DESCRIPTION: PROJECT SUMMARY: The primary goal of our research is to characterize the role of the lipid mediator Platelet-activating factor (PAF) in skin pathophysiology. PAF generates an acute pro- inflammatory response and delayed immunosuppression. Our previous studies have demonstrated that PAF is involved in the acute inflammation and mediates the delayed systemic immunosuppression following treatment of skin with high doses of ultraviolet B radiation. We have recently shown that photodynamic therapy (PDT) which consists of a photosensitizing agent followed by irradiation with blue light (which is used to treat pre- and skin cancers) produces high levels of PAF in keratinocytes in vitro and murine skin in vivo. More importantly, PDT treatment was found to induce systemic immunosuppression only in wild-type, but not in mice lacking PAF-receptors (PAF-R). Given that PDT is associated with significant treatment-limiting acute side effects of a painful sunburn-like reaction, and that the immunosuppressive effects of PDT might explain long-term failure rates of this modality, understanding the mechanisms of PDT actions has clinical significance. The planned studies take advantage of our expertise and tools we have used to define the role of PAF in UV responses. Three aims will test the hypothesis that PDT generates PAF which results in both an early pro-inflammatory response as well as delayed immunosuppressive effects. The first aim will explore the consequences of PAF-R and the PAF-metabolizing enzyme serum PAF-acetylhydrolase (PAF-AH) loss-of-function to define the role of PDT-generated PAF in the sunburn-like acute side effects. The role of tumor necrosis factor and cyclooxygenase-2 as downstream effectors of PAF-R signaling will be defined. The second aim will test the effectiveness of experimental PDT therapy in wildtype and PAF-R-deficient mice that have underwent a UVB carcinogenesis protocol to generate actinic damage. The ability of PAF-R antagonists and cyclooxygenase-2 inhibitors to modulate the effectiveness of experimental PDT will be defined. The third aim will use human skin explants and human subjects undergoing PDT to define if PAF is generated and the effects of topical PAF-R antagonists on PDT acute effects. Given that PDT-generated PAF could explain both the acute inflammation and delayed immunosuppression associated with PDT, these studies have clinical importance and could result in novel therapeutics to improve the effectiveness of this modality commonly used in our veteran population.