KAWATANI Masahito Akita University, School of Medicine, Professor, 医学部, 教授 (00177700)
SATO Kazunari Akita University, School of Medicine, Assistant professor, 医学部, 助教授 (90270842)
MATSUURA Shinobu Akita University, School of Medicine, Research assistant, 医学部, 助手 (40332465)
KATO Tetsuro Akita University, School of Medicine, Professor, 医学部, 教授 (40004642)
|Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2001: ¥2,300,000 (Direct Cost: ¥2,300,000)
Neurogenic bladder requiring the augmentation cystoplasty is the irreversible end result of dense connective tissue. For prevention or restoration of the fibrous bladder with low compliance, it is important to know the biological mechanisms associated with the fibrous changes following the outlet obstruction.
In several organs, interactions between cell and extracellular matrix (ECM) components regulate the cellular response to injury and extracellular matrix remodeling. Among plenty of cytokines, both of hepatocyte growth factor (HGF) and transforming growth factor-β1 (TGF-β1) are indicated to be main keys of this process. HGF is believed to be an organotrophic factor for regeneration and protection in a wide variety of organs. The receptor for HGF is a c-met proto-oncogene product containing an intracellular tyrosine kinase domain. TGF-β1, on the other hand, is a pathogenic mediator in tissue fibrosis in distinct organs, and encourages ECM protein production. Such reciprocal expressio
n of HGF and TGF-β1 is thought to be important in the regulation between tissue reconstruction and the fibrous changes in chronically damaged organs. We investigated the changes of bladder tissue HGF, TGF-β1 and c-Met expression secondary to the chronic bladder outlet obstruction in rats.
Female Sprague-Dawley rats underwent partial bladder outlet obstruction under anesthesia, while sham operated rats used as controls. Bladders were harvested at 1, 3, 5, 7 days, and 2, 4, 12, 16, 20, 28 weeks following the surgery (n=6 each). Bladders were fixed and stained by HE and Azan staining. Stereological analysis using video-captured images was performed to measure the ratio of extracellular matrix to smooth muscles. Tissue concentration of HGF and TGF-β1 was determined by ELISA kit, and c-Met expression by western immunoblot analysis.
The significant increase in bladder weight was confirmed 5 days and later after the obstruction. Microscopic views revealed obvious increase of connective tissue, in addition to smooth muscle hypertrophy. The ELISAs indicated that the HGF and TGF-β1 expression level in the obstructed bladder peaked rapidly following the surgery, reaching the maximum level around 5days. The TGF-β1 level in the obstructed bladder returned to control levels by 7 days. Western blot showed that the expression of c-Met decreased soon after the surgery and that this lower expression level lasted in the present during the observation.
We observed the changes of expression of HGF and its associates in obstructed bladder. It is suggested that acute increase of bladder TGF-β1 triggers the bladder fibrosis, whereas lowered expression of c-Met contributes to the long-lasting tissue repair retardation in the bladder with outlet obstruction. The results indicate the HGF, c-Met and TGF-β1 systems may be important therapeutic targets in preventing irreversible fibrous changes following bladder outlet obstruction. Less