A Role for Advanced Glycation End-Products in Diabetic Lung Injury

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

DESCRIPTION (provided by applicant): Pneumoconioses are occupational lung diseases caused by the inhalation of dust fibers/particles such as asbestos and silica. Experimental models of asbestosis recapitulate the salient features of idiopathic pulmonary fibrosis (IPF), a debilitating disease with both high morbidity and mortality due to a lack of effective therapies. Recent epidemiological studies have suggested that diabetics are at increased risk of developing idiopathic pulmonary fibrosis. This has led our lab to hypothesize that diabetics are at increased risk of developing pulmonary disease after environmental exposures. As the diabetic population increases at an alarming rate it is important to determine the mechanism by which diabetics are more susceptible to pulmonary injury so that it can be better prevented and treated. Recently our lab has implicated loss of the receptor for advanced glycation end-products (RAGE) as a key pathogenic step in the development of pulmonary fibrosis. This receptor has also been implicated in numerous other diabetic pathologies including neuropathy, atherosclerosis, and nephropathy. This has led us to investigate its potential role in increasing diabetics susceptibility to pulmonary injury. Preliminary studies have shown that aged diabetic mice have a loss of RAGE in their lung tissue. This could provide a potential mechanism by which diabetics are more likely to develop pulmonary fibrosis. This project will focus on the mechanisms by which RAGE promotes wound healing and prevents de-epithelialization and subsequent disease. We will also investigate the role that increased advanced glycation end-products (AGEs) play in the disease pathogenesis. Ultimately, we hope to determine if clearing RAGE ligands by use of a non-signaling decoy receptor, sRAGE, protects against the fibrotic response after asbestos exposure. This project will investigate the possibility that diabetics are at increased risk of developing pulmonary fibrosis after being exposed to occupational dust particles. It will provide a better understanding of how the disease develops which will help us develop better ways to prevent and treat the disease and its symptoms.