Pentoxifylline inhibits human peritoneal mesothelial cell growth and collagen synthesis: Effects on TGF-beta

Background Prevention or treatment of peritoneal fibrosing syndrome has bec ome an important issue in patients on continuous ambulatory peritoneal dial ysis (CAPD). Recent evidence has suggested that mesothelial stem cell proli feration and matrix over-production predispose the development of peritonea l fibrosis. We investigated whether pentoxifylline (PTX) affects human peri toneal mesothelial cell (HPMC) growth and collagen synthesis. Methods. HPMC was cultured from human omentum by an enzymic disaggregation method. Cell proliferation was assayed using a methyltetrazolium uptake met hod. Cell cycle analysis was performed by flow cytometry. Collagen synthesi s was measured by H-3-proline incorporation into pepsin-resistant, salt-pre cipitated collagen. Prostaglandins and cAMP were determined by enzyme immun oassay. Northern blot analysis was used to determine mRNA expression. Results. Our data show that PTX inhibited serum-stimulated HPMC growth and collagen synthesis in a dose-dependent manner. Cell cycle analysis showed t hat PTX arrested the HPMCs in the G1 phase. PTX decreased the procollagen a lpha 1 (I) mRNA expression either stimulated by serum or transforming growt h factor-beta (TGF-beta). PTX did not alter prostaglandins synthesis but do se-dependently increased intracellular cAMP level. PTX, the same as 3-isobu tyl-1-methylxanthine, could potentiate prostaglandin E-1 (PGE(1)) increased cAMP levels of HPMC. The antimitogenic and antifibrogenic effects of PTX o n HPMC were reversed by N-[2]-((p-Bromocinnamyl)amino)ethyl]-5-isoquinoline sulfonamide (H-89). Therefore, the mechanism of these effects may be due to the phospodiesterase inhibitory property of PTX. Conclusions. These data suggest that PTX may have a role in treating perito neal fibrosing syndrome.