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.