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 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.
Diaz-Granados
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Intestinal Disease Research Programme, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Howe
K
K
Lu
J
J
McKay
D M
DM
D000818:Animals; D001692:Biological Transport; D003092:Colitis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D003106:Colon / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000494:pharmacology; D004848:Epithelium / Q000378:metabolism; D007413:Intestinal Mucosa / Q000503:physiopathology; D007477:Ions; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010431:Pentoxifylline / Q000494:pharmacology*; D009195:Peroxidase / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D020127:Recovery of Function; D020889:Rolipram / Q000494:pharmacology*
D016207:Cytokines; D007477:Ions; D010726:Phosphodiesterase Inhibitors; D016264:Dextran Sulfate; D009195:Peroxidase; D020889:Rolipram; D010431:Pentoxifylline