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The selective phosphodiesterase 4 inhibitor roflumilast and phosphodiesterase 3/4 inhibitor pumafentrine reduce clinical score and TNF expression in experimental colitis in mice.

Rieder F, Siegmund B, Bundschuh DS, Lehr HA, Endres S, Eigler A - PLoS ONE (2013)

Bottom Line: Roflumilast 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Pharmacology and Section of Gastroenterology, University of Munich, Munich, Germany.

ABSTRACT

Objective: The 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.

Methods: The 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.

Results: Roflumilast 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.

Conclusions: These series of experiments document the ameliorating effect of roflumilast and pumafentrine on the clinical score and TNF expression of experimental colitis in mice.

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Related in: MedlinePlus

Reduction of colonic mucosa TNFα content by roflumilast.Mice were exposed to 3.5% DSS in drinking water for eleven days and were treated with roflumilast (either 1 or 5 mg/kg/d orally once daily for 11 days, n = 8) or 4% methocel (n = 5). At day 11 the colon was removed, weighed, vortexed in PBS and centrifuged. TNFα was quantified in the eluate by ELISA. Values represent mean ± SEM; *p<0.05.
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pone-0056867-g003: Reduction of colonic mucosa TNFα content by roflumilast.Mice were exposed to 3.5% DSS in drinking water for eleven days and were treated with roflumilast (either 1 or 5 mg/kg/d orally once daily for 11 days, n = 8) or 4% methocel (n = 5). At day 11 the colon was removed, weighed, vortexed in PBS and centrifuged. TNFα was quantified in the eluate by ELISA. Values represent mean ± SEM; *p<0.05.

Mentions: TNFα concentration in the colonic tissue was reduced in roflumilast (5 mg/kg/d)-treated DSS-mice on day 11 compared to the 4% methocel-treated DSS group (Figure 3; n = 5). Colons of control mice not being exposed to DSS but receiving roflumilast showed mean TNFα concentrations comparable to the DSS/roflumilast group (Figure 3). Preliminary experiments showed that the colonic TNFα concentration in control animals receiving regular water was not different if PDE4 was inhibited or not (data not shown).


The selective phosphodiesterase 4 inhibitor roflumilast and phosphodiesterase 3/4 inhibitor pumafentrine reduce clinical score and TNF expression in experimental colitis in mice.

Rieder F, Siegmund B, Bundschuh DS, Lehr HA, Endres S, Eigler A - PLoS ONE (2013)

Reduction of colonic mucosa TNFα content by roflumilast.Mice were exposed to 3.5% DSS in drinking water for eleven days and were treated with roflumilast (either 1 or 5 mg/kg/d orally once daily for 11 days, n = 8) or 4% methocel (n = 5). At day 11 the colon was removed, weighed, vortexed in PBS and centrifuged. TNFα was quantified in the eluate by ELISA. Values represent mean ± SEM; *p<0.05.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585290&req=5

pone-0056867-g003: Reduction of colonic mucosa TNFα content by roflumilast.Mice were exposed to 3.5% DSS in drinking water for eleven days and were treated with roflumilast (either 1 or 5 mg/kg/d orally once daily for 11 days, n = 8) or 4% methocel (n = 5). At day 11 the colon was removed, weighed, vortexed in PBS and centrifuged. TNFα was quantified in the eluate by ELISA. Values represent mean ± SEM; *p<0.05.
Mentions: TNFα concentration in the colonic tissue was reduced in roflumilast (5 mg/kg/d)-treated DSS-mice on day 11 compared to the 4% methocel-treated DSS group (Figure 3; n = 5). Colons of control mice not being exposed to DSS but receiving roflumilast showed mean TNFα concentrations comparable to the DSS/roflumilast group (Figure 3). Preliminary experiments showed that the colonic TNFα concentration in control animals receiving regular water was not different if PDE4 was inhibited or not (data not shown).

Bottom Line: Roflumilast 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Pharmacology and Section of Gastroenterology, University of Munich, Munich, Germany.

ABSTRACT

Objective: The 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.

Methods: The 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.

Results: Roflumilast 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.

Conclusions: These series of experiments document the ameliorating effect of roflumilast and pumafentrine on the clinical score and TNF expression of experimental colitis in mice.

Show MeSH
Related in: MedlinePlus