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

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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.