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Effects of uridine, isomatitol and 4-thiouridine on in vitro cell adhesion and in vivo effects of 4-thiouridine in a lung inflammation model.
Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
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.

Place, publisher, year, edition, pages
2004. Vol. 4, no 9, 1241-1248 p.
Keyword [en]
Inflammation; Adhesion; TNFa; Uridine; Isomaltitol; 4-thiouridine
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-19093DOI: 10.1016/j.intimp.2004.04.016PubMedID: 15251120OAI: diva2:223273
Available from: 2009-06-11 Created: 2009-06-11 Last updated: 2010-06-28Bibliographically approved
In thesis
1. Uridine, 4-thiouridine and isomaltitol in an asthma-like model: Anti-inflammatory and modulating effects
Open this publication in new window or tab >>Uridine, 4-thiouridine and isomaltitol in an asthma-like model: Anti-inflammatory and modulating effects
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.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1137
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
urn:nbn:se:liu:diva-19122 (URN)978-91-7393-596-8 (ISBN)
Public defence
2009-08-28, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings Universitet, Linköping, 13:00 (Swedish)
Available from: 2009-06-16 Created: 2009-06-12 Last updated: 2012-05-09Bibliographically approved

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