PDF(Pubmed)
Abstract：
COVID-19 patients can present with pulmonary edema early in disease. We propose that this is due to a local vascular problem because of activation of bradykinin 1 receptor (B1R) and B2R on endothelial cells in the lungs. SARS-CoV-2 enters the cell via ACE2 that next to its role in RAAS is needed to inactivate des-Arg9 bradykinin, the potent ligand of the B1R. Without ACE2 acting as a guardian to inactivate the ligands of B1R, the lung environment is prone for local vascular leakage leading to angioedema. Here, we hypothesize that a kinin-dependent local lung angioedema via B1R and eventually B2R is an important feature of COVID-19. We propose that blocking the B2R and inhibiting plasma kallikrein activity might have an ameliorating effect on early disease caused by COVID-19 and might prevent acute respiratory distress syndrome (ARDS). In addition, this pathway might indirectly be responsive to anti-inflammatory agents.
The COVID-19 pandemic represents an unprecedented threat to global health. Millions of cases have been confirmed around the world, and hundreds of thousands of people have lost their lives. Common symptoms include a fever and persistent cough and COVID-19 patients also often experience an excess of fluid in the lungs, which makes it difficult to breathe. In some cases, this develops into a life-threatening condition whereby the lungs cannot provide the body\'s vital organs with enough oxygen. The SARS-CoV-2 virus, which causes COVID-19, enters the lining of the lungs via an enzyme called the ACE2 receptor, which is present on the outer surface of the lungs’ cells. The related coronavirus that was responsible for the SARS outbreak in the early 2000s also needs the ACE2 receptor to enter the cells of the lungs. In SARS, the levels of ACE2 in the lung decline during the infection. Studies with mice have previously revealed that a shortage of ACE2 leads to increased levels of a hormone called angiotensin II, which regulates blood pressure. As a result, much attention has turned to the potential link between this hormone system in relation to COVID-19. However, other mouse studies have shown that ACE2 protects against a build-up of fluid in the lungs caused by a different molecule made by the body. This molecule, which is actually a small fragment of a protein, lowers blood pressure and causes fluid to leak out of blood vessels. It belongs to a family of molecules known as kinins, and ACE2 is known to inactivate certain kinins. This led van de Veerdonk et al. to propose that the excess of fluid in the lungs seen in COVID-19 patients may be because kinins are not being neutralized due to the shortage of the ACE2 receptor. This had not been hypothesized before, even though the mechanism could be the same in SARS which has been researched for the past 17 years. If this hypothesis is correct, it would mean that directly inhibiting the receptor for the kinins (or the proteins that they come from) may be the only way to stop fluid leaking into the lungs of COVID-19 patients in the early stage of disease. This hypothesis is unproven, and more work is needed to see if it is clinically relevant. If that work provides a proof of concept, it means that existing treatments and registered drugs could potentially help patients with COVID-19, by preventing the need for mechanical ventilation and saving many lives.
The COVID-19 pandemic represents an unprecedented threat to global health. Millions of cases have been confirmed around the world, and hundreds of thousands of people have lost their lives. Common symptoms include a fever and persistent cough and COVID-19 patients also often experience an excess of fluid in the lungs, which makes it difficult to breathe. In some cases, this develops into a life-threatening condition whereby the lungs cannot provide the body\'s vital organs with enough oxygen. The SARS-CoV-2 virus, which causes COVID-19, enters the lining of the lungs via an enzyme called the ACE2 receptor, which is present on the outer surface of the lungs’ cells. The related coronavirus that was responsible for the SARS outbreak in the early 2000s also needs the ACE2 receptor to enter the cells of the lungs. In SARS, the levels of ACE2 in the lung decline during the infection. Studies with mice have previously revealed that a shortage of ACE2 leads to increased levels of a hormone called angiotensin II, which regulates blood pressure. As a result, much attention has turned to the potential link between this hormone system in relation to COVID-19. However, other mouse studies have shown that ACE2 protects against a build-up of fluid in the lungs caused by a different molecule made by the body. This molecule, which is actually a small fragment of a protein, lowers blood pressure and causes fluid to leak out of blood vessels. It belongs to a family of molecules known as kinins, and ACE2 is known to inactivate certain kinins. This led van de Veerdonk et al. to propose that the excess of fluid in the lungs seen in COVID-19 patients may be because kinins are not being neutralized due to the shortage of the ACE2 receptor. This had not been hypothesized before, even though the mechanism could be the same in SARS which has been researched for the past 17 years. If this hypothesis is correct, it would mean that directly inhibiting the receptor for the kinins (or the proteins that they come from) may be the only way to stop fluid leaking into the lungs of COVID-19 patients in the early stage of disease. This hypothesis is unproven, and more work is needed to see if it is clinically relevant. If that work provides a proof of concept, it means that existing treatments and registered drugs could potentially help patients with COVID-19, by preventing the need for mechanical ventilation and saving many lives.
