Role of DHRS9 in oxylipin metabolism - Oxylipins comprise a rapidly growing in numbers class of lipid mediators derived from polyunsaturated fatty acids such as arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, linoleic acid, etc. Collectively, oxylipins have been implicated in the regulation of a vast variety of physiological responses from pain and inflammation to blood clotting and gastric acid secretion. As a result of important physiological roles played by oxylipin mediators, their metabolic interconversions received an intense scrutiny. To date, these efforts allowed to identify the main metabolic pathways responsible for the biosynthesis of major classes of oxylipins. On the other hand, their catabolic interconversions, i.e. subsets of biochemical reactions which frequently alter their biological activities, still remain rather poorly understood. Recently, we demonstrated that human microsomal dehydrogenase reductase 9 (DHRS9) exhibits a robust activity oxidizing hydroxyl groups of many important oxylipins such as pro-inflammatory mediator leukotriene B4 or pro-resolving mediators such as resolvin D1 and lipoxin A4, for example. These findings strongly suggest that DHRS9 activity can alter the tissue balance between pro-inflammatory and pro-resolving mediators and, thereby, affect the progression of inflammation as well as the resolution of inflammation. In agreement with this hypothesis, our preliminary data show that lungs of naïve, untreated DHRS9 deficient mice display all characteristic signs of inflammation, which are further exacerbated by lipopolysaccharide treatment. Together, these observations suggest that DHRS9 deficiency promotes lung inflammation and makes the lungs more susceptible to injury. Thus, experiments outlined in this application have been designed to test our major working hypothesis that DHRS9 is a highly potent oxylipin dehydrogenase with broad substrate specificity which plays a critically important role in body’s ability to control inflammation. This hypothesis will be explored through the following Specific Aims: 1) to elucidate the molecular basis underlying the broad substrate specificity of DHRS9 in order to define the spectrum of its naturally occurring substrates and 2) to establish the physiological role of DHRS9 in controlling lung inflammation and injury. The results of these studies will define the pathways of oxylipin metabolism controlled by DHRS9 and will lay the foundation for development of better informed therapeutic approaches targeting lung inflammation.
