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

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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.