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Uridine, 4-thiouridine and isomaltitol in an asthma-like model: Anti-inflammatory and modulating effects
Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In chronic inflammatory diseases like asthma or rheumatoid arthritis, erroneous and exaggerated accumulation of leukocytes in a tissue inadvertently causes the body harm. Several efficient anti-inflammatory drugs exist, for example corticosteroids and cyclo-oxygenase inhibitors. However, these drugs have potent and diverse effects and often act by inhibiting events subsequent to initiation of the inflammatory response, leading to more or less severe side-effects, especially when used in high doses for long periods of time. For this reason, strategies aimed at early inhibition of recruitment and activation of leukocytes have been suggested as safer and more specific approaches to reduce inflammation.

Leukocyte adhesion to activated endothelium is a prerequisite to the following activation and extravasation, and takes place in the initial phase of inflammation. By using a model that allows leukocytes to adhere to tumour necrosis factor (TNF)-activated endothelial cells, thus mimicking aspects of an inflammatory reaction, we found that uridine, 4-thiouridine and isomaltitol could all reduce adhesion. This suggested that they may have anti-inflammatory potential.

We therefore tried the three substances in a Sephadex-induced lung inflammation model and found that uridine and 4-thiouridine have several anti-inflammatory effects, such as being able to reduce leukocyte accumulation, decrease TNF protein levels and partly inhibit the oedema induced by Sephadex. Isomaltitol turned out to have immunomodulating, rather than anti-inflammatory, effects, which could be of interest in diseases where inadequate inflammatory responses are a problem.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2009. , 140 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1137
Keyword [en]
Uridine, asthma, 4-thiouridine, isomaltitol, isomalt, inflammation, eosinophilia, Sephadex, animal model, rat
National Category
Pharmacology and Toxicology Medical and Health Sciences Respiratory Medicine and Allergy
Identifiers
URN: urn:nbn:se:liu:diva-19122ISBN: 978-91-7393-596-8 (print)OAI: oai:DiVA.org:liu-19122DiVA: diva2:223368
Public defence
2009-08-28, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings Universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2009-06-16 Created: 2009-06-12 Last updated: 2012-05-09Bibliographically approved
List of papers
1. Effects of uridine, isomatitol and 4-thiouridine on in vitro cell adhesion and in vivo effects of 4-thiouridine in a lung inflammation model.
Open this publication in new window or tab >>Effects of uridine, isomatitol and 4-thiouridine on in vitro cell adhesion and in vivo effects of 4-thiouridine in a lung inflammation model.
2004 (English)In: International Immunopharmacology, ISSN 1567-5769, E-ISSN 1878-1705, Vol. 4, no 9, 1241-1248 p.Article in journal (Refereed) Published
Abstract [en]

Since leukocyte adhesion to endothelial cells is crucial for extravasation of leukocytes to sites of inflammation, inhibition of cell-cell adhesion has been suggested as a means to achieve selective modulation of the immune system. We have, using a static in vitro adhesion assay involving adhesion of granulocytes to tumor necrosis factor alpha (TNFalpha)-stimulated human umbilical vein endothelial cells (HUVEC), found three substances--uridine, isomaltitol and 4-thiouridine-that, independently and significantly, reduced leukocyte adhesion by approximately 30-65%. 4-Thiouridine was also tested in an in vivo model of Sephadex (SDX)-induced lung inflammation with Sprague-Dawley rats. Intratracheal instillation of Sephadex (5 mg/kg) alone resulted in a dramatic increase in lung edema and total leukocyte count after 24 h. A differential count of bronchoalveolar lavage (BAL) cells indicated an increased influx of macrophages, eosinophils and neutrophils. Co-administration of 4-thiouridine significantly reduced lung edema by 38%. There was also a significant reduction of the total leukocyte count by 58%. The differential leukocyte count indicated that eosinophil influx alone was reduced by 70%. After Sephadex challenge, we found elevated levels of TNFalpha--an important inflammatory mediator--in the bronchoalveolar lavage fluid (BALF). TNFalpha levels were significantly reduced by more than 80% by co-administration of 4-thoiuridine. These results suggest that uridine, isomaltitol and, especially, 4-thiouridine affect adhesion between leukocytes and activated endothelium, and warrant further in vitro and in vivo studies.

Keyword
Inflammation; Adhesion; TNFa; Uridine; Isomaltitol; 4-thiouridine
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-19093 (URN)10.1016/j.intimp.2004.04.016 (DOI)15251120 (PubMedID)
Available from: 2009-06-11 Created: 2009-06-11 Last updated: 2010-06-28Bibliographically approved
2. 4-Thiouridine induces dose-dependent reduction of oedema, leucocyte influx and tumour necrosis factor in lung inflammation
Open this publication in new window or tab >>4-Thiouridine induces dose-dependent reduction of oedema, leucocyte influx and tumour necrosis factor in lung inflammation
2009 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 155, no 2, 330-338 p.Article in journal (Refereed) Published
Abstract [en]

Recent reports demonstrate a role for nucleotides as inflammatory modulators. Uridine, for example, reduces oedema formation and leucocyte infiltration in a Sephadex-induced lung inflammation model. Tumour necrosis factor (TNF) concentration was also reduced. Previous in vivo observations indicated that 4-thiouridine might have similar effects on leucocyte infiltration and TNF release. The aim of this study was thus to investigate the effects of 4-thiouridine in greater detail. We used a Sephadex-induced acute lung inflammation model in Sprague-Dawley rats. The dextran beads were instilled intratracheally into the lungs, which were excised and examined after 24 h. Sephadex alone led to massive oedema formation and infiltration of macrophages, neutrophils and eosinophils. Microgranulomas with giant cell formations were clearly visible around the partially degraded beads. A significant increase in bronchoalveolar lavage fluid (BALF) content of TNF and leukotrienes was also seen. 4-Thiouridine co-administration affected all variables investigated in this model, i.e. oedema, microscopic and macroscopic appearance of lung tissue, total leucocyte and differential leucocyte counts in BALF, TNF and leukotrienes C-4 (LTC4), LTD4 and LTE4 in BALF, indicating a reproducible anti-inflammatory effect. In conclusion, we have demonstrated that 4-thiouridine has anti-inflammatory effects similar to those of uridine. To our knowledge, this is the first demonstration of pharmacological 4-thiouridine effects in vivo. The results suggest nucleoside/nucleotide involvement in inflammatory processes, warranting further studies on nucleoside analogues as attractive new alternatives in the treatment of inflammatory diseases.

Keyword
4-thiouridine, inflammation, leukotriene, TNF, uridine
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-16418 (URN)10.1111/j.1365-2249.2008.03795.x (DOI)
Note
The definitive version is available at www.blackwell-synergy.com: Chamilly Evaldsson, Ingvar Rydén, Anders Rosén and Srinivas Uppugunduri, 4-Thiouridine induces dose-dependent reduction of oedema, leucocyte influx and tumour necrosis factor in lung inflammation, 2009, CLINICAL AND EXPERIMENTAL IMMUNOLOGY, (155), 2, 330-338. http://dx.doi.org/10.1111/j.1365-2249.2008.03795.x Copyright: Blackwell Publishing Ltd http://www.blackwellpublishing.com/ Available from: 2009-01-28 Created: 2009-01-23 Last updated: 2017-09-22Bibliographically approved
3. Anti-inflammatory effects of exogenous uridine in an animal model of lung inflammation.
Open this publication in new window or tab >>Anti-inflammatory effects of exogenous uridine in an animal model of lung inflammation.
2007 (English)In: International Immunopharmacology, ISSN 1567-5769, E-ISSN 1878-1705, Vol. 7, no 8, 1025-1032 p.Article in journal (Refereed) Published
Abstract [en]

Nucleosides like adenosine, uridine and their nucleotide derivatives (e.g. ATP and UTP) play important roles in many cellular functions, sometimes by acting as signalling molecules through binding to specific P2 nucleotide receptors. P2 receptors are subdivided into P2X and P2Y subfamilies, the latter of which are G-protein coupled receptors. P2Y receptors and nucleoside transporters have been detected in human and rat lungs, where they mediate effects of interest in airway diseases. The aim of this study was to investigate whether uridine has any anti-inflammatory properties in an asthma-like animal model of lung inflammation.

