Effects of pentoxifylline on peritoneal fibroblasts and silica-induced peritoneal fibrosis.
BACKGROUND
Peritoneal fibrosis is a long-term complication following continuous ambulatory peritoneal dialysis (CAPD). Peritoneal fibroblasts may play an important role in peritoneal fibrosis. Up to now, the treatment of peritoneal fibrosis in patients with CAPD remains unsatisfactory. Pentoxifylline (PTX) is a xanthine derivative and is used in the treatment of peripheral vascular and cerebrovascular diseases. Several studies have demonstrated that PTX can ameliorate fibrosis of the skin, liver, and kidney.


OBJECTIVE
To investigate the effect of PTX on in vitro growth and collagen synthesis of human peritoneal fibroblasts (HPFBs), and to evaluate the effects of PTX on silica-induced peritoneal fibrosis in vivo.


METHODS
In the in vitro study, HPFBs were cultured from human omentum. The effect of PTX on the growth of serum-stimulated HPFBs was evaluated by MTT assay. The effect of PTX on the collagen synthesis of HPFB was measured by [3H]-proline incorporation. Expression of type I and type III collagen mRNA was evaluated by Northern blotting. The effects of PTX on matrix metalloproteinase (MMP) activity and cAMP level in HPFBs were measured by immunoassays. In the in vivo study, Wistar rats were randomly divided into five groups. All rats received intraperitoneal (IP) injection of silica suspension (250 mg/100 g body weight) on day 0. The rats of group 1 (control group) were injected with vehicle IP every day for 14 days. The rats of groups 2, 3, and 4 were injected with PTX (4 mg/100 g body weight) IP every day for 3, 7, and 14 days, respectively. The rats in group 5 received an intravenous infusion of PTX (8 mg/100 g body weight) every day for 7 days. On the 15th day after silica injection, all rats were sacrificed. Their parietal and visceral peritoneums were removed and processed for pathology, and the severity of fibrosis was measured and scored.


RESULTS
In vitro, PTX inhibited serum-stimulated HPFB growth (maximum was 93% at 1 mg PTX/mL) in a dose-dependent manner. Collagen synthesis by HPFB was reduced (47% at 1 mg PTX/mL), and collagen I and III mRNA expression in HPFBs was suppressed by PTX. The PTX did not affect the MMP (including MMP-1, MMP-8, and MMP-13) activities of HPFBs. The mechanism of PTX was through increasing cAMP by its phosphodiesterase inhibiting activity. In vivo, the severity of fibrosis was significantly reduced in groups 4 and 5 compared to group 1 (p < 0.05).


CONCLUSIONS
These results suggest that PTX can inhibit growth of and collagen synthesis by HPFBs in vitro. The fibrosis derived from silica-induced peritonitis in vivo was also ameliorated by PTX. Therefore, pentoxifylline may have the potential to be used to treat peritoneal fibrosis in patients on CAPD.
Fang
Cheng-Chung
CC
Department of Emergency Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan, Republic of China.
Lai
Ming-Nan
MN
Chien
Chiang-Ting
CT
Hung
Kuan-Yu
KY
Tsai
Chien-Chen
CC
Tsai
Tun-Jun
TJ
Hsieh
Bor-Shen
BS
D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D009852:Omentum / Q000378:metabolism / Q000473:pathology*; D010431:Pentoxifylline / Q000494:pharmacology* / Q000627:therapeutic use; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012822:Silicon Dioxide
D010726:Phosphodiesterase Inhibitors; D012822:Silicon Dioxide; D003094:Collagen; D010431:Pentoxifylline