Selective Inhibition of Phosphodiesterase-4 Ameliorates Chronic Colitis and Prevents Intestinal Fibrosis

Abstract

The phosphodiesterase-4 (PDE4) inhibitors may be an important target in the treatment of several inflammatory conditions. The anti-inflammatory effect of PDE4 inhibitors bears similarities with that of steroids, without interfering with the hypophysary-adrenal-axis. We compared the effect of rolipram, a selective PDE4 inhibitor, with steroids on the clinical course of experimental colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS). Three groups of rats (n ϭ 20) received TNBS. One group received methylprednisolone from day 7, another group received rolipram from the same day, and control group received no further treatment. On days 14 and 21 after TNBS instillation, sets of 10 rats underwent colonic dialysis to measure eicosanoid release. Colonic lesions were blindly scored, and colons were homogenized for quantification of myeloperoxidase (MPO) activity and collagen content. Concentration of tumor necrosis factor ␣ (TNF-␣) and transforming growth factor ␤1 (TGF-␤1) in colonic tissue was also measured. Both treatments reduced significantly the eicosanoid release and MPO activity. On day 14, both rolipram and methylprednisolone significantly reduced TNF-␣ content, but TGF-␤1 was only inhibited by rolipram. On day 21, lesion scores and collagen content were significantly reduced only in rolipram-treated group. In conclusion, PDE4 inhibition by rolipram markedly ameliorates the course of chronic colitis and it is superior to methylprednisolone in preventing late collagen deposition.

Efficacy of a novel sphingosine kinase inhibitor in experimental Crohn’s disease

“…The TNBS-induced increase in MPO activity was reduced by approximately 60% in mice receiving daily doses of ABC294640. As anticipated from the literature (Videla et al 2006), prednisolone also suppressed neutrophil accumulation in the colon. Variability did not allow any changes to reach statistical significance.…”

Tetomilast suppressed production of proinflammatory cytokines from human monocytes and ameliorated chronic colitis in IL-10-deficient mice

“…Videla et al 45 reported that rolipram ameliorated intestinal fibrosis by downregulating TGF-␤1. Sanz et al 46 demonstrated that roflumilast inhibited leukocyte-endothelial cells interaction.…”

Inhibition of Phosphodiesterase Type 4 Decreases Stress-Induced Defecation in Rats and Mice

“…In any event, the effects of PDE4 inhibition on reducing stressinduced colonic evacuation have clearly been demonstrated for the first time in the present studies. [48] . Previous studies in this model have demonstrated that the increased stress-induced defecation is associated with increased colonic transit/evacuation [13] , and available literature has demonstrated PDE inhibition can act to decrease colonic motility and increase intestinal secretion.…”