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Part 2: Cellular and Molecular Biology of the Peritoneum and Peritoneal Dialysis |
Second Department of Surgery1 Dokkyo University School of Medicine, Mibu; Department of Surgery2 Kidney Center, Tokyo Women's Medical University, Tokyo, Japan
Correspondence to: T. Sawada, Second Department of Surgery, Dokkyo University School of Medicine, Kitakobayashi 880, Mibu, Tochigi 321-0293, Japan. tsawada{at}dokkyomed.ac.jp
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ABSTRACT |
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In Japan, only about 3% of all patients with end-stage renal disease are
maintained by continuous ambulatory peritoneal dialysis (CAPD). Although the
reasons for the low proportion of patients receiving CAPD are multifactorial,
encapsulating peritoneal sclerosis (EPS), a fatal complication of CAPD, is a
major factor. In 1995 we developed a rat model of EPS, and in 2001 also
developed an EPS model in mice. These rodent EPS models are reliable,
reproducible, and inexpensive and have been used by other investigators. The
renin–angiotensin system negatively regulates the transforming growth
factor-beta signaling pathway, which plays a major role in tissue fibrosis. To
investigate the anti-EPS effect of renin–angiotensin system inhibition,
an angiotensin-converting enzyme inhibitor, quinapril, was administered to an
EPS model in mice. Quinapril was found to inhibit EPS, both macro- and
microscopically, in a dose-dependent manner. We report our experience of
developing the experimental in vivo EPS model, and the inhibitory
effect of this angiotensin-converting enzyme inhibitor on EPS.
KEY WORDS: Encapsulating peritoneal sclerosis; angiotensin-converting enzyme inhibitor; quinapril; mouse model.
In Japan, about 260 000 patients were maintained by artificial kidney in 2006; about 9000 (3%) were maintained by continuous ambulatory peritoneal dialysis (CAPD). Although the reasons for the low proportion of patients receiving CAPD are multifactorial, encapsulating peritoneal sclerosis (EPS), a fatal complication of CAPD, is a major factor.
Encapsulating peritoneal sclerosis, formerly known as sclerosing encapsulating peritonitis (SEP), occurs in about 1% – 3% of CAPD patients (1) and its occurrence increases with time spent on CAPD, being 8% at 5 years and 19% at 8 years. With a reported mortality of more than 56%, EPS is a life-threatening complication of CAPD (2).
It has been difficult to study EPS due partly to the lack of a suitable in vivo model. In 1995, Suga et al., from our laboratory, developed a reproducible EPS model in rats (3), and in 2001 Ishii et al., also from our laboratory, developed a similar EPS model in mice (4). These rodent EPS models are reliable, reproducible, and inexpensive and have been used by other investigators.
The renin–angiotensin system negatively regulates the transforming growth factor-beta signaling pathway, which plays a major role in tissue fibrosis. To investigate the anti-EPS effect of renin–angiotensin system inhibition, an angiotensin-converting enzyme inhibitor, quinapril, was administered to EPS model mice and was found to inhibit the development of EPS, both macro- and microscopically, in a dose-dependent manner (5).
Here we report our experience of developing our experimental in vivo EPS model and the inhibitory effect of this angiotensin-converting enzyme inhibitor on EPS.
In the first experiment, C57BL/6 mice were intraperitoneally administered 0.3 mL 0.1% chlorhexidine gluconate and 15% ethanol, dissolved in saline, on a daily basis for 56 days (group 1, n = 15). As a control group, C57BL/6 mice were administered, in the same manner, 0.3 mL phosphate-buffered saline only (group 2, n = 15). The mice were sacrificed on days 3, 7, 21, or 56 and histologically analyzed.
Macroscopically, all mice in group 1 developed EPS by day 56 after intraperitoneal injection. Microscopically, peritoneal fibrosis and infiltration of mononuclear cells advanced with time, and peritoneal fibrosis reached the chronic inflammatory stage by day 56 after injection (Table 1). Thus, we succeeded in developing a convenient experimental EPS model in mice that is useful for elucidating the pathogenesis of EPS and for establishing possible treatments.
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In the second experiment, the inhibitory effect of an angiotensin-converting enzyme inhibitor, quinapril, on peritoneal fibrosis was examined in experimental EPS model mice. C57BL/6 mice were divided into three groups: group 1 (n = 20) mice received a daily intraperitoneal injection of 0.3 mL SH solution, consisting of 0.1% chlorhexidine gluconate and 15% ethanol dissolved in saline; group 2 mice (n = 20) and group 3 mice (n = 20) received SH solution in the same manner, but were also given 1 mg/kg or 3 mg/kg quinapril respectively, orally, on a daily basis. Five mice from each group were sacrificed on days 3, 7, 21, or 56 and evaluated macroscopically and histologically.
Macroscopic examination revealed that the fibrotic change in the parietal peritoneum was significantly more severe in group 1 than in groups 2 and 3. Histological examination demonstrated that peritoneal thickening in groups 2 and 3 was markedly attenuated in comparison to group 1. Semiquantitative analysis showed that the histological fibrosis score was significantly higher in group 1 than in groups 2 and 3 (Table 2).
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These results suggest that quinapril ameliorates the fibrotic change in parietal peritoneum in this experimental murine EPS model, and may have clinical utility for prevention of EPS. Thus, we have developed a reliable EPS model in mice and showed that quinapril ameliorates the EPS in this model.
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