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Comparison of PDE 4 Inhibitors, Rolipram and SB 207499 (ArifloTM, in a Rat Model of Pulmonary Neutrophilia

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Abstract

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 μg or 100 μg 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 μg 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 μg LPS caused the local pulmonary production of TNF- α. In contrast to the cellular influx, TNF- α production peaked at 2 h and rapidly declined to negligible levels by 8 h. While low levels were detected, the levels of IL-1 β 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- α and IL-1β was unaffected by either SB 207499 or rolipram. When provoked with the 10 μg 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-α or the inhibition of IL-1 β, and occur independently of endogenous catecholamine or corticosteroid release.

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    Author for correspondence: Michael Minnicozzi, Ph.DAssociate Principal Scientist, Schering Plough Research Institute, 2015 Galloping Hill Rd, Kenilworth New Jersey 07033, USA. Fax: +1 908-740-7175. E-mail: [email protected]

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