Milutinovic, Pavle
(2012)
The receptor for advanced glycation end products is a central mediator of asthma pathogenesis.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The receptor for advanced glycation end products (RAGE) is a multiligand, cell surface receptor. Isolated from lung, the organ in which it is most abundant, RAGE has since been shown to be a pro-inflammatory mediator in the pathogenesis of diabetes, atherosclerosis, rheumatic and neurodegenerative syndromes, and cancer. However, despite its localization, the role of RAGE in asthma and allergic airway disease is largely unknown.
The studies described herein explore RAGE’s effect on disease phenotype using several different models of allergic airway disease/asthma in mice, with house dust mite extract or ovalbumin as the provoking allergen. Respiratory mechanics were assessed using mechanical ventilation and the forced oscillation technique; bronchovascular architecture and airway remodeling were evaluated using general histochemical stains. Expression of RAGE, immunoglobulin, and relevant cytokines was characterized by standard protein detection methods and/or real-time PCR, while immunohistofluorescence microscopy was used to determine the cellular localization of proteins of interest.
In both house dust mite and ovalbumin models of chronic allergic airway disease/asthma, the absence of RAGE abolishes most assessed measures of pathology, including airway hypersensitivity (resistance, tissue damping, and elastance), eosinophilic inflammation, and mucus hypersecretion. IL-17 demonstrates complex regulation, with elevated baseline expression in RAGE knockouts, but no induction in response to allergen challenge. IL-4 and IL-25 secretion, immunoglobulin isotype class switching and antigen recognition are intact in the absence of RAGE. In contrast, allergen-induced up-regulation of eotaxin, eotaxin-2, IL-5, IL-13, and IL-33 is abrogated in RAGE’s absence.
RAGE’s soluble isoform is a decoy receptor that impedes ligand binding to the membrane isoform and thus downstream signaling. Soluble RAGE (sRAGE) has been efficacious in ameliorating disease in a broad array of models in which the membrane RAGE isoform is thought to be involved. Because few studies have explored the use of this agent in the lung, clearance and biodistribution studies were performed, exploring three common routes of administration; intratracheal delivery was found to be substantially superior to other modes. sRAGE was used as a therapeutic in an animal model of asthma and was shown to markedly reduce inflammation, suggesting that inhibition of RAGE may serve as a promising therapeutic strategy.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Milutinovic, Pavle | psm6@pitt.edu | PSM6 | |
|
| ETD Committee: |
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| Date: |
26 July 2012 |
| Date Type: |
Publication |
| Defense Date: |
17 July 2012 |
| Approval Date: |
26 July 2012 |
| Submission Date: |
26 July 2012 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
234 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cellular and Molecular Pathology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
RAGE; lung biology; asthma; allergy; immunology; Th2 |
| Date Deposited: |
26 Jul 2012 18:10 |
| Last Modified: |
26 Jul 2017 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/12994 |
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