摘要：
COVID-19患者在疾病早期可出现肺水肿。我们认为这是由于肺内皮细胞上缓激肽1受体（B1R）和B2R的激活而引起的局部血管问题。SARS-CoV-2通过ACE2进入细胞，除了其在RAAS中的作用外，还需要灭活des-Arg9缓激肽，B1R的有效配体。没有ACE2作为监护人来使B1R的配体失活，肺部环境容易发生局部血管渗漏，导致血管性水肿。这里,我们假设通过B1R和最终通过B2R的激肽依赖性局部肺血管性水肿是COVID-19的一个重要特征.我们认为阻断B2R和抑制血浆激肽释放酶活性可能对COVID-19引起的早期疾病有改善作用，并可能预防急性呼吸窘迫综合征（ARDS）。此外,该途径可能间接响应抗炎药.
COVID-19大流行对全球健康构成了前所未有的威胁。世界各地已经确认了数百万例，成千上万的人失去了生命。常见的症状包括发烧和持续咳嗽，COVID-19患者的肺部液体也经常过多，让人呼吸困难.在某些情况下,这发展成一种危及生命的状况，即肺部无法为身体的重要器官提供足够的氧气。SARS-CoV-2病毒,导致COVID-19，通过一种称为ACE2受体的酶进入肺部，它存在于肺细胞的外表面上。导致2000年代初期SARS爆发的相关冠状病毒也需要ACE2受体进入肺部细胞。在SARS中,肺部ACE2水平在感染期间下降。先前对小鼠的研究表明，ACE2的缺乏会导致一种称为血管紧张素II的激素水平升高，调节血压。因此,人们已经将注意力转向了这种激素系统与COVID-19之间的潜在联系。然而,其他小鼠研究表明，ACE2可以防止由身体产生的不同分子引起的肺部液体积聚。这个分子,实际上是蛋白质的一小部分，降低血压并导致液体从血管中泄漏。它属于一个被称为激肽的分子家族，已知ACE2会使某些激肽失活。这导致了vandeVeerdonk等人。认为在COVID-19患者中看到的肺部液体过多可能是因为激肽由于ACE2受体短缺而没有被中和。这以前没有被假设过，尽管这种机制在过去17年的SARS中可能是相同的。如果这个假设是正确的,这意味着直接抑制激肽(或它们来自的蛋白质)的受体可能是在疾病早期阻止液体泄漏到COVID-19患者肺部的唯一方法。这个假设是未经证实的,并且需要更多的工作来查看它是否具有临床相关性。如果这项工作提供了概念证明，这意味着现有的治疗方法和注册药物可能会通过防止机械通气并挽救许多生命来帮助COVID-19患者。
COVID-19大流行对全球健康构成了前所未有的威胁。世界各地已经确认了数百万例，成千上万的人失去了生命。常见的症状包括发烧和持续咳嗽，COVID-19患者的肺部液体也经常过多，让人呼吸困难.在某些情况下,这发展成一种危及生命的状况，即肺部无法为身体的重要器官提供足够的氧气。SARS-CoV-2病毒,导致COVID-19，通过一种称为ACE2受体的酶进入肺部，它存在于肺细胞的外表面上。导致2000年代初期SARS爆发的相关冠状病毒也需要ACE2受体进入肺部细胞。在SARS中,肺部ACE2水平在感染期间下降。先前对小鼠的研究表明，ACE2的缺乏会导致一种称为血管紧张素II的激素水平升高，调节血压。因此,人们已经将注意力转向了这种激素系统与COVID-19之间的潜在联系。然而,其他小鼠研究表明，ACE2可以防止由身体产生的不同分子引起的肺部液体积聚。这个分子,实际上是蛋白质的一小部分，降低血压并导致液体从血管中泄漏。它属于一个被称为激肽的分子家族，已知ACE2会使某些激肽失活。这导致了vandeVeerdonk等人。认为在COVID-19患者中看到的肺部液体过多可能是因为激肽由于ACE2受体短缺而没有被中和。这以前没有被假设过，尽管这种机制在过去17年的SARS中可能是相同的。如果这个假设是正确的,这意味着直接抑制激肽(或它们来自的蛋白质)的受体可能是在疾病早期阻止液体泄漏到COVID-19患者肺部的唯一方法。这个假设是未经证实的,并且需要更多的工作来查看它是否具有临床相关性。如果这项工作提供了概念证明，这意味着现有的治疗方法和注册药物可能会通过防止机械通气并挽救许多生命来帮助COVID-19患者。
