Effect of treatment with interleukin-1 receptor antagonist on the development of carrageenan-induced pleurisy in the rat.
Pretreatment of rats with the human interleukin-1 receptor antagonist (IL-1ra) by the subcutaneous route at -0.5 h, relative to the intrapleural injection of carrageenan (CG), suppressed the infiltration of cells into the pleural cavity of intact and adrenalectomized rats at 5 h (28 and 74% reduction in intact animals at 0.3 and 10 mg/kg, respectively). Exudate volume at 5 h was also suppressed at dosages of IL-1ra > or = 3 mg/kg. IL-1ra was still effective as an antiinflammatory agent in the 5-h pleurisy model when administered 1 or 2 h, but not 3 h, after CG. The addition of IL-1ra to a maximally effective antiinflammatory dosage of indomethacin (5 mg/kg) resulted in further reductions of cell number and exudate volume, suggesting that the antiinflammatory effects of IL-1ra in the 5-h model were not due solely to inhibition of IL-1-induced prostaglandin biosynthesis. The antiinflammatory effects of suboptimal dosages of IL-1ra and dexamethasone, administered in combination, were essentially additive. In 24-h pleurisy, IL-1ra reduced exudate volume and PMN number after a single dosage of 10 mg/kg, subcutaneously at -0.5 h and after dosages of 3 mg/kg at -0.5 and 5 h. Additional dosages of IL-1ra (3 mg/kg) at 10 and 15 h did not further inhibit PMN accumulation. Treatment with IL-1ra did not affect macrophage accumulation in 24-h CG-induced pleurisy. IL-1ra was not active as an antiinflammatory agent in the 24-h pleurisy model after three dosages of IL-1ra (3 mg/kg) at 5, 10 and 15 h.
Preclinical Research, Hoffmann-La Roche, Inc. Nutley, New Jersey 07110.
K P
KP
Meyers
C L
CL
Czachowski
J W
JW
Coffey
D000315:Adrenalectomy; D000818:Animals; D002351:Carrageenan; D003907:Dexamethasone / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D007213:Indomethacin / Q000627:therapeutic use; D008297:Male; D010998:Pleurisy / Q000139:chemically induced* / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins; D013997:Time Factors
D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D003907:Dexamethasone; D002351:Carrageenan; D007213:Indomethacin