引起ALI时，出现肺动脉高压及肺纤维化，最终临床出现ARDS。ARDS的病理核心是肺毛细血管内皮细胞的损害，血管内皮细胞可作为治疗ARDS及SARS的靶点。SARS病毒感染后，引起细胞因子的释放，其中包括内皮素-1(ET-1)，ET-1可强烈收缩血管及致炎症反应。本文讨论在致病因子作用下，ET-1的增多与形成ARDS、败血症、休克的关系，致病机制包括ET-1诱导iNOS生成、使细胞膜Ca^2 内流增多、促使氧化应激而造成ALI。ET-1致肺损伤主要由于激活ETB受体，而ALI时肺内纤维化，ET-1亦起着重要的作用。过多的ET-1可使ARDS病人形成肺动脉高压，以ET-1及其所参与的SARS及ARDS发病的各个环节为靶点，应用抗病毒药、抑制炎症的糖皮质激素及阻断冠状病毒侵入细胞的大分子药物，使用内皮素受体拮抗剂和多离子通道阻断剂CPU86017，可阻断感染冠状病毒后形成肺损伤、肺纤维化、肺动脉痉挛及肺动脉高压等，有可能明显降低SARS及ARDS的发病率及致死率。     

Evolution of treatments for patients with acute lung injury

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are acute life-threatening forms of hypoxemic respiratory failure. ALI/ARDS patients require intensive care with prolonged mechanical ventilation. Despite advances in our understanding of the pathophysiology of ALI/ARDS, mortality rates remain > 30% and survivors suffer significant decrements in their quality of life. The evolving understanding of ALI/ARDS and the complex interactions involved in ALI/ARDS open the door for many potential targets for treatment. The condition is characterised by an acute inflammatory state that leads to increased capillary permeability and accumulation of proteinaceous pulmonary oedema. The changes that occur as a result of this inflammation clinically manifest themselves as hypoxemia, infiltrates on chest radiograph and reduced lung compliance. Many years have been dedicated to analysing the complexities involved in ALI/ARDS in order to improve current and future possibilities for treatment, with the aim of improving patient outcomes. Although some therapies have demonstrated benefits of improved oxygenation, such as surfactant and nitric oxide, these benefits have not translated into reductions in the duration of mechanical ventilation or mortality. Inflammatory mediator-targeted therapies were promising early on; however, larger trials have found therapies such as cytokine modulation, platelet-activating factor inhibition and neutrophil elastase inhibitors to be ineffective in the treatment of ALI/ARDS. Preclinical studies with β2-agonists and granulocyte macrophage colony-stimulating factor have shown promise for restoring alveolar capillary barrier integrity or reducing pulmonary oedema, and further studies are being conducted to test for true clinical benefit. Despite previous therapeutic failures, newer surfactant formulations have shown promise, particularly in patients with direct forms of lung injury, and are currently in Phase III trials. Anticoagulant therapy with activated protein C has been shown to improve survival in sepsis, the most common risk factor for the development of ALI/ARDS, and is now being studied in ALI/ARDS. Until new data emerge, the focus must remain on supportive care, including optimised mechanical ventilation, nutritional support, manipulation of fluid balance and prevention of intervening medical complications.     

新型冠状病毒SARS-CoV-2及临床相关药物研究进展

新型冠状病毒SARS-CoV-2是一种β属的冠状病毒,与SARS-CoV均以血管紧张素转换酶2为侵入宿主细胞的受体。在临床上,病毒感染患者表现出呼吸道和肺部损伤。以SARS-CoV作为参照研究SARS-CoV-2是目前的常用方法。主要介绍了冠状病毒的分类、结构和生命周期、血管紧张素转换酶2在SARS-CoV中的作用,并且总结了SARS-CoV-2的相关研究进展和临床治疗药物的药代动力学特性,为医药工作者充分了解SARS-CoV-2的发展过程以及相关药物研发提供参考。     

Design and biological activities of novel inhibitory peptides for SARS-CoV spike protein and angiotensin-converting enzyme 2 interaction

Severe acute respiratory syndrome (SARS) is an emerging infectious disease caused by a novel coronavirus (SARS-CoV). The binding of SARS-CoV spike (S) protein to cellular angiotensin-converting enzyme 2 (ACE2) is the first step in SARS-CoV infection. Therefore, we assayed the inhibitory effects of small peptides derived from S protein on the binding of S protein to ACE2 and on the S-protein-pseudotyped retrovirus infectivity. SP-4 (residues 192-203), SP-8 (residues 483-494), and SP-10 (residues 668-679) significantly blocked the interaction between S protein and ACE2 by biotinylated enzyme-linked immunosorbent assay, with IC(50) values of 4.30 +/- 2.18, 6.99 +/- 0.71, and 1.88 +/- 0.52 nmol, respectively. Peptide scanning suggested the region spanning residues 660-683 might act as a receptor-binding domain. SP-10 blocked both binding of the S protein and infectivity of S protein-pseudotyped retrovirus to Vero E6 cells. In conclusion, this is the first report of small peptides designed to disrupt the binding of SARS-CoV S protein to ACE2. Our findings suggest that SP-10 may be developed as an anti-SARS-CoV agent for the treatment of SARS-CoV infection.     

