Dipyridamole inhibits human peritoneal mesothelial cell proliferation in vitro and attenuates rat peritoneal fibrosis in vivo

Background. Peritoneal fibrosis (PF) is one of the most serious complicatio ns after long-term continuous ambulatory peritoneal dialysis (CAPD). Prolif eration of human peritoneal mesothelial cells (HPMC) and matrix over-produc tion are regarded as the main processes predisposing to PF. Dipyridamole (D P) has been reported to have potential as an antiproliferative and antifibr otic agent. We thus investigated the effect of DP in inhibiting proliferati on and collagen synthesis of HPMC. A rat model of peritonitis-induced PF wa s also established to demonstrate the in vivo preventive effect of DP. Methods. HPMC was cultured from human omentum by an enzyme digestion method . Cell proliferation was measured by the methyltetrazolium assay. Intracell ular cAMP was measured using an enzyme immunoassay (EIA) kit. Total collage n syn thesis was measured by H-3-proline incorporation assay. Expression of collagen alpha1 (I) and collagen alpha1 (III) mRNAs was deter mined by Nor thern blotting. The rat model of peritonitis-induced PF was developed by ad ding dextran microbeads (Cytodex, 8 mg/1 mL volume) to a standardized suspe nsion (3 x 10(9)) of Staphylococcus aureus. DP was administrated via intrav enous infusion (4 mg in 1 h) daily for seven days. Macroscopic grading of i ntraperitoneal adhesions and histological analyses of peritoneal thickness and collagen expression were performed. Results. Addition of DP to HPMC cultures suppressed serum-stimulated cell p roliferation and collagen synthesis. The antimitogenic and antifibrotic eff ects of DP appear to be predominantly mediated through the cAMP pathway. as DP increased intracellular cAMP in a dose-dependent manner. The macroscopi c grade of intraperitoneal adhesion and peritoneal thickness were both sign ificantly increased in animals treated with Cytodex plus S. aureus: on the other hand. DP attenuated these fibrotic changes with statistical significa nce (P < 0.01). Analysis of gene expression of collagen <alpha>1 (I) and al pha1 (III) in the peritoneal tissue of experimental animals yielded similar results. Conclusions. This study suggests that dipyridamole may have therapeutic pot ential in treating peritoneal fibrosis.