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From the Intestinal Disease Research Programme, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
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-
(TNF-) 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.
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