Inhibition of
phosphodiesterase (PDE) activity is beneficial in models of
arthritis and airway
inflammation. Here we assessed the ability of PDE inhibitors to modulate
colitis by exposing mice to 4% (w/v)
dextran sulfate sodium (DSS)
drinking water for 5 days with or without
rolipram, an inhibitor of 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 lesser 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, although stimulated ion transport events were still reduced 3 days after DSS treatment, colonic segments from DSS +
rolipram-treated mice displayed enhanced recovery in their secretory responsiveness, particularly to
carbachol. These findings indicate that specific PDE4 inhibition can significantly reduce the tissue damage that accompanies
colitis and enhance recovery of normal colonic function.