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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

Effect of pumafentrine on colonic mucosa TNFα concentration.Mice were exposed to 3.5% DSS in drinking water for 11 days and were treated with pumafentrine (either 1.5 mg/kg/d (n = 8) or 5 mg/kg/d (n = 16) orally once daily for 11 days) or 4% methocel (n = 12). Non-DSS mice received 20 mg/kg/d pumafentrine or 4% methocel (n = 8). At day 11, the end of experiment, 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 versus DSS+methocel.
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pone-0056867-g005: Effect of pumafentrine on colonic mucosa TNFα concentration.Mice were exposed to 3.5% DSS in drinking water for 11 days and were treated with pumafentrine (either 1.5 mg/kg/d (n = 8) or 5 mg/kg/d (n = 16) orally once daily for 11 days) or 4% methocel (n = 12). Non-DSS mice received 20 mg/kg/d pumafentrine or 4% methocel (n = 8). At day 11, the end of experiment, 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 versus DSS+methocel.

Mentions: For measurement of colonic tissue TNFα concentrations the colons of mice treated as described above were obtained at day 11. The TNFα concentration in the colonic tissue was reduced in pumafentrine-treated DSS-mice compared to the methocel group at day 11 (Figure 5). Colons displaying no signs of inflammation in the pumafentrine control groups showed low mean TNFα concentrations (Figure 5).


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)

Effect of pumafentrine on colonic mucosa TNFα concentration.Mice were exposed to 3.5% DSS in drinking water for 11 days and were treated with pumafentrine (either 1.5 mg/kg/d (n = 8) or 5 mg/kg/d (n = 16) orally once daily for 11 days) or 4% methocel (n = 12). Non-DSS mice received 20 mg/kg/d pumafentrine or 4% methocel (n = 8). At day 11, the end of experiment, 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 versus DSS+methocel.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0056867-g005: Effect of pumafentrine on colonic mucosa TNFα concentration.Mice were exposed to 3.5% DSS in drinking water for 11 days and were treated with pumafentrine (either 1.5 mg/kg/d (n = 8) or 5 mg/kg/d (n = 16) orally once daily for 11 days) or 4% methocel (n = 12). Non-DSS mice received 20 mg/kg/d pumafentrine or 4% methocel (n = 8). At day 11, the end of experiment, 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 versus DSS+methocel.
Mentions: For measurement of colonic tissue TNFα concentrations the colons of mice treated as described above were obtained at day 11. The TNFα concentration in the colonic tissue was reduced in pumafentrine-treated DSS-mice compared to the methocel group at day 11 (Figure 5). Colons displaying no signs of inflammation in the pumafentrine control groups showed low mean TNFα concentrations (Figure 5).

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