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

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Title: Identification of Acyloxyacyl Hydrolase, a Lipopolysaccharide Detoxifying Enzyme, in the Murine Urinary Tract
Author: Feulner, J. Amelia
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 .
URI: http : / /hdl .handle .net /2152 .5 /692
Date: 2003-10-8

Citation

Identification of Acyloxyacyl Hydrolase, a Lipopolysaccharide Detoxifying Enzyme, in the Murine Urinary Tract. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /692 .

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