Solar elastosis is a hallmark of photoaging, the accumulated response of skin to injury caused by years of environmental exposure to solar ultraviolet irradiation (UVR). In solar elastosis, the elastic fibers in the dermis are greatly increased in amount and appear to be thickened and contain large amorphous areas. Despite this increase in elastin, the skin shows decreased elasticity and loss of resilience. Increased synthesis and degradation are part of the dermal remodeling resulting from chronic sun exposure. The processes involved in stimulating synthesis of tropoelastin by fibroblasts in response to UVR are only inadequately understood. This application addresses mechanisms whereby chronic UVR exposure may increase elastin by synthesis of tropoelastin and fibrillin, major components of elastin fibers. The overall goal is to identify key control points in order to devise protective measures.
The Specific Aims of this application are: 1) to test the hypothesis that reactive oxygen species (ROS) produced by neutrophils enhance development of solar elastosis in murine skin that is chronically treated with UV irradiation. 2) to test the hypothesis that increased elastase activity in response to chronic UV irradiation up-regulates tropoelastin and fibrillin synthesis by dermal fibroblasts thereby contributing to the development of solar elastosis, and 3) to determine whether UVR absorbed by keratinocytes or fibroblasts induce the synthesis of tropoelastin and fibrillin by dermal fibroblasts.
The Specific Aims will be addressed using mouse strains that are deficient in the generation of ROS by neutrophils, or are deficient in the release of neutrophil elastase or alpha-1 protease inhibitor. Elastase inhibitors will also be employed in vivo. In vitro experiments using human dermal fibroblasts grown in contracted collagen gels or skin equivalents will be used to define mechanisms for the phenomena observed in vivo.
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