Hydroxysteroid Dehydrogenase activity and the vitamin D axis in acute lung injury - mechanistic and functional importance.

感染的患者可能会产生夸大的反应，导致包括肺在内的器官受损。在肺部，这被称为急性肺损伤。包括烟雾吸入、创伤以及细菌和病毒感染在内的各种侮辱都可能导致急性肺损伤。这会导致肺脏充满水，这意味着患者的呼吸变得非常困难。因此，这些患者需要在重症监护室接受护理，包括呼吸支持(机械呼吸)。与这种情况相关的死亡率约为35%-45%。即使那些在急性肺损伤中幸存下来的人也有相当长的恢复期和12个月后生活质量的下降。在这一应用中，我们提出了广泛的新的研究结果，发现ALI患者存在两种内分泌异常-即肺内11-β羟基类固醇脱氢酶1(HSD-1)活性缺陷和严重的维生素D缺乏。通过使用肺损伤的动物模型，我们发现HSD-1基因修饰的小鼠缺乏HSD-1会导致过度和持续的炎症性肺损伤。有趣的是，HSD-1缺乏的小鼠非常缺乏维生素D，这可能是一些夸大的肺损伤的原因。HSD-1的活性(它在肺等组织中产生活性类固醇激素)与维生素D之间的联系此前尚不清楚。因此，这项研究的目的是研究为什么HSD-1基因敲除的动物体内维生素d水平较低。我们将通过研究这些动物在6个月内的钙水平和骨密度来确定这种维生素D缺乏症是否具有重要的功能。我们将通过一系列实验来确定这些小鼠维生素D缺乏的机制。此外，我们还将测试HSD-1 KO小鼠抵抗肺炎和肠道感染(腹膜炎)感染模型的能力，作为临床相关模型。我们将替换HSD-1 KO小鼠的维生素D缺乏症，以确定这是否可以减少肺损伤。为了在小鼠身上解释我们的发现，我们将确定在一组有急性肺损伤或有急性肺损伤风险的患者中，尿液中HSD-1的含量之间是否存在联系(预计尿液中的HSD-1活性标志物较低)。因此，这项研究应该扩大我们对局部组织产生活性类固醇皮质醇和维生素D之间相互作用的了解。如果我们的假设是正确的，这项研究将为使用维生素D治疗急性肺损伤患者提供理论基础，或者提供一种基于细胞的治疗方法，以提高炎症组织中HSD-1的活性。

Patients who get infection may develop an exaggerated response that results in damage to organs including the lung. In the lung this is known as acute lung injury. Acute lung injury can occur due to a variety of insults including smoke inhalation, trauma as well as bacterial and viral infection. It causes the lu8ngs to fill up with water and this means that patients' breathing becomes very laboured. These patients therefore need care in the intensive care unit including support with their breathing (mechanical ventilation). The death rate associated with this happening is about 35-45%. Even those who survive acute lung injury have considerable recuperation periods and reduced quality of life 12 months afterwards.In this application we present extensive novel research findings that identify two endocrine abnormalities in patients with ALI- namely defective 11-beta hydroxysteroid dehydrogenase type 1 (HSD-1) activity within the lungs and severe vitamin D deficiency. By using animal models of lung injury we have found that HSD-1 deficiency in genetically modified mice results in exaggerated and persistent inflammatory lung damage. Intriguingly, the HSD-1 deficient mice are very vitamin D deficient which may account for some of the exaggerated lung damage. The link between the activity of HSD-1 (which generates active steroid hormones within tissues such as the lung) and vitamin D is previously unrecognised.The aims of this research are therefore to study why vitamin d levels are low in animals with the HSD-1 gene knocked out. We will establish if this vitamin D deficiency is functionally important by studying the levels of calcium and bone density in these animals over 6 months. We will ascertain through a series of experiments the mechanism of these mice becoming vitamin D deficient. In addition, we will test the ability of HSD-1 KO mice to resist infectious models of pneumonia and gut infection (peritonitis) as clinically relevant models. We will replace the vitamin D deficiency in the HSD-1 KO mice to establish if this can reduce lung injury. In order to translate our findings in mice we will establish whether there is a link between urinary measures of HSD-1 in a cohort of patients with or at risk of acute lung injury (expected low HSD-1 activity markers in urine). This research should therefore expand our knowledge about the interactions between the local tissue production of active steroid cortisol and vitamin D. If our hypotheses are correct this research would provide a rationale for treating patients with acute lung injury with vitamin D or a therapy perhaps cell based to boost HSD-1 activity in inflamed tissues.