Received for publication March 24, 2006.
Revised July 17, 2006.
Accepted for publication July 20, 2006.

Phosphodiesterase type 4 inhibitors cause pro-inflammatory effects in vivo

Abstract

PDE₄ inhibitors are currently being evaluated as potential therapies for inflammatory airway diseases. However, this class of compounds has been shown to cause an arteritis/vasculitis of unknown etiology in rats and cynomolgus monkeys. Studies in rodents have demonstrated the anti-inflammatory effects of PDE₄ inhibitors on LPS-induced airway inflammation. The aim of this work was to assess the direct effects of PDE₄ inhibitors on inflammatory cells and cytokine levels in the lung in relation to therapeutic effects. The effects of the PDE₄ inhibitors, roflumilast(3-cyclo-propylmethoxy-4-difluoromethoxy-N-[3,5-di-chloropyrid-4-yl]-benzamide) and piclamilast (3-(cyclopentyloxy)-N-(3,5-dichloro-4-pyridyl)-4-methoxybenzamide)), were assessed in vivo, using Balb/c mice, and in vitro, in un-stimulated human endothelial and epithelial cell lines. In Balb/c mice, LPS challenge caused an increase in neutrophils in BAL and lung tissue and BAL TNF- levels, which were inhibited by treatment with either roflumilast or piclamilast (30-100 mg/kg, s.c.). However, roflumilast and piclamilast alone (100 mg/kg) caused a significant increase in plasma and lung tissue keratinocyte-derived chemokine (KC) levels, and lung tissue neutrophils. In vitro, both piclamilast and roflumilast caused an increase in IL-8 release from HUVEC but not BEAS-2B cells, suggesting that one source of the increased KC may be endothelial cells. At doses that antagonized an LPS-induced inflammatory response, the PDE₄ inhibitors possessed pro-inflammatory activities in the lung that may limit their therapeutic potential. The pro-inflammatory cytokines KC and IL-8 therefore may provide surrogate biomarkers, both in pre-clinical animal models and in the clinic, to assess potential pro-inflammatory effects of this class of compounds.

Key words: LPS, chemokine, cytokine, inflammation, neutrophil, rodent