Asbestosis, a form of pneumoconiosis caused by inhalation of asbestos fibers, is the prototype of diseases caused by inhalation of mineral fibers. There is currently no treatment for this disease. Pathologically, asbestosis is characterized by interstitial fibrosis in a pattern identical to that observed in patients with idiopathic pulmonary fibrosis (IPF) with the additional finding of asbestos bodies in histologic sections. The pathogenesis of asbestosis is not fully understood, but inflammation, reactive oxygen species (ROS), and increased expression of TGF-B all play important roles in this disease. Notably, the receptor for advanced glycation end products (RAGE) when activated by its ligands induces chronic inflammation, enhances ROS production and leads to TGF-B synthesis. Over the last decade, RAGE has been implicated as a progression factor in a number of diseases, including diabetic atherosclerosis, chronic inflammation and renal fibrosis to name a few. The role of RAGE in asbestosis has not been evaluated. However, in renal fibrosis RAGE signaling has been found to be a central mechanism in stimulating myofibroblast metaplasia. Importantly, myofibroblastic foci are believed to be key mediators of disease progression in fibrotic lung injuries such as asbestosis and IPF. Thus, RAGE signaling, which induces chronic inflammation, ROS production, TGF-B synthesis, and myofibroblast metaplasia has many features that suggest it may be a central mediator in the pathogenesis of asbestosis. In addition to the membrane RAGE just described, there is also a soluble isoform of RAGE (sRAGE) that has an extracellular (ligand-binding) sequence identical to that of RAGE, but lacks a transmembrane domain and consequently is secreted. sRAGE is thus a decoy molecule, and has successfully been used in animal models to stop progression of the diseases listed above. Notably, we have found that the lung contains extremely high concentrations of sRAGE compared to all other tissues, yet there have not been any studies of this protein in lung disease. Thus, sRAGE may have an important anti-inflammatory and anti-fibrotic role in the lung by preventing ligands from binding the membrane RAGE. In this proposal we will directly test the hypothesis that RAGE-mediated signaling is a central mechanism in the pathogenesis of asbestosis and that sRAGE can protect against this disease. ? ? ?
