Dextran sulfate sodium-induced colonic histopathology, but not altered epithelial ion transport, is reduced by inhibition of phosphodiesterase activity

Inhibition of phosphodiesterase (PDE) activity is beneficial in models of a rthritis and airway inflammation, Here we assessed the ability of PDE inhib itors to modulate colitis by exposing mice to 4% (w/v) dextran sulfate sodi um (DSS) drinking water for 5 days with or without rolipram, an Inhibitor o f PDE type 4, or the nonselective PDE inhibitor, pentoxifylline (both at 5 mg/kg, i.p., twice daily). Controls received saline, vehicle, or drug only. Colonic histology, myeloperoxidase (MPO) and tumor necrosis factor-alpha ( TNF-alpha) levels, and epithelial ion transport (baseline and stimulated by electrical nerve stimulation, carbachol, and forskolin) were examined. DSS -treated mice displayed a variable diarrhea, significant histopathology in the mid-distal colon, elevated MPO activity, and reduced (> 50%) responses to all three pro-secretory stimuli. Treatment with rolipram, and to a lesse r extent pentoxifylline, significantly reduced the severity of the colonic histopathology and MPO levels. Neither PDE inhibitor had any affect on the diminished ion transport events caused by DSS-induced colitis. However, alt hough stimulated ion transport events were still reduced 3 days after DSS t reatment, colonic segments from DSS + rolipram-treated mice displayed enhan ced recovery in their secretory responsiveness, particularly to carbachol, These findings indicate that specific PDE4 inhibition can significantly red uce the tissue damage that accompanies colitis and enhance recovery of norm al colonic function.