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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 on histologic signs of colonic inflammation by roflumilast.Mice were exposed to 3.5% DSS in drinking water for 11 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). Non-DSS mice received 5 mg/kg/d roflumilast (n = 8) or 4% methocel (n = 5). At day 11 mice were euthanized, colon rings were stained and the histologic score (degree of inflammation and tissue damage: 0 = no changes to 6 = extensive cell infiltration and tissue damage) was determined in a blinded fashion as described in the Materials and Methods. A. Representative cross sections of the transversing colon. Magnification of the images is 200-fold. B. Scores are depicted as means ± SEM.
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pone-0056867-g002: Effect on histologic signs of colonic inflammation by roflumilast.Mice were exposed to 3.5% DSS in drinking water for 11 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). Non-DSS mice received 5 mg/kg/d roflumilast (n = 8) or 4% methocel (n = 5). At day 11 mice were euthanized, colon rings were stained and the histologic score (degree of inflammation and tissue damage: 0 = no changes to 6 = extensive cell infiltration and tissue damage) was determined in a blinded fashion as described in the Materials and Methods. A. Representative cross sections of the transversing colon. Magnification of the images is 200-fold. B. Scores are depicted as means ± SEM.

Mentions: Histology of rings of the transverse part of the colon in DSS-exposed mice revealed multiple erosive lesions and inflammatory cell infiltration composed of mainly macrophages with fewer lymphocytes and occasional eosinophils and neutrophils (Figure 2A). After 11 days of continuous DSS administration, treatment with roflumilast showed a tendency to decrease the histologic score as compared to the DSS control group (Figure 2B). In the control groups not exposed to DSS, no histologic signs of inflammation were detected.


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 on histologic signs of colonic inflammation by roflumilast.Mice were exposed to 3.5% DSS in drinking water for 11 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). Non-DSS mice received 5 mg/kg/d roflumilast (n = 8) or 4% methocel (n = 5). At day 11 mice were euthanized, colon rings were stained and the histologic score (degree of inflammation and tissue damage: 0 = no changes to 6 = extensive cell infiltration and tissue damage) was determined in a blinded fashion as described in the Materials and Methods. A. Representative cross sections of the transversing colon. Magnification of the images is 200-fold. B. Scores are depicted as means ± SEM.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0056867-g002: Effect on histologic signs of colonic inflammation by roflumilast.Mice were exposed to 3.5% DSS in drinking water for 11 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). Non-DSS mice received 5 mg/kg/d roflumilast (n = 8) or 4% methocel (n = 5). At day 11 mice were euthanized, colon rings were stained and the histologic score (degree of inflammation and tissue damage: 0 = no changes to 6 = extensive cell infiltration and tissue damage) was determined in a blinded fashion as described in the Materials and Methods. A. Representative cross sections of the transversing colon. Magnification of the images is 200-fold. B. Scores are depicted as means ± SEM.
Mentions: Histology of rings of the transverse part of the colon in DSS-exposed mice revealed multiple erosive lesions and inflammatory cell infiltration composed of mainly macrophages with fewer lymphocytes and occasional eosinophils and neutrophils (Figure 2A). After 11 days of continuous DSS administration, treatment with roflumilast showed a tendency to decrease the histologic score as compared to the DSS control group (Figure 2B). In the control groups not exposed to DSS, no histologic signs of inflammation were detected.

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