The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin super-family of cell surface receptors whose activation has been suggested to contribute to various pathologies. RAGE has been primarily studied in diabetes where its upregulation has been linked to disease in the kidney, vasculature, and nervous system. This protein is highly expressed in the lung under normal conditions, but its function is unknown. We therefore investigated the normal function of RAGE in the lung and its pulmonary expression in two disease states.
Idiopathic pulmonary fibrosis (IPF) is a debilitating disease with both high morbidity and mortality. Unfortunately, there are currently no effective therapies for IPF necessitating mechanistic insight into the disease pathogenesis. We found that pulmonary fibrosis led to a depletion of RAGE in both animal models and tissue from patients with idiopathic pulmonary fibrosis. In contrast to other diseases in which RAGE signaling promotes pathology, we found that aged RAGE null mice spontaneously develop pulmonary fibrosis-like alterations and more severe fibrosis in response to asbestos injury. In addition, we found that RAGE null mice were fully protected from the fibrotic effects of bleomycin.
In addition, we investigated the expression of RAGE in the lungs of diabetic rodents. Diabetes has been shown to alter RAGE expression in a number of tissues that do not normally express RAGE. We hypothesized that diabetes would alter pulmonary RAGE expression and contribute to the susceptibility to pulmonary injury. We found that pulmonary RAGE expression was unaltered in five rodent models suggesting that diabetes does not effect RAGE expression in the lung.
Lastly, we identified that RAGE has a very high affinity for components in the basement membrane of the lung. A few RAGE studies suggested that it might serve a role as an adhesion molecule. We found that RAGE extensively colocalized with the alveolar basement membrane and had very high affinity for collagen I, collagen IV, and laminin, but not fibronectin. These findings along with the fact that RAGE null mice spontaneously develop fibrosis suggest a potential homeostatic function of RAGE in the lung. This is in stark contrast to the vast majority of studies, which suggest that its expression is solely pathologic.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-11172009-213538 |
| Date | 19 November 2009 |
| Creators | Englert, Judson Matthew |
| Contributors | Tim Oury, MD, PhD, Donna Beer-Stolz, PhD, Bruce Pitt, PhD, Steven Shapiro, MD, Youhua Liu, PhD |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-11172009-213538/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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