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

当一些人受到严重感染时，他们身体的防御系统可能会反应过度，通过一种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，就称为急性呼吸窘迫综合征(ARDS)。这可能是由于各种侮辱造成的，包括吸入烟雾、身体受伤以及细菌和病毒感染。ARDS导致肺部充满水分，使呼吸变得非常困难。因此，这些患者需要在重症监护病房得到照顾，那里的机器可以帮助支持他们的呼吸。与此相关的死亡率为35%-45%。即使那些在ARDS中幸存下来的人也有相当长的恢复期，生活质量也降低了。身体会产生有助于减少炎症的天然类固醇。这些类固醇被一种名为HSD-1(11β-羟基类固醇脱氢酶1)的蛋白质激活。我们之前的工作表明，与正常小鼠相比，完全不产生HSD-1的转基因小鼠在感染后会出现更严重和更持久的肺损伤。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中类固醇被激活的情况较少，肺部炎症和损伤仍未得到控制。如果我们能够提供一种治疗方法，专门增加ARDS患者肺部中HSD-1的含量，这可能会有效地减少这种疾病造成的炎症和损害。其他研究表明，在成人骨髓中发现的一种干细胞有可能用于ARDS的治疗。这些细胞被称为“间充质干细胞”(MSCs)。已经证明，在肺损伤的小鼠中，注射这些干细胞可以帮助减少肺部炎症，对抗感染，并修复受损的肺。众所周知，这些干细胞在注射后会专门运往受损的器官。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。MSCs的抗炎和保护作用意味着它们也是治疗ARDS的潜在药物。到目前为止，我们已经讨论了两种不同的治疗ARDS的方法：1)注射MSCs和2)增加肺中HSD-1的水平。然而，我们认为通过将这两种想法结合起来，可以开发出一种更有效的治疗方法。我们认为，通过基因改造产生高水平HSD-1蛋白的骨髓间充质干细胞，在未来可能被用于ARDS的治疗。从理论上讲，转基因的MSCs会进入ARDS患者受损的肺；一旦到达那里，MSCs的抗炎作用和高水平的HSD-1将减少对肺的损害。我们已经成功地对MSCs进行了基因改造，使其能够产生高水平的HSD-1蛋白，并在实验室中证明了这些细胞可以激活天然类固醇。我们研究的目的是调查转基因MSCs是否有能力减少ARDS的肺损伤。然后我们将把转基因MSCs注射到有肺损伤的小鼠体内，以模拟当它们患上ARDS时在人类身上发生的情况。我们将使用根本不制造自己的HSD-1的转基因小鼠。然后我们将监测这些小鼠，看看那些接受治疗的小鼠是否比没有接受治疗的小鼠的肺损伤更少。我们还将在从人类ARDS患者的肺洗液中提取的巨噬细胞(人体的防御细胞之一)上测试转基因干细胞，看看巨噬细胞通过清除死亡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被拒绝移植的人类肺上的转基因干细胞，看看它们是否可以减少人类肺组织的炎症。

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.