Abstract: SA-PO938
Implication of Inflammasome Activation in the Progression of Peritoneal Fibrosis in Mice
Session Information
- Peritoneal Dialysis: Inflammation, Peritoneal Transport
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Dialysis
- 703 Dialysis: Peritoneal Dialysis
Authors
- Kadoya, Hiroyuki, Kawasaki Medical School, Kurashiki, Japan
- Sogawa, Yuji, Kawasaki Medical School, Kurashiki, Japan
- Satoh, Minoru, Kawasaki Medical School, Kurashiki, Japan
- Sasaki, Tamaki, Kawasaki Medical School, Kurashiki, Japan
- Kashihara, Naoki, Kawasaki Medical School, Kurashiki, Japan
Background
During peritoneal dialysis, the peritoneum is exposed to bioincompatible dialysate, which causes tissue fibrosis, which then limit the long-term effectiveness of peritoneal dialysis. Peritoneal fibrosis is the end result of chronic inflammation reactions induced by a variety of stimuli including peritonitis, allergic responses. Thus, understanding the molecular events that drive fibroproliferation and matrix deposition has been a favored area of investigation. However, the detailed mechanisms underlying peritoneal fibrosis process have not been elucidated. Considering that activation of inflammasome triggers chronic inflammation, which ultimately causes fibrosis. We investigated whether inflammasome activation causes peritoneal fibrosis.
Methods
We used ASC-deficient mice (ASCKO) to investigate the role of inflammasome, which ASC are critical components of the inflammasome. C57Bl/6 mice (WT) were used for control. Peritoneal fibrosis was induced by chlorhexidine gluconate (CG) into the peritoneal cavity of mice every other day for 4 weeks. VX-765 (100 mg/kg/day), an inhibitor of caspase-1 activity, was administered by gavage for 2 weeks. The mice were divided into the following groups; (1) WT-vehicle, (2) WT-CG, (3) ASCKO-vehicle, (4) ASKO-CG, and (5) WT-CG/VX-765.
Results
After exposure to CG, WT-CG mice showed the progression of peritoneal fibrosis evaluated by Masson’s trichrome stain, and also been observed to enhance mRNA expression of TGF-β in peritoneal tissue. Increased expressions of inflammasome components, NLRP-3 and ASC, were demonstrated in WT-CG. Increased Caspase-1 activity and concomitant overproduction of IL-1β and IL-18 were also demonstrated in the WT-CG. These changes were suppressed in the ASCKO-CG and VX-765 injected mice. Furthermore, ASC-positive cells were merged with the immunofluorescent staining for the macrophage marker F4/80. Therefore, inflammasomes were mainly activated in the infiltrating macrophages.
Conclusion
Our results suggest that inflammasome activation plays a pivotal role in the development of peritoneal fibrosis in infiltrated macrophages. Thus, inflammasome activation in macrophages could be a new therapeutic target for chronic inflammation-induced peritoneal fibrosis.