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

doi:10.1006/pupt.2001.0291

Pulmonary Pharmacology & Therapeutics

Volume 14, Issue 2, March 2001, Pages 157-164

https://doi.org/10.1006/pupt.2001.0291 Get rights and content

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

Abstract

Chest

Am J Med Sci

TIBS

Prog Med Chem

Int J Immunopharm

Chest

Int J Immunopharm

Eur J Pharm

Cellular mechanisms in the pathogenesis of COPD

Eur Respir Rev

ARDS-History, Definitions and Physiology

Resp Care Clinics

Inflammatory cells in the bronchial glands of smokers with chronic bronchitis

Am J Respir Crit Care Med

Phosphodiesterase IV inhibitors as therapy for eosinophil-induced lung injury in asthma

Environ Health Perspect

Inhibition of phosphodiesterase IV and intracellular calcium levels in human polymorphonuclear leukocytes

Method Find Exp Clin Pharm

Phosphodiesterase 4B2 is the predominant phosphodiesterase species and undergoes differential regulation of gene expression in human monocytes and neutrophils

Mol Pharm

1,4-cyclohexane carobylates: potent and selective inhibitors of phosphodiesterase 4 for the treatment of asthma

J Med Chem

Evidence that cyclic AMP phosphodiesterase inhibitors suppress TNF alpha generation from human monocytes by interacting with a low affinity phosphodiesterase 4 conformer

Br J Pharm

Therapeutic intervention in a rat model of ARDS: IV. Phosphodiesterase IV inhibition

Circ Shock

The role of anti-microbial therapy in acute exacerbations of chronic bronchitis

Am J Med Sci

The association of circulating endotoxin with the development of the adult respiratory distress syndrome

Am Rev Respir Dis

Regular Article
Comparison of PDE 4 Inhibitors, Rolipram and SB 207499 (Ariflo^TM, in a Rat Model of Pulmonary Neutrophilia☆