4-thiouridine induces dose-dependent reduction of oedema, leucocyte influx and tumour necrosis factor in lung inflammation.
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) (LTC(4)), LTD(4 )and LTE(4) 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.
Evaldsson
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C
Division of Clinical Chemistry, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. chamilly.evaldsson@liu.se
Rydén
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I
Rosén
A
A
Uppugunduri
S
S
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D003911:Dextrans; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007958:Leukocyte Count; D007962:Leukocytes / Q000187:drug effects* / Q000276:immunology; D015289:Leukotrienes / Q000378:metabolism; D008297:Male; D008863:Microspheres; D011014:Pneumonia / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D011654:Pulmonary Edema / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013891:Thiouridine / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000893:Anti-Inflammatory Agents; D003911:Dextrans; D015289:Leukotrienes; D014409:Tumor Necrosis Factor-alpha; D013891:Thiouridine