Pentoxifylline inhibits human peritoneal mesothelial cell growth and collagen synthesis: effects on TGF-beta.
BACKGROUND
Prevention or treatment of peritoneal fibrosing syndrome has become an important issue in patients on continuous ambulatory peritoneal dialysis (CAPD). Recent evidence has suggested that mesothelial stem cell proliferation and matrix over-production predispose the development of peritoneal fibrosis. We investigated whether pentoxifylline (PTX) affects human peritoneal 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 method. Cell cycle analysis was performed by flow cytometry. Collagen synthesis was measured by 3H-proline incorporation into pepsin-resistant, salt-precipitated collagen. Prostaglandins and cAMP were determined by enzyme immunoassay. 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 that PTX arrested the HPMCs in the G1 phase. PTX decreased the procollagen alpha1 (I) mRNA expression either stimulated by serum or transforming growth factor-beta (TGF-beta). PTX did not alter prostaglandins synthesis but dose-dependently increased intracellular cAMP level. PTX, the same as 3-isobutyl-l-methylxanthine, could potentiate prostaglandin E1 (PGE1) increased cAMP levels of HPMC. The antimitogenic and antifibrogenic effects of PTX on HPMC were reversed by N-[2]-((p-Bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide (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 peritoneal fibrosing syndrome.
Fang
C C
CC
Departments of Emergency Medicine, Internal Medicine and Surgery, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China.
Yen
C J
CJ
Chen
Y M
YM
Shyu
R S
RS
Tsai
T J
TJ
Lee
P H
PH
Hsieh
B S
BS
D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis*; D000242:Cyclic AMP / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D010431:Pentoxifylline / Q000494:pharmacology*; D010529:Peritoneal Cavity / Q000166:cytology*; D010537:Peritoneum / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; D016212:Transforming Growth Factor beta; D003094:Collagen; D000242:Cyclic AMP; D010431:Pentoxifylline; D007213:Indomethacin