Can combined cellular and 11beta-hydroxysteroid dehydrogenase-1 gene therapy attenuate inflammation in acute respiratory distress syndrome?

联合细胞疗法和 11β-羟基类固醇脱氢酶 1 基因疗法能否减轻急性呼吸窘迫综合征的炎症？

• 批准号: MR/N021185/1
• 负责人: RAHUL MAHIDA
• 金额: $ 30.39万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN021185%2F1
• 关键词: combined; cellular; 11beta; hydroxysteroid; dehydrogenase

When some people have a severe infection, their body's defence systems can over-react and cause damage to their own organs through a process called inflammation. When the lungs are damaged in this way, it is called acute respiratory distress syndrome (ARDS). This can occur due to a variety of insults including smoke inhalation, physical injury, as well as bacterial and viral infection. ARDS causes the lungs to fill up with water, making it very difficult to breathe. These patients therefore need to be looked after in the intensive care unit, where a machine can help support their breathing. The death rate associated with this is 35-45%. Even those who survive ARDS have considerable recuperation periods and reduced quality of life.The body produces natural steroids which can help reduce inflammation. These steroids are activated by a protein called HSD-1 (11beta-hydroxysteroid dehydrogenase type 1). Our previous work showed that mice which have been genetically modified to not make HSD-1 at all, develop more severe and persistent lung damage following infection, compared to normal mice. We also found that patients with ARDS have lower than normal levels of HSD-1 in their lungs. This suggests that less steroid is being activated in the lungs of these patients, and that the lung inflammation and damage is continuing unchecked. If we were able to give a treatment which increased the amount of HSD-1 specifically in the lungs of patients with ARDS, this could be effective in reducing the inflammation and damage caused by the disease.Other work has shown that a type of stem cell found in the bone marrow of adults has the potential to be used as a treatment for ARDS. These cells are called "mesenchymal" stem cells (MSCs). It has been shown that in mice with lungdamage, injection of these stem cells can help reduce lung inflammation, fight infection, and repair damaged lung. These stem cells are known to travel to damaged organs specifically, after being injected. Since these stem cells have been taken safely from the bone marrow of adult volunteers, we therefore avoid the ethical problems associated with using foetal stem cells. The anti-inflammatory, protective quality of MSCs, mean they are also a potential treatment for ARDS. So far we have discussed two separate potential treatments for ARDS: 1) injection of MSCs and 2) increasing HSD-1 levels in the lungs. However, we think that by combining these two ideas, a more effective treatment could be developed. We think that MSCs which are genetically modified to produce high levels of HSD-1 protein, could potentially be used as a treatment for ARDS in the future. In theory, the genetically modified MSCs would travel to the damaged lung in ARDS patients; once there, the anti-inflammatory effects of the MSCs and high levels of HSD-1 would reduce damage caused to the lungs. We have already successfully genetically modified the MSCs so that they produce high levels of HSD-1 protein, and shown that these cells can activate natural steroids in the lab. The aims of our research are to investigate whether genetically modified MSCs will have the ability to reduce lung injury in ARDS.We will then inject the genetically modified MSCs into mice with lung injury, to mimic what happens in humans when they get ARDS. We will use genetically modified mice which do not make their own HSD-1 at all. We will then monitor the mice to see if those who receive the treatment have less lung damage than the untreated mice. We will also test the genetically modified stem cells on macrophages (one of the body's defender cells) taken from the lung washings of human ARDS patients, and see if the ability of the macrophages to reduce inflammation by clearing away dead cells and bacteria is improved. We will also use the genetically modified stem cells on human lungs in the lab which have been rejected for transplantation, to see if they can reduce inflammation in human lung tissue.

