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Uricase Inhibits Nitrogen Dioxide-Promoted Allergic Sensitization to Inhaled Ovalbumin Independent of Uric Acid Catabolism.

ABSTRACT: Nitrogen dioxide (NO2) is an environmental air pollutant and endogenously generated oxidant that contributes to the exacerbation of respiratory disease and can function as an adjuvant to allergically sensitize to an innocuous inhaled Ag. Because uric acid has been implicated as a mediator of adjuvant activity, we sought to determine whether uric acid was elevated and participated in a mouse model of NO2-promoted allergic sensitization. We found that uric acid was increased in the airways of mice exposed to NO2 and that administration of uricase inhibited the development of OVA-driven allergic airway disease subsequent to OVA challenge, as well as the generation of OVA-specific Abs. However, uricase was itself immunogenic, inducing a uricase-specific adaptive immune response that occurred even when the enzymatic activity of uricase had been inactivated. Inhibition of the OVA-specific response was not due to the capacity of uricase to inhibit the early steps of OVA uptake or processing and presentation by dendritic cells, but occurred at a later step that blocked OVA-specific CD4(+) T cell proliferation and cytokine production. Although blocking uric acid formation by allopurinol did not affect outcomes, administration of ultra-clean human serum albumin at protein concentrations equivalent to that of uricase inhibited NO2-promoted allergic airway disease. These results indicate that, although uric acid levels are elevated in the airways of NO2-exposed mice, the powerful inhibitory effect of uricase administration on allergic sensitization is mediated more through Ag-specific immune deviation than via suppression of allergic sensitization, a mechanism to be considered in the interpretation of results from other experimental systems.

SUBMITTER: Ather JL

PROVIDER: S-EPMC4992621 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Uricase Inhibits Nitrogen Dioxide-Promoted Allergic Sensitization to Inhaled Ovalbumin Independent of Uric Acid Catabolism.

Ather Jennifer L JL Burgess Edward J EJ Hoyt Laura R LR Randall Matthew J MJ Mandal Mridul K MK Matthews Dwight E DE Boyson Jonathan E JE Poynter Matthew E ME

Journal of immunology (Baltimore, Md. : 1950) 20160727 5

Nitrogen dioxide (NO2) is an environmental air pollutant and endogenously generated oxidant that contributes to the exacerbation of respiratory disease and can function as an adjuvant to allergically sensitize to an innocuous inhaled Ag. Because uric acid has been implicated as a mediator of adjuvant activity, we sought to determine whether uric acid was elevated and participated in a mouse model of NO2-promoted allergic sensitization. We found that uric acid was increased in the airways of mice ...[more]

PMID: 27465529

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Project description:An elevated level of serum uric acid-hyperuricemia, is strongly associated with the development of gout and chronic kidney disease (CKD) which is often accompanied by a significantly reduced glomerular filtration rate (GFR). In the present study, we investigated the extra-renal elimination of uric acid via the intestine in a healthy pig model and the effect of oral uricase therapy on plasma uric acid concentrations in pigs with induced hyperuricemia and CKD. The experiment was conducted on eleven, ten-week-old pigs (n = 11). The porcine model of CKD was developed by performing 9/10 nephrectomy surgery on eight pigs. A stable model of hyperuricemia was established in only five of the eight nephrectomized pigs by frequent injections of uric acid (UA) into the jugular vein. All pigs (three healthy pigs and five CKD pigs) were operated for implantation of jugular vein catheters and the three healthy pigs also had portal vein catheters inserted. Blood uric acid concentrations were measured spectrophotometrically, using the Uric Acid Assay Kit (BioAssay Systems, Hayward, USA). The piglets with CKD received orally administered uricase (treatment) and served as their own controls (without uricase supplementation). Oral uricase therapy significantly decreased plasma uric acid concentrations in pigs with CKD, whereas hyperuricemia was observed in the pigs whilst not being treated with uricase. Urinary uric acid excretion was similar during both the treatment and control periods during the first 8 h and 24 h after UA infusions in the CKD pigs. To demonstrate the elimination of UA via the intestine, the healthy pigs were infused with UA into the jugular vein. The blood collected from the jugular vein represents circulating UA concentrations and the blood collected from the portal vein represents the concentration of UA leaving the intestine. The final (after 2 h) concentration of UA was significantly lower in blood collected from the portal vein compared to that collected from the jugular vein (3.34 vs. 2.43 mg/dL, respectively, p = 0.024). The latter allows us to suggest that UA is eliminated from the blood via the gut tissue.

Project description:The aim of this study was to determine the kinetics of the reactions between the gaseous free-radical pollutant, nitrogen dioxide (NO2), and the water-soluble antioxidants present in respiratory tract lining fluid (RTLF). Samples of RTLF, recovered from 12 subjects (mean age 54.1+/-16.3 years; eight male, four female) as bronchoalveolar lavage (BAL) fluid were exposed ex vivo to NO2 [50-1000 parts per billion (ppb)] for 4 h. For comparison, similar exposures were carried out with single and composite solutions with relevant RTLF antioxidant concentrations. Ascorbic acid (AA), uric acid (UA), GSH depletion, and GSSG and malondialdehyde (MDA) formation were determined with time. In the three models, UA and AA were consumed in a time- and NO2-concentration-related fashion. In addition, their rate of depletion correlated positively with their initial concentration (UA, r=0.92, P<0.05; AA, r=0.94, P<0.05). Little difference was found between the rate of loss of AA (2.2+/-0. 2; 1.9+/-0.5; 1.4+/-0.3 nmol.l-1.h-1.ppb-1), and that of UA (2.4+/-0. 2; 2.1+/-0.6; 1.3+/-0.2 nmol.l-1.h-1.ppb-1) in the three RTLF models examined (single, composite, BAL fluid respectively). GSH loss from BAL fluid (0.2+/-0.1) was significantly less than that seen in either single (1.4+/-0.3) or composite (1.2+/-0.5 nmol.l-1.h-1. ppb-1) antioxidant solutions. In all cases, GSH consumption was significantly less than AA or UA. As model complexity increased, the rate of individual antioxidant loss decreased, such that in BAL fluid, AA, UA and GSH consumption rates were significantly less (P<0. 05) than in the pure or composite antioxidant mixtures. In BAL fluid, little GSSG production was observed at any NO2 concentration. MDA concentration, determined as a measure of lipid peroxidation, did not change following exposure to 50, 150 or 400 ppb NO2, but increased MDA was seen in BAL fluid from 8/12 subjects following exposure to 1000 ppb NO2 for 1 h or more. In conclusion, NO2, at environmentally relevant concentrations, depletes BAL fluid of the antioxidant defences, UA and AA, but not GSH.

Dataset Information

Uricase Inhibits Nitrogen Dioxide-Promoted Allergic Sensitization to Inhaled Ovalbumin Independent of Uric Acid Catabolism.

Publications

Uricase Inhibits Nitrogen Dioxide-Promoted Allergic Sensitization to Inhaled Ovalbumin Independent of Uric Acid Catabolism.

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