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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Phosphodiesterase Type 4 Inhibitors Cause Proinflammatory Effects in Vivo

Departments of Pharmacology (K.M., A.Y., G.R.T.), Molecular and Cellular Biology (U.K., C.L.), and Medicinal Chemistry (Y.J., C.H.), Theravance Inc., South San Francisco, California

Phosphodiesterase type 4 (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 lipopolysaccharide (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 3-cyclo-propylmethoxy-4-difluoromethoxy-N-[3,5-di-chloropyrid-4-yl]-benzamide (roflumilast) and 3-(cyclopentyloxy)-N-(3,5-dichloro-4-pyridyl)-4-methoxybenzamide (piclamilast) were assessed in vivo, using BALB/c mice, and in vitro, in unstimulated human endothelial and epithelial cell lines. In BALB/c mice, LPS challenge caused an increase in neutrophils in bronchoalveolar lavage (BAL) and lung tissue and BAL tumor necrosis factor- levels, which were inhibited by treatment with either roflumilast or piclamilast (30-100 mg/kg subcutaneously). 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 interleukin (IL)-8 release from human umbilical vein endothelial cells 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 proinflammatory activities in the lung that may limit their therapeutic potential. The proinflammatory cytokines KC and IL-8 therefore may provide surrogate biomarkers, both in preclinical animal models and in the clinic, to assess potential proinflammatory effects of this class of compounds.

Address correspondence to: Dr. Kerryn McCluskie, Catalyst Biosciences, 290 Utah Ave., South San Francisco, CA 94080. E-mail: kmccluskie{at}catbio.com