Identification of Acyloxyacyl Hydrolase, a Lipopolysaccharide Detoxifying Enzyme, in the Murine Urinary Tract

DSpace/Manakin Repository

Identification of Acyloxyacyl Hydrolase, a Lipopolysaccharide Detoxifying Enzyme, in the Murine Urinary Tract

Show simple item record


dc.contributor.advisor Munford, Robert S. en
dc.creator Feulner, J. Amelia en
dc.date.accessioned 2010-07-12T18:50:53Z en
dc.date.available 2010-07-12T18:50:53Z en
dc.date.issued 2003-10-8 en
dc.identifier.other 60129165 en
dc.identifier.uri http://hdl.handle.net/2152.5/692 en
dc.description.abstract Acyloxyacyl hydrolase (AOAH) is a lipase that removes the secondary fatty acyl chains that are substituted to the hydroxyl groups of glucosamine-linked 3-hydroxyacyl residues in lipid A, the bioactive center of Gram-negative bacterial lipopolysaccharides (LPS). Such limited deacylation has been shown to attenuate cytokine and chemokine responses to LPS, suggesting a role for AOAH in modulating (downregulating) inflammatory responses to invading Gramnegative bacteria. Prior to the experiments described in this report, AOAH had only been found in myeloid lineage cells (monocyte-macrophages, neutrophils and dendritic cells). In the work presented here, AOAH was found in murine renal proximal tubule cells and in human renal v cortex. Proximal tubule cells are known targets for invading Gram-negative uropathogens and we hypothesize that possessing AOAH may help them degrade the LPS contained within these bacteria. I further found that AOAH is secreted from proximal tubules in vitro and that it can be detected in murine urine, where it is able to deacylate purified LPS. AOAH may also associate with downstream bladder epithelial cells (which do not express AOAH) and be processed by them to its more enzymatically active, mature form. Bladder cells that have taken up AOAH in vitro are able to deacylate LPS. To determine the in vivo role of AOAH, I induced ascending urinary tract infections (UTIs) in wild type and AOAH null mice. To my surprise, AOAH null mice were able to clear bacteria from their urine faster than did wild type mice. An analysis of the immune response by histological analysis of bladder tissue and enumeration of neutrophils in the urine did not show a significant difference between wild type and AOAH null mice at any of the time points examined. Although I do not yet understand the mechanism for such increased clearance in AOAH null animals, we hypothesize that, due to their inability to deacylate LPS, they might have a more effective immune response to invading Gram-negative bacteria. A more detailed analysis of such responses to invading Gram-negative uropathogens will be important for understanding the in vivo role of AOAH in the urinary tract. en
dc.format.medium Electronic en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.subject Carboxylic Ester Hydrolases en
dc.subject Urinary Tract Infections en
dc.subject Lipopolysaccharides en
dc.title Identification of Acyloxyacyl Hydrolase, a Lipopolysaccharide Detoxifying Enzyme, in the Murine Urinary Tract en
dc.type.material Text en
dc.type.genre dissertation en
dc.format.digitalOrigin born digital en
thesis.degree.grantor Graduate School of Biomedical Sciences en
thesis.degree.department en
thesis.degree.name Doctor of Philosophy en
thesis.degree.level Ph.D. en
thesis.degree.discipline Molecular Microbiology en
thesis.date.available 2004-10-08 en

Files in this item

Files Size Format View
feulnerj.pdf 2.484Mb PDF View/Open

This item appears in the following Collection(s)

Show simple item record

Search DSpace


Advanced Search

Browse

My Account