Comparison of PDE 4 inhibitors, rolipram and SB 207499 (ariflo), in a rat model of pulmonary neutrophilia.
Using a rat model of lipopolysaccharide (LPS)-induced pulmonary inflammation, the antiinflammatory activity of SB 207499 was evaluated and compared to that of the prototypic type-4 phosphodiesterase (PDE4) inhibitor, rolipram. In dose-response experiments, we found that rats exposed to 10 microg or 100 microg of intratracheal (it) LPS developed a prominent pulmonary inflammation, due to a significant increase in the number of recoverable bronchoalveolar lavage neutrophils. The pulmonary neutrophilia, provoked by the challenge of 10 microg LPS/rat, was significant at 2 h, peaked by 16 h, declined thereafter but remained elevated for up to 48 h. Additionally, the exposure of rats to 10 microg LPS caused the local pulmonary production of TNF- alpha. In contrast to the cellular influx, TNF- alpha production peaked at 2 h and rapidly declined to negligible levels by 8 h. While low levels were detected, the levels of IL-1 beta in bronchoalveolar lavage did not significantly differ from saline challenged animals. Rats pretreated with rolipram or SB 207499, displayed dose-dependent inhibition of the LPS-induced pulmonary inflammation. Nevertheless, the pulmonary production of TNF- alpha and IL-1 beta was unaffected by either SB 207499 or rolipram. When provoked with the 10 microg dose of LPS, adrenalectomized rats produced a similar 24 h induction of pulmonary neutrophilia. Pretreatment of adrenalectomized rats with the PDE4 inhibitors showed similar inhibitory results to those obtained in normal rats. In summary, we have shown, using a rat model of LPS-induced pulmonary neutrophilic inflammation, that the inhibitory activities of rolipram or SB207499 are not linked to the production of TNF- alpha or the inhibition of IL-1 beta, and occur independently of endogenous catecholamine or corticosteroid release.
Schering Plough Research Institute, Kenilworth, New Jersey, USA.
J
J
Spond
R
R
Chapman
J
J
Fine
H
H
Jones
W
W
Kreutner
T T
TT
Kung
M
M
Minnicozzi
D000315:Adrenalectomy; D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000473:pathology / Q000662:veterinary; D007375:Interleukin-1 / Q000096:biosynthesis; D008171:Lung Diseases / Q000188:drug therapy*; D008173:Lung Diseases, Obstructive / Q000276:immunology / Q000503:physiopathology; D008297:Male; D009504:Neutrophils / Q000187:drug effects* / Q000473:pathology; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000276:immunology / Q000503:physiopathology; D020889:Rolipram / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D003509:Cyclohexanecarboxylic Acids; D007375:Interleukin-1; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; C433247:Cilomilast; D020889:Rolipram