Effect of TNF alpha production inhibitors BRL 61063 and pentoxifylline on the response of rats to poly I:C.
BRL 61063 is a novel xanthine phosphodiesterase (PDE) type IV inhibitor with selective inhibitory activity for tumor necrosis factor (TNF) alpha production. This compound inhibits TNF alpha production by activated human blood monocytes in vitro and in animal models of endotoxemia and influenza infection. Inhibition of TNF alpha may be beneficial in many diseases; however, little is known about potential adverse effects of such inhibition on host defense. In an ex vivo study, we examined the effect of BRL 61,063 on the microbicidal and tumoricidal activity of pulmonary lavage cells during a local inflammatory response in rats challenged with Poly I:C. Pentoxifylline, a PDE inhibitor which also blocks TNF alpha production, was used for comparison. Treatment with BRL 61063 or pentoxifylline did not block the inflammatory response to Poly I:C or the activation of bronchoalveolar lavage (BAL) cells but reduced the level of tumoricidal activity attained. At the dosages used, pentoxifylline was more inhibitory than BRL 61063. Drug treatment did not prevent further stimulation of tumoricidal activity by LPS in vitro. LPS-stimulated cells from BRL 61063-treated rats reached a level of activation similar to the control group while the LPS-stimulated activity of BAL cells from pentoxifylline treated rats remained lower than control. Although pentoxifylline was more inhibitory for tumoricidal activity than BRL 61063, the latter was a more potent inhibitor of TNF alpha release as measured in vivo in LPS-challenged rats. This finding indicates that TNF alpha is not the main mediator involved in the activation of pulmonary macrophage tumoricidal function. Treatment with either BRL 61063 or pentoxifylline had little or no effect on the Poly I:C-induced candidacidal activity of BAL cells indicating that these compounds are unlikely to compromise non-specific host defense against infection.
Kaplan
J M
JM
Department of Toxicology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.
Herzyk
D J
DJ
Ruggieri
E V
EV
Bartus
J O
JO
Esser
K M
KM
Bugelski
P J
PJ
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002176:Candida albicans / Q000166:cytology / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D008168:Lung / Q000166:cytology / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects; D010431:Pentoxifylline / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011070:Poly I-C / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D014970:Xanthines / Q000494:pharmacology*
D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D014970:Xanthines; C086163:8-amino-1,3-bis(cyclopropylmethyl)xanthine; D011070:Poly I-C; D010431:Pentoxifylline