Potential clinical application of KGF-2 (FGF-10) for acute lung injury/acute respiratory distress syndrome

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an acute life-threatening form of hypoxemic respiratory failure with a high mortality rate, and there is still a great need for more effective therapies for such a severe and lethal disease. Dysfunction of endothelial and epithelial barriers is one of the most important mechanisms in hypoxia-associated ALI/ARDS. The acceleration of the epithelial repair process in the injured lung may provide an effective therapeutic target. KGF-2, a potent alveolar epithelial cell mitogen, plays an important role in organ morphogenesis and epithelial differentiation, and modulates a variety of mechanisms recognized to be important in alveolar repair and resolution in ALI/ARDS. Preclinical and clinical studies have suggested that KGF-2 may be the candidate of novel therapies for alveolar epithelial damage during ALI/ARDS.     

Preventive effect of tranilast on oleic acid-induced lung injury in guinea pigs

Acute respiratory distress syndrome or acute lung injury (ARDS)/(ALI) involve the severe lung injury with pulmonary vascular hyper-permeability and hypoxemia induced by inflammatory reactions. Since ARDS/ALI carries high mortality, the development of new drugs against ARDS/ALI is required. We examined the effect of tranilast, an anti-allergic drug, on vascular hyper-permeability in the lungs and airways, and on hypoxemia, in oleic acid (OA)-induced acute lung injury, an animal model of ARDS/ALI. The increase in pulmonary and airway vascular permeability and the decrease in partial oxygen pressure of arterial blood induced by an intravenous injection of OA were drastically ameliorated by the oral administration of tranilast in a dose-dependent manner. This is the first report to prove that tranilast prevents pulmonary and airway vascular permeability and hypoxemia induced by OA. These results suggest that tranilast may be a candidate drug for the treatment of ARDS/ALI.     

Epac/Rap1信号通路在急性肺损伤中作用的研究进展

急性肺损伤(ALI)中炎症信号通路的失调控以及炎症因子平衡紊乱是其发生和发展的重要原因。能直接被cAMP活化的交换蛋白(Epac)在调节肺部气道炎症和细胞增殖方面是一个新的效应器,新的关于cAMP依赖性蛋白激酶A(PKA)非依赖性通路研究表明,cAMP/Epac/Rap1信号通路参与并行使许多类型细胞的功能,包括细胞分泌、细胞间黏附和连接、细胞凋亡、细胞增殖和分化等。cAMP能通过Epac/Rap1信号通路参与ALI的发病过程,Epac/Rap1信号通路是ALI防治的潜在靶点。本文综述Epac/Rap1信号通路在肺部相关炎症及急性肺损伤中作用机制的国内外研究进展。     

Endothelial pathomechanisms in acute lung injury

Acute lung injury (ALI) and its most severe extreme the acute respiratory distress syndrome (ARDS) refer to increased-permeability pulmonary edema caused by a variety of pulmonary or systemic insults. ALI and in particular ARDS, are usually accompanied by refractory hypoxemia and the need for mechanical ventilation. In most cases, an exaggerated inflammatory and pro-thrombotic reaction to an initial stimulus, such as systemic infection, elicits disruption of the alveolo-capillary membrane and vascular fluid leak. The pulmonary endothelium is a major metabolic organ promoting adequate pulmonary and systemic vascular homeostasis, and a main target of circulating cells and humoral mediators under injury; pulmonary endothelium is therefore critically involved in the pathogenesis of ALI. In this review we will discuss mechanisms of pulmonary endothelial dysfunction and edema generation in the lung with special emphasis on the interplay between the endothelium, the immune and hemostatic systems, and highlight how these principles apply in the context of defined disorders and specific insults implicated in ALI pathogenesis.     

Endothelial pathomechanisms in acute lung injury

Acute lung injury (ALI) and its most severe extreme the acute respiratory distress syndrome (ARDS) refer to increased-permeability pulmonary edema caused by a variety of pulmonary or systemic insults. ALI and in particular ARDS, are usually accompanied by refractory hypoxemia and the need for mechanical ventilation. In most cases, an exaggerated inflammatory and pro-thrombotic reaction to an initial stimulus, such as systemic infection, elicits disruption of the alveolo-capillary membrane and vascular fluid leak. The pulmonary endothelium is a major metabolic organ promoting adequate pulmonary and systemic vascular homeostasis, and a main target of circulating cells and humoral mediators under injury; pulmonary endothelium is therefore critically involved in the pathogenesis of ALI. In this review we will discuss mechanisms of pulmonary endothelial dysfunction and edema generation in the lung with special emphasis on the interplay between the endothelium, the immune and hemostatic systems, and highlight how these principles apply in the context of defined disorders and specific insults implicated in ALI pathogenesis.