The Sephadex-induced lung inflammation model in Sprague-Dawley rats was chosen mainly due to its localised inflammatory response and uridine's limited oral bioavailability. The dextran beads, with or without the addition of uridine, were instilled intratracheally into the lungs, which were excised and examined after 24 h.

Sephadex alone led to massive oedema and infiltration of macrophages, neutrophils and eosinophils. Microgranulomas with giant cell formations were clearly visible around the partially degraded beads. Uridine reduced both the oedema and the infiltration of leukocytes significantly, measured as lung wet weight and leukocyte counts in bronchoalveolar lavage fluid, respectively. Uridine appeared to affect the tumour necrosis factor (TNF) levels, although this could not be statistically confirmed due to large variations within the Sephadex control group.

We conclude that uridine has anti-inflammatory effects, and that the exact mechanism(s) of action requires further study.

Keyword
Asthma, Inflammation, Leukocytes, Sephadex, Tumour necrosis factor, Uridine
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-19095 (URN)10.1016/j.intimp.2007.03.008 (DOI)17570319 (PubMedID)
Available from: 2009-06-11 Created: 2009-06-11 Last updated: 2010-06-28Bibliographically approved
4. Isomaltitol exacerbates neutrophilia but reduces eosinophilia: New insights into the Sephadex model of lung inflammation
Open this publication in new window or tab >>Isomaltitol exacerbates neutrophilia but reduces eosinophilia: New insights into the Sephadex model of lung inflammation
2011 (English)In: International Archives of Allergy and Immunology, ISSN 1018-2438, E-ISSN 1423-0097, Vol. 154, no 4, 286-294 p.Article in journal (Refereed) Published
Abstract [en]

We have previously examined isomaltitol in an in vitro static adhesion assay between isolated granulocytes and cultured human umbilical cord vein cells and were interested in investigating whether the potentially anti-inflammatory effects observed there could be reproduced in vivo. The Sephadex-induced lung inflammation model was considered a suitable model due to the significant changes in global inflammatory endpoints, like oedema and leukocyte migration, usually seen upon provocation with Sephadex.

Male Sprague-Dawley rats were instilled intratracheally with Sephadex (5 mg/ml), vehicle (0.9% NaCl), isomaltitol (50 mg/ml) or a combination of isomaltitol and Sephadex. After 24 h, the lungs were weighed to measure oedema and preserved for histology. Bronchoalveolar lavage fluid was used for analysis of tumour necrosis factor, cysteinyl leukotrienes, and differential and total leukocyte counts. In addition, blood differential counts and thymus weights were analysed.

Contrary to what we expected from in vitro experiments, differential counts showed that isomaltitol increased the neutrophil component while decreasing the eosinophilia. Isomaltitol thus asserted a modulatory role on the usually eosinophil-dominated Sephadex-induced cell profile. Isomaltitol alone also increased several inflammatory parameters, including oedema and cysteinyl leukotrienes, and generally aggravated total inflammation in combination with Sephadex. Although the mechanisms were not investigated in this study, the effects could relate to a combination of isomaltitol's osmotic and structure-specific properties.

Our results indicate that isomaltitol can modulate the inflammatory response induced by Sephadex instillation in addition to have pro-inflammatory effects on it its own, and may therefore provide new insights into the mechanisms of this widely used animal model. Sugar alcohols similar to isomaltitol have already been used to aid mucus clearance in cystic fibrosis patients, and it is possible that isomaltitol could also be used for this purpose.

Place, publisher, year, edition, pages
Karger, 2011
Keyword
Isomaltitol, Sephadex, inflammation, oedema, asthma
National Category
Respiratory Medicine and Allergy Pharmacology and Toxicology
Identifiers
urn:nbn:se:liu:diva-19097 (URN)10.1159/000321820 (DOI)000288529200003 ()
Note
Original Publication: Chamilly Evaldsson, Ingvar Rydén and Srinivas Uppugunduri, Isomaltitol exacerbates neutrophilia but reduces eosinophilia: New insights into the Sephadex model of lung inflammation, 2011, International Archives of Allergy and Immunology, (154), 4, 286-294. http://dx.doi.org/10.1159/000321820 Copyright: S. Karger AG http://www.karger.com/ Available from: 2009-06-11 Created: 2009-06-11 Last updated: 2011-04-19Bibliographically approved

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