Effects of uridine, isomatitol and 4-thiouridine on in vitro cell adhesion and in vivo effects of 4-thiouridine in a lung inflammation model.
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.
Uppugunduri
Srinivas
S
Division of Clinical Chemistry, Department of Biomedicine and Surgery, Faculty of Health Sciences, 581 85 Linköping, Sweden; Hospital Pharmacy, The University Hospital, 581 85 Linköping, Sweden. srinivas.uppugunduri@apoteket.se
Gautam
Chamilly
C
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002021:Buffers; D002448:Cell Adhesion / Q000187:drug effects*; D002469:Cell Separation; D003470:Culture Media; D003911:Dextrans; D006801:Humans; D008168:Lung / Q000473:pathology*; D008297:Male; D008970:Molecular Weight; D009504:Neutrophils / Q000276:immunology; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D011134:Polysaccharides / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013891:Thiouridine / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014470:Umbilical Cord / Q000166:cytology; D014529:Uridine / Q000494:pharmacology*
D002021:Buffers; D003470:Culture Media; D003911:Dextrans; D011134:Polysaccharides; D014409:Tumor Necrosis Factor-alpha; D013891:Thiouridine; C025614:sephadex; D014529:Uridine