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Title: The role of the receptor for advanced glycation end products in acute lung injury
Author: Thompson, Ben Arthur
ISNI:       0000 0004 2745 490X
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2012
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Acute lung injury (All) is a devastating pulmonary condition with no effective therapeutic. Uncontrolled inflammation and tissue destruction cause rapid deterioration of gas exchange and often result in permanently impaired lung function or mortality. The receptor for advanced glycation end products (RAGE) is a multiligand receptor highly expressed on pulmonary epithelial and endothelial cells. RAGE and its ligands have been implicated in inflammation in a variety of diseases, including ALL This project showed that the RAGE ligands HMGBl and calgranulin C were present in high concentrations in the airspace of patients with ALL These ligands drove RAGE-dependant cell activation through MAPK and NF-KB pathways in several in vitro pulmonary epithelial and endothelial cell models, as well as in a novel ex vivo murine pulmonary tissue model. This cell activation was combined with increases in apoptosis, IL-8 and matrix metalloproteinase concentrations in these cells as well as decreases in TIMP-l(tissue inhibitor of metalloproteinase) anti-protease protection. If mirrored in vivo, these results ) would cause increases in inflammatory cell infiltration and destruction of the lung tissue, worsening inflammation in ALL When used as a pre-treatment, soluble RAGE (sRAGE), which is thought to act as a scavenger of RAGE ligands, showed potent inhibition of cell activation and reduced inflammatory molecule release mediated by RAGE-ligands and by lavage fluid isolated from the lungs of patients with ALL RAGE ligands caused MAPK and NF-KB cell activation as well as increases in MIP-2 and KC inflammatory markers in ex vivo mouse lung tissue. These responses were reduced in RAGE-KO animal tissue treated the same way and through use of sRAGE. This evidence suggests that RAGE adds to the uncontrolled inflammation seen in All and that sRAGE has potential as an inhibitor of the inflammatory functions of RAGE.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available