Publication: Enkapsüle Sklerozan Peritonit Rat Modelinde İmatinib’in etkileri
Abstract
Giriş: Enkapsüle Sklerozan Peritonit (ESP) kronik periton diyalizinin (PD) uzun dönemde karşılaşılan nadir ancak ölümcül olabilecek komplikasyonudur. Peritonda yeni damar oluşumu, artmış inflamasyon ve abartılı fibrosis ile karakterizedir. Bir tirozin kinaz inhibitörü olan imatinibin hem in vivo hem de in vitro antifibrotik etkileri olduğu bilinmektedir. Çalışmamızda imatinibin EPS rat modelinde periton membranı üzerine etkilerini incelemeyi amaçladık. Materyal-Metod: Yirmidört üremik olmayan Wistar albino rat dört gruba ayrıldı: 3 hafta 2 ml/ gün serum fizyolojik intraperitoneal injeksiyon (Kontrol grubu); 3 hafta 2 ml/ 200 g klorheksidin glukonat (%0.1) ve etanol (%15) / gün intraperitoneal injeksiyon (KG grubu); 3 hafta KG sonrasında 3 hafta bekleme (dinlenme grubu); 3 hafta KG sonrasında 3 hafta 50 mg/ kg/ gün dozunda imatinib mesilat (nasogastrik sonda yoluyla) (KG + İMA). Çalışma sonunda 1 saatlik periton eşitlenme testi (PET) yapıldıktan sonra hayvanlar sakrifiye edildi. Ultrafiltrasyon miktarı (UF), PET parametreleri [diyalizat/ plasma üre (D/ Püre); diyalizat/ plasma kreatinin (D/ Pkr); Diyalizat1.saat/ Diyalizat0.saat glukoz (D/ D0glu)] ve periton morfolojisi (periton kalılnlığı, fibroblast sayısı, inflamasyon skoru, aktive mezotel hücresi oranı, kapiller sayısı, fibrosis skoru) incelendi. Sonuçlar: Üç hafta KG injeksiyonu peritoneal membranda kontrol grubuna göre anlamlı olacak şekilde hem fonksiyonel hem de morfolojik değişiklikler yapmaktadır. KG+İMA grubu KG grubu ile kıyaslandığında UF, D/ Pkr, D/ D0glu ve mezotel hücre aktivasyonunda anlamlı düzelme sağlamaktadır. Ancak dinlenme grubu ile kıyaslandığında sadece aktive mezotel hücre durumunda fark bulundu. Bulgular tablo 1’de özetlenmiştir. Tablo 1. Çalışma gruplarının fonkiyonel ve morfolojik bulgularının karşılaştırılması Kontrol (n=6) KG (n=6) Dinlenme (n=6) KG + İmatinib (n=6) UF miktarı (ml) 7.15±1.2 -0.17±1.6a 3.7±4.3 6.1±3.8b D/ P üre 0.83±0.08 0.72±0.04a 0.83±0.12 0.84±0.11 D/ P kreatinin 1.16±0.22 0.87±0.09a 1.14±0.21b 1.2±0.18b D1/ D0 glukoz 0.77±0.14 0.45±0.04a 0.72±0.16b 0.67±0.1b Periton kalınlığı (μm) 15.67±2.3 62.2±5.5a 59.7±7a 62.3±9.7a Kapiller sayısı (n) 4.8±2.2 16.5±5.4a 13.7±6.6a 17.5±6.7a İnflamasyon skoru 0.17±0.1 1.5±0.22a 1.17±0.17a 1.0±0.0a,b Aktif mezotel hücre oranı (%) 0 100a 83.3a 16.6b,c Fibrosis skoru 0.17±0.1 2.17±0.17a 2.33±0.0a 2.0±0.0a Tartışma: Uzun süre PD tedavisinin bir sonucu olabilecek EPS’nin tedavisinde imatinib umut verici bir ajan olarak dikkati çekmektedir. İmatinib ile tirozin kinaz inhibisyonu peritoneal membranda fibrosisden ziyade inflamasyonu azaltmada bir hedef olabilir. Anti-fibrotik etkilerinin gösterilmesi için eş zamanlı KG+İMA verilmesi gibi deneysel modelde modifikasyonlar yapılabilir. iv
Background: Encapsulating peritoneal sclerosis (EPS) is most serious complication of peritoneal dialysis treatment. Depite its low rates of prevalence, EPS results high mortality. It characterizes with neovascularization, increased inflammation and exaggerated interstitial fibrosis of peritoneum. In vivo and in vitro antifibrotic effects of imatinib, a tyrozin kinase inhibitor, has been suggested previously. In our study, we investigated effects of imatinib on peritoneal membrane in experimental EPS model. Material-Methods: We allocated 24 non-uremic albino Wistar rats to 4 groups: control group, 2 mL isotonic saline injected intraperitoneally (IP) daily for 3 weeks; CG group, 2 mL/ 200 g (0.1%) chlorhexidine gluconate (CG) injected IP daily and ethanol (15%) dissolved in saline, for 3 weeks; resting group, CG (weeks 0 – 3), plus peritoneal rest (weeks 3 – 6); and CG+Imatinib mesylate (IMA) , CG (weeks 0 – 3), plus 50 mg/ kg imatinib mesylate diluted in drinking water via oragastric tube (weeks 3 – 6). At the end of the study, we performed a 1-hour peritoneal equilibration test with 25 mL 3.86% PD solution, and examined the dialysate-to-plasma ratio of urea (D/ P urea), dialysate-toplasma ratio of creatinin (D/ P cr), end-to-initiate dialysate glucose (D1/ D0 glucose), ultrafiltration (UF) volume, and morphologic change (peritoneal thickness, capiller number, inflammation score, active mesothelial cell ratio, fibrosis score) in the parietal peritoneum. Results: KG exposure for 3weeks resulted in obvious alteration in peritoneal transport and morphology. An increased UF, D/ P cr, D1/ D0glucoseand decreased active mesothelial cell ratio was found in KG+IMA group comparing KG alone. Furthermore KG+IMA group was superior than peritoneal rest group with regard to active mesothelial cell ratio. The results are shown in table 1. v Table 1. Comparison of study groups regarding functional and morphologic alternations. Kontrol (n=6) KG (n=6) Dinlenme (n=6) KG + İmatinib (n=6) UF miktarı (ml) 7.15±1.2 -0.17±1.6a 3.7±4.3 6.1±3.8b D/ P üre 0.83±0.08 0.72±0.04a 0.83±0.12 0.84±0.11 D/ P kreatinin 1.16±0.22 0.87±0.09a 1.14±0.21b 1.2±0.18b D1/ D0 glukoz 0.77±0.14 0.45±0.04a 0.72±0.16b 0.67±0.1b Periton kalınlığı (μm) 15.67±2.3 62.2±5.5a 59.7±7a 62.3±9.7a Kapiller sayısı (n) 4.8±2.2 16.5±5.4a 13.7±6.6a 17.5±6.7a İnflamasyon skoru 0.17±0.1 1.5±0.22a 1.17±0.17a 1.0±0.0a,b Aktif mezotel hücre oranı (%) 0 100a 83.3a 16.6b,c Fibrosis skoru 0.17±0.1 2.17±0.17a 2.33±0.0a 2.0±0.0a Conclusion: Imatinib has some beneficial effects on EPS. Tyrosine kinase inhibition with imatinib could be a pathway for decreasing mesothelial cell activity and inflammation. Peritoneal fibrosis has not decreased with imatinib in this experimental EPS model. Simultaneous administration of KG and imatinib could be another model for suggest anti-fibrotic effects of imatinib on peritoneal fibrosis.
Background: Encapsulating peritoneal sclerosis (EPS) is most serious complication of peritoneal dialysis treatment. Depite its low rates of prevalence, EPS results high mortality. It characterizes with neovascularization, increased inflammation and exaggerated interstitial fibrosis of peritoneum. In vivo and in vitro antifibrotic effects of imatinib, a tyrozin kinase inhibitor, has been suggested previously. In our study, we investigated effects of imatinib on peritoneal membrane in experimental EPS model. Material-Methods: We allocated 24 non-uremic albino Wistar rats to 4 groups: control group, 2 mL isotonic saline injected intraperitoneally (IP) daily for 3 weeks; CG group, 2 mL/ 200 g (0.1%) chlorhexidine gluconate (CG) injected IP daily and ethanol (15%) dissolved in saline, for 3 weeks; resting group, CG (weeks 0 – 3), plus peritoneal rest (weeks 3 – 6); and CG+Imatinib mesylate (IMA) , CG (weeks 0 – 3), plus 50 mg/ kg imatinib mesylate diluted in drinking water via oragastric tube (weeks 3 – 6). At the end of the study, we performed a 1-hour peritoneal equilibration test with 25 mL 3.86% PD solution, and examined the dialysate-to-plasma ratio of urea (D/ P urea), dialysate-toplasma ratio of creatinin (D/ P cr), end-to-initiate dialysate glucose (D1/ D0 glucose), ultrafiltration (UF) volume, and morphologic change (peritoneal thickness, capiller number, inflammation score, active mesothelial cell ratio, fibrosis score) in the parietal peritoneum. Results: KG exposure for 3weeks resulted in obvious alteration in peritoneal transport and morphology. An increased UF, D/ P cr, D1/ D0glucoseand decreased active mesothelial cell ratio was found in KG+IMA group comparing KG alone. Furthermore KG+IMA group was superior than peritoneal rest group with regard to active mesothelial cell ratio. The results are shown in table 1. v Table 1. Comparison of study groups regarding functional and morphologic alternations. Kontrol (n=6) KG (n=6) Dinlenme (n=6) KG + İmatinib (n=6) UF miktarı (ml) 7.15±1.2 -0.17±1.6a 3.7±4.3 6.1±3.8b D/ P üre 0.83±0.08 0.72±0.04a 0.83±0.12 0.84±0.11 D/ P kreatinin 1.16±0.22 0.87±0.09a 1.14±0.21b 1.2±0.18b D1/ D0 glukoz 0.77±0.14 0.45±0.04a 0.72±0.16b 0.67±0.1b Periton kalınlığı (μm) 15.67±2.3 62.2±5.5a 59.7±7a 62.3±9.7a Kapiller sayısı (n) 4.8±2.2 16.5±5.4a 13.7±6.6a 17.5±6.7a İnflamasyon skoru 0.17±0.1 1.5±0.22a 1.17±0.17a 1.0±0.0a,b Aktif mezotel hücre oranı (%) 0 100a 83.3a 16.6b,c Fibrosis skoru 0.17±0.1 2.17±0.17a 2.33±0.0a 2.0±0.0a Conclusion: Imatinib has some beneficial effects on EPS. Tyrosine kinase inhibition with imatinib could be a pathway for decreasing mesothelial cell activity and inflammation. Peritoneal fibrosis has not decreased with imatinib in this experimental EPS model. Simultaneous administration of KG and imatinib could be another model for suggest anti-fibrotic effects of imatinib on peritoneal fibrosis.