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Title Page
ABSTRACT
Contents
LIST OF ABBREVIATIONS 11
INTRODUCTION 12
MATERIALS AND METHODS 15
Study design 15
Peritoneal adhesion induction 17
Peritoneal adhesion evaluation 19
Histologic examination 20
Quantitative real-time polymerase chain reaction (qRT-PCR) analysis 21
Western blot analysis 22
Immunohistochemical analysis 23
Immunofluorescence analysis 24
Statistical analysis 25
RESULTS 26
EW-7197 decreased the incidence and severity of peritoneal adhesions 26
Fibrosis and collagen deposition were attenuated in EW-7197 treated peritoneal ischemic buttons 30
TGF-β/Smad2/3 signaling and expression of CTGF and VEGF were reduced in EW-7197 treated peritoneal ischemic buttons 36
Markers of MMT and ECM synthesis and degradation were altered in EW-7197 treated peritoneal ischemic buttons 40
MMT was inhibited in a Smad-dependent manner in EW-7197 treated peritoneal ischemic buttons 46
DISCUSSION 47
REFERENCES 51
Table 1. Adhesion Score 19
Table 2. Fibrosis and inflammation grading scale 20
Table 3. List of primers Used for qRT-PCR 21
Fig. 1. A flow diagram showing randomization process and study follow-up. 16
Fig. 2. Photograph shows four ischemic buttons (arrows) created with 4-0 silk suture (Ailee,... 18
Fig. 3. Bar graph of incidence of peritoneal adhesions. 27
Fig. 4. Bar graph of quality score of peritoneal adhesions. 27
Fig. 5. Bar graph of tenacity score of peritoneal adhesions. 28
Fig. 6. Photograph shows severe peritoneal adhesion formation (arrows ＝ 3 quality score;... 28
Fig. 7. Photograph shows moderate peritoneal adhesion formation (arrows ＝ 1 quality score;... 29
Fig. 8. Photograph shows mild peritoneal adhesion formation (arrows ＝ 1 quality score) in... 29
Fig. 9. Bar graph of fibrosis score of peritoneal ischemic buttons. 31
Fig. 10. Bar graph of inflammation score of peritoneal ischemic buttons. 31
Fig. 11. Bar graph of collagen deposition score of peritoneal ischemic buttons. 32
Fig. 12. Histologic section of a peritoneal ischemic button from control group shows dense... 32
Fig. 13. Histologic section of a peritoneal ischemic button from 10 mg EW-7197 group... 33
Fig. 14. Histologic section of a peritoneal ischemic button from 20 mg EW-7197 group... 33
Fig. 15. Histologic section of a peritoneal ischemic button from control group shows... 34
Fig. 16. Histologic section of a peritoneal ischemic button from 10 mg EW-7197 group... 34
Fig. 17. Histologic section of a peritoneal ischemic button from 20 mg EW-7197 group... 35
Fig. 18. Bar graph of mean mRNA expression of TGF-β 37
Fig. 19. Bar graph of mean protein expression of Smad2/3 with representative bands 37
Fig. 20. Bar graph of mean protein expression of p-Smad2/3 with representative bands 38
Fig. 21. Bar graph of mean mRNA expression of CTGF 38
Fig. 22. Bar graph of mean mRNA expression of VEGF 39
Fig. 23. Bar graph of mean mRNA expression of Snail-1 41
Fig. 24. Bar graph of mean protein expression of Snail-1 with representative bands 42
Fig. 25. Bar graph of mean mRNA expression of E-Cadherin 42
Fig. 26. Bar graph of mean mRNA expression of α-SMA 43
Fig. 27. Bar graph of mean mRNA expression of COL-1 43
Fig. 28. Bar graph of mean protein expression of COL-1 with representative bands 44
Fig. 29. Bar graph of mean mRNA expression of TIMP-1 44
Fig. 30. Bar graph of mean mRNA expression of TIMP-1 45
Fig. 31. Immunofluorescence (DAPI ＝ blue; E-Cadherin ＝ green; α-SMA ＝ red) and... 46
초록보기 더보기
Background and Purpose: Peritoneal adhesions are a normal response to injury of the peritoneal surface and occurin approximately 95% of patients following abdominal surgery. Although adhesions are integral to the healing process of the peritoneum, they can occasionally cause significant morbidity, such as small-bowel obstruction, female infertility, and chronic abdominal and/or pelvic pain. Transforming growth factor-β1 (TGF-β1) is a part of the TGF-β super family of proteins that regulate a wide variety of cellular processes, such as fibrinolysis, mesothelial-to-mesenchymal transition (MMT), and extracellular matrix (ECM) synthesis and degradation, which are implicated in peritoneal adhesion formation. EW-7197 is a novel oral TGF-β type I receptor kinase inhibitor with high selectivity and low toxicity. The purpose of this study was to evaluate if EW-7197 suppresses peritoneal adhesion formation in a rat experimental model.
Materials and Methods: Thirty-six non-pregnant female Wistar rats (250-300 g; Orient Bio, Seongnam, Korea) underwent peritoneal adhesion induction by the creation of ischemic buttons within the peritoneal wall. These animals were randomly divided into three groups: control (n ＝ 12), 10 mg EW-7197 (n ＝ 12), and 20 mg EW-7197 (n ＝ 12). The control group received 0.3 ml of artificial gastric juice (2 g sodium chloride, 3.2 g pepsin powder, and 80 mL hydrochloric acid) by gavage once daily for 7 days. The 10 mg EW-7197 group received a solution consisting of 0.3 ml of artificial gastric juice and 10 mg/kg EW-7197 phosphate by gavage once daily for 7 days. The 20 mg EW-7197 group received a solution consisting of 0.3 ml of artificial gastric juice and 20 mg/kg EW-7197 phosphate by gavage once daily for 7 days. After the respective periods of treatments were completed, the animals were killed by carbon dioxide asphyxiation.
Results: Peritoneal ischemic buttons creation was technically successful in all 36 rats. There were no complications related to EW-7197 administration. All animals survived until the end of the study. EW-7197 significantly decreased the incidence and severity of peritoneal adhesions in a dose-dependent manner. Histologic examination showed that fibrosis and inflammation were significantly attenuated in EW-7197 treated peritoneal ischemic buttons. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analyses showed that TGF-β/Smad2/3 signaling and expression of connective tissue growth factor and vascular endothelial growth factor were significantly reduced in EW-7197 treated peritoneal ischemic buttons. qRT-PCR and western blot analyses showed that markers of MMT and ECM synthesis and degradation were significantly altered in EW-7197 treated peritoneal ischemic buttons. Immunohistochemical and immunofluorescence analyses showed that MMT was inhibited in a Smad-dependent manner in EW-7197 treated peritoneal ischemic buttons.
Conclusion: In conclusion, EW-7197 suppresses peritoneal adhesion formation in a rat experimental model. The effects of EW-7197-induced suppression of peritoneal adhesion formation seems to be due to inhibition of TGF-β1/Smad2/3-induced MMT and ECM synthesis.
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