当一些人患有严重感染时，他们身体的防御系统可能会过度反应，并通过称为炎症的过程对自己的器官造成损害。当肺部以这种方式受损时，它被称为急性呼吸窘迫综合征（ARDS）。这可能是由于各种各样的侮辱，包括吸入烟雾，身体伤害，以及细菌和病毒感染。急性呼吸窘迫综合征导致肺部充满水，使呼吸非常困难。因此，这些患者需要在重症监护室接受护理，在那里机器可以帮助支持他们的呼吸。与此相关的死亡率为35- 45%。即使是那些从ARDS中幸存下来的人也有相当长的恢复期和降低的生活质量。身体产生天然的类固醇，可以帮助减轻炎症。这些类固醇被称为HSD-1（11 β-羟基类固醇脱氢酶1型）的蛋白质激活。我们以前的工作表明，与正常小鼠相比，经过基因修饰而完全不产生HSD-1的小鼠在感染后会产生更严重和持久的肺损伤。我们还发现，ARDS患者的肺部HSD-1水平低于正常水平。这表明这些患者的肺部激活的类固醇较少，并且肺部炎症和损伤仍在继续。如果我们能够提供一种治疗方法，特别是增加HSD-1在ARDS患者肺部的含量，这可能会有效地减少炎症和疾病引起的损害。其他工作表明，在成人骨髓中发现的一种干细胞有可能被用作治疗ARDS。这些细胞被称为“间充质”干细胞（MSC）。研究表明，在肺损伤的小鼠中，注射这些干细胞可以帮助减轻肺部炎症，对抗感染，修复受损的肺部。已知这些干细胞在被注射后会专门前往受损器官。由于这些干细胞是从成年志愿者的骨髓中安全提取的，因此我们避免了与使用胎儿干细胞相关的伦理问题。MSC的抗炎，保护质量意味着它们也是ARDS的潜在治疗方法。到目前为止，我们已经讨论了两种单独的ARDS潜在治疗方法：1）注射MSC和2）增加肺中的HSD-1水平。然而，我们认为，通过结合这两个想法，可以开发出更有效的治疗方法。我们认为，经过基因修饰以产生高水平HSD-1蛋白的MSC在未来可能被用作ARDS的治疗。从理论上讲，基因修饰的MSC将前往ARDS患者受损的肺部;一旦到达那里，MSC的抗炎作用和高水平的HSD-1将减少对肺部造成的损害。我们已经成功地对MSC进行了遗传修饰，使它们产生高水平的HSD-1蛋白，并表明这些细胞可以在实验室中激活天然类固醇。本研究的目的是探讨转基因骨髓间充质干细胞是否具有减轻急性呼吸窘迫综合征（ARDS）肺损伤的能力，然后将转基因骨髓间充质干细胞注射到肺损伤小鼠体内，模拟人类ARDS时的情况。我们将使用转基因小鼠，它们根本不会产生自己的HSD-1。然后我们将监测小鼠，看看接受治疗的小鼠是否比未治疗的小鼠肺损伤更少。我们还将在从人类ARDS患者的肺冲洗液中提取的巨噬细胞（身体的防御细胞之一）上测试转基因干细胞，并观察巨噬细胞通过清除死细胞和细菌来减少炎症的能力是否得到改善。我们还将在实验室中使用人类肺部的转基因干细胞，这些细胞在移植时被拒绝，看看它们是否可以减少人类肺部组织的炎症。

项目成果

Acute Respiratory Distress Syndrome is associated with impaired alveolar macrophage efferocytosis

急性呼吸窘迫综合征与肺泡巨噬细胞胞吞作用受损有关

• DOI: 10.1101/2021.03.15.21253591
• 发表时间: 2021
• 作者: Mahida R

CD14-positive extracellular vesicles in bronchoalveolar lavage fluid as a new biomarker of acute respiratory distress syndrome.

• DOI: 10.1152/ajplung.00052.2022
• 发表时间: 2022-04-01
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Mahida RY;Price J;Lugg ST;Li H;Parekh D;Scott A;Harrison P;Matthay MA;Thickett DR
• 通讯作者: Thickett DR