Inhibition of Sephadex-induced lung injury in the rat by Ro 45-2081, a tumor necrosis factor receptor fusion protein.
Tumor necrosis factor (TNF) is an inflammatory cytokine produced by many cell types which may contribute to the pathophysiology of a variety of lung diseases. In this study we have used Ro 45-2081 (a soluble receptor composed of the human p55 TNF receptor and human heavy-chain immunoglobulin G) to explore the role of TNF in the acute inflammatory response in the rat lung to intravenous injection of Sephadex beads. The effects of Ro 45-2081 have also been compared with those of dexamethasone. At 24 and 72 h after Sephadex, there was a significant increase in the total number of leukocytes in bronchoalveolar lavage fluid (BALF). At 24 h, the number of neutrophils comprised around 50% of the total leukocyte number, decreasing to around 10% of total by 72 h. The eosinophil count was maintained at around 10% of the total leukocyte number. Pretreatment with either Ro 45-2081 [1 and 3 mg kg-1, intraperitoneally (i.p.)] or dexamethasone (0.1 and 0.3 mg kg-1, i.p.) inhibited the neutrophilia at 24 h after Sephadex, although Ro 45-2081 had no significant effect on total cell number. At 72 h after Sephadex, Ro 45-2081 (1 and 3 mg kg-1, i.p., daily) significantly reduced the neutrophil influx into BALF but had no inhibitory effect on eosinophil number. In contrast, dexamethasone (0.1 and 0.3 mg kg-1, i.p., daily) virtually abolished the infiltration of neutrophils and eosinophils into BALF. The lack of effect of Ro 45-2081 on eosinophil infiltration into the rat lung and the inhibition caused by dexamethasone suggest that factors other than TNF are involved in this part of the inflammatory response induced by Sephadex. However, the inhibitory effects of Ro 45-2081 show that TNF may play an important role in the recruitment of neutrophils into the lungs of Sephadex-treated rats.
Gater
P R
PR
Department of Inflammation/Autoimmune Disease, Roche Pharmaceuticals, Hoffmann-La Roche, Inc., Nutley, New Jersey 07110-1199.
Wasserman
M A
MA
Paciorek
P M
PM
Renzetti
L M
LM
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015703:Antigens, CD; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D003907:Dexamethasone / Q000494:pharmacology; D003911:Dextrans / Q000037:antagonists & inhibitors / Q000633:toxicity*; D006801:Humans; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains / Q000378:metabolism*; D007142:Immunoglobulin gamma-Chains; D007249:Inflammation; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D008297:Male; D009504:Neutrophils / Q000166:cytology / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015703:Antigens, CD; D003911:Dextrans; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007142:Immunoglobulin gamma-Chains; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C099374:Ro 45-2081; D003907:Dexamethasone; C025614:sephadex