Abstract
ObjectiveThe specific inhibition of phosphodiesterase (PDE)4 and dual inhibition of PDE3 and PDE4 has been shown to decrease inflammation by suppression of pro-inflammatory cytokine synthesis. We examined the effect of roflumilast, a selective PDE4 inhibitor marketed for severe COPD, and the investigational compound pumafentrine, a dual PDE3/PDE4 inhibitor, in the preventive dextran sodium sulfate (DSS)-induced colitis model.MethodsThe clinical score, colon length, histologic score and colon cytokine production from mice with DSS-induced colitis (3.5% DSS in drinking water for 11 days) receiving either roflumilast (1 or 5 mg/kg body weight/d p.o.) or pumafentrine (1.5 or 5 mg/kg/d p.o.) were determined and compared to vehicle treated control mice. In the pumafentrine-treated animals, splenocytes were analyzed for interferon-γ (IFNγ) production and CD69 expression.ResultsRoflumilast treatment resulted in dose-dependent improvements of clinical score (weight loss, stool consistency and bleeding), colon length, and local tumor necrosis factor-α (TNFα) production in the colonic tissue. These findings, however, were not associated with an improvement of the histologic score. Administration of pumafentrine at 5 mg/kg/d alleviated the clinical score, the colon length shortening, and local TNFα production. In vitro stimulated splenocytes after in vivo treatment with pumafentrine showed a significantly lower state of activation and production of IFNγ compared to no treatment in vivo.ConclusionsThese series of experiments document the ameliorating effect of roflumilast and pumafentrine on the clinical score and TNF expression of experimental colitis in mice.
Highlights
Inflammatory bowel disease (IBD) is characterized by a disturbed balance of pro- and anti-inflammatory cytokines
Tumor necrosis factor-a (TNFa), which is elevated in the intestinal mucosa of both of its entities – Crohn’s disease (CD) and ulcerative colitis (UC) [1] plays a crucial role in the pathogenesis of IBD [2], a fact further underlined by the efficacious treatment of patients with CD and UC with anti-TNFa antibodies [3,4,5]
In the present study we investigated the effect of the PDE4 inhibitor roflumilast and the PDE3/4 inhibitor pumafentrine [22] in the preventive model of murine dextran sulphate sodium (DSS)induced colitis [23]
Summary
Inflammatory bowel disease (IBD) is characterized by a disturbed balance of pro- and anti-inflammatory cytokines. Among the agents known to inhibit pro-inflammatory cytokine production rather than to block its biological function are cyclic adenosine-39,59-monophosphate (cAMP)-elevating PDE inhibitors. A major PDE isoenzyme family in mononuclear inflammatory cells, the main source of TNFa production, is PDE4 [7]. The specific inhibition of PDE4 with rolipram is 500-fold more potent in suppressing TNFa synthesis in human mononuclear cells compared to pentoxifylline [8]. The clinical use of rolipram and other investigational PDE4 inhibitors was limited by its adverse effects profile [7,12]. Another major PDE isoenzyme found in several human immune and inflammatory cells (T-cells, macrophages, dendritic cells) is PDE3 [13]. Dual selective inhibition of PDE3 and PDE4 frequently leads to an over additive modulation of inflammatory cell functions compared to inhibition of either isoform alone [14,15]
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