Interleukin (IL)-8 and growth related oncogene-alpha in severe endotoxemia and the effects of a tumor necrosis factor-alpha/IL-1beta inhibitor on these chemokines.
FR167653 inhibits the production of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta, powerful inducers of CXC chemokines IL-8 and growth related oncogene (GRO)-alpha. The production of IL-8 and GRO-alpha was investigated and the effects of FR167653 were examined in a rabbit model of endotoxin shock. Male New Zealand rabbits were given endotoxin at a dose sufficient to induce DIC. Three groups of rabbits received FR167653 at different doses. TNF-alpha, IL-1beta, IL-8, and GRO-alpha levels were measured, several pathologic features were evaluated, and the results were compared with those obtained in control rabbits, which received only endotoxin. Endotoxin increased serum levels of IL-8 and GRO-alpha, which were associated with hypotension, renal dysfunction, and mortality, peaking at 4 h. FR167653 improved mortality, an event that was associated with decreased levels of not only TNF-alpha and IL-1beta but also IL-8 and GRO-alpha. TNF-alpha peaked at 2 h, at a time point before IL-8 and GRO-alpha reached their peak, and the TNF-alpha level was tightly correlated with that of IL-8 and GRO-alpha. Altogether, these data suggest the possible involvement of IL-8 and GRO-alpha in endotoxin shock, and FR167653 may foster a beneficial outcome in part by modulating the chemokines level by inhibiting TNF-alpha and IL-1beta.
Rodríguez-Wilhelmi
Pablo
P
Hemostasis and Thrombosis Research Unit, School of Medicine, University Clinic, University of Navarra, 31008 Pamplona, Spain.
Montes
Ramón
R
Matsukawa
Akihiro
A
Hurtado
Verónica
V
Montes
Marta
M
Hermida
José
J
Rocha
Eduardo
E
D000818:Animals; D018925:Chemokines / Q000378:metabolism*; D019743:Chemokines, CXC / Q000378:metabolism; D002630:Chemotactic Factors / Q000378:metabolism*; D019446:Endotoxemia / Q000378:metabolism*; D006131:Growth Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D016209:Interleukin-8 / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D009363:Neoplasm Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D011817:Rabbits; D013223:Statistics as Topic; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C104334:FR 167653; D006131:Growth Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D016209:Interleukin-8; D008070:Lipopolysaccharides; D009363:Neoplasm Proteins; D011720:Pyrazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide