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백서 동계신이식(Renal Isograft) 모델에서 Tacrolimus(FK-506)신독성과 α-Tocopherol의 효과

Other Titles
 Tacrolimus(FK-506) nephrotoxicity and the effect of α-Tocopherol in the rat renal isograft 
Issue Date
1998
Description
의학과/박사
Abstract
[한글] Tacrolimus(FK-506)는 Streptomyces tsukubaensis로부터 추출된 Macrolide계 약제로서 Cy-closporin A(CyA)보다 더 강력한 면역억제 효과와 많은 장점을 가지므로 장기이식에 사용하여 좋은 성적을 나타내고 있으나, CyA와 마찬가지로 신독성이 가장 흔하고도 심각한 부작용이다. Tacrolimus 신독성의 기전 및 형태학적 변화는 CyA의 경우와 유사하며 여러 방법으로 신독성을 줄여보려 하였으나 현재 용량 조절 외에는 특별한 방법이 없는 실정이다. 신장이식시 일어나는 허혈-재관류 손상은 특히 신세뇨관에서 심하며 산소유리기 또는 활성산소종(reactive oxygen species)이 손상에 관여하므로 항산화제를 투여하면 완화될 수 있다. CyA 신독성 실험에서 항산화제를 투여하면 신피질 사립체(mitochondria)의 malondialdehyde(MDA)치가 감소되고 신장의 손상 정도가 경감되어 CyA신독성도 허혈-재관류 손상처럼 산소유리기 및 지질과산화와 관련이 있음을 알게 되었다. 그러나 Tacrolimus의 대사 및 신독성이 CyA처럼 산소유리기 및 지질과산화 현상과 관련이 있는지는 아직 불확실하다. 만약 관련이 있다면, 이식 후에 허혈-재관류 손상을 더 악화시킬 것이며 a-tocopherol을 투여할 때 신독성의 정도가 감소하여야 한다. 그러나 아직 이와 같은 실험 보고가 없었으며, 또한 대부분의 실험이 신동맥을 결찰한 온허혈 또는 일측 신절제 모델이었다. 따라서 저자는 동계신이식(renal isograft) 모델을 이용하여 Tacrolimus 신독성과 산소유리기의 관련성을 규명하고, 냉허혈-재관류 손상 및 Tacrolimus 신독성에 대한 a-tocopherol의 이식신 보호 효과를 조사하며, 이 두가지 손상의 형태학적 변화를 이해하기 위해 본 연구를 시행하였다. 총 66예의 Lewis 백서에서 신장 동계이식(isograft)을 하였으며, 공여쥐의 좌측 신장과 신정맥 및 하대정맥의 일부, 신동맥 및 대동맥의 일부, 요관 및 방광 일부를 획득하여 UW용액에 24시간, 4℃ 냉장 보존하였다가, 수여 쥐의 우측 신장과 방광 일부를 절제한 후, 수여 쥐의 대동맥 및 하대정맥에 단측문합하고 방광은 단단문합하였다. 백서는 4군으로 나누어 Ⅰ군은 대조군으로 생리식염수를 주사하였고, Ⅱ군에는 Tacrolimus를 체중(kg)당 2 mg을 이식후 매일 근육주사 하였으며, Ⅲ군에는 마찬가지로 Tacrolimus를 체중(kg)당 2 mg을 매일 근육주사하고 a-tocopherol은 체중(kg)당 20 mg을 이식 2일 전부터 시작하여 희생시까지 매일 복강 주사하였다. Ⅳ군에는 a-tocopherol만 체중(kg)당 20 mg을 이식 2일 전부터 시작하여 희생시까지 매일 복강 주사하였다. 각 군마다 5∼6마리씩 이식후 3일, 7일, 14일에 희생하고 이식신 및 수여쥐 자신의 신장을 적출하여 조직학적 검사 및 변형된 TBA법을 이용한 신장조직의 MDA치를 측정하여 다음과 같은 결과를 얻었다. 1. 냉허혈-재관류로 인한 신세뇨관의 형태학적 변화 및 지질과산화 현상은 이식후 3일에 가장 심하였으며 1주가 경과하면서 감소하였다. 2. 이와 같은 신세뇨관 손상에 대한 a-tocopherol의 억제 효과는 투여후 1주부터 나타나기 시작하여 2주째 뚜렷해졌다. 3. Tacrolimus 신독성으로 인한 신세뇨관의 손상은 냉허혈-재관류 손상 단독군보다 그 정도가 심하였고, 시간이 경과함에 따라 세뇨관 간질성신염의 빈도가 증가하였으나, a-tocopherol을 투여하면 2주째 손상이 경감 또는 회복되는 경향을 보였다. 4. Tacrolimus 신독성에서 a-tocopherol 투여시 MDA치는 이식후 1주 이전에 현저히 감소하였다. 이상의 결과로부터 백서의 동계신이식 모델에서 Tacrolimus 신독성은 급성 세뇨관 괴사의 연장 및 세뇨관 간질성신염을 초래하였으며, 이는 허혈-재관류 손상을 악화시키는 것으로 생각되었다. 냉허혈-재관류 및 Tacrolimus에 의한 신손상은 a-tocopherol로 경감되어 이 모델에서 Tacrolimus에 의한 신독성에 산화성 손상이 관련되어 있음을 알 수 있었다. Tacrolimus(FK-506) nephrotoxicity and the effect of α -Tocopherol in the rat renal isograft In Chul Hong Department of Medicine The Graduate School, Yonsei University (Directed by Professor Kiil Park) Tacrolimus(FK-506) is a Macrolide which possesses similar but more potent immunosuppessant properties than cyclosporine. However nephrotoxicity is the most common and important complication. Many authors have reported the morphologic similarity between Tacrolimus and Cyclosporin A(CyA) nephrotoxicity, but others have not agreed with this opinion. There have been many reports about oxygen tee radical injury as a pathogenetic mechanism of CyA nephrotoxicity, but few reports have investigated the relationship between Tacrolimus nephrotoxicity and oxygen free radical injury. Therefore, I decided to evaluate the relationship between Tacrolimus nephrotoxicity and oxygen free radicals, to examine the protective effect of a-tocopherol as an antioxidant, and finally to determine the histological changes of these injuries. En bloc resection of the left kidney, left renal artery including a portion of aorta, left renal vein with vena cave, and left ureter including a portion of bladder from male Lewis rats was done, and then preserved in UW solution and stored in the refrigerator at 4℃ for 24 hours. After right nephrectomy in the recipients, the harvested organs were transplanted into the right peritoneal cavity using anastomoses between the sides of the aorta and vena cave of recipients and the ends of the aorta and vena cave of donors under a microscope. Also, anastomosis was made between the bladder portion of donors and recipients after resection of a portion of the bladder from recipients. After transplantations, rats were divided into 4 groups( Ⅰ -Ⅳ). 2 mg of Tacrolimus per kilogram body weight was injected intramuscularly daily into groups Ⅱ and Ⅲ. a-Tocopherol was injected intraperitoneally daily in the amount of 20 mg/kg from 2 days prior to transplantation in groups Ⅲ andⅣ. The comtrol group( Ⅰ ) received the same amount of saline. 5 or 6 rats from each group were sacrificed at 3 days, 7 days, and 14 days after transplantation respectively. The grafted and native kidneys were removed far histopathologic examination and the measurement of malondialdehyde(MDA) using a modified TBA method(Ohkawa). Both morphologic renal tubular injury and the increase of MDA due to cold ischemia-reperfusion were highest at 3 days after transplantation, then were alleviated after 7 days. The inhibitory effect of a-tocopherol to renal tubular damage from cold ischemia-reperfusion began to appear after 1 week, and was distinct 2 weel after transplantation. The degree of renal tubular damage was the most severe in Tacrolimus nephrotoxicity, and the frequency of tubulointerstitial nephritis increased with the passage of time, as compared with the ischemia-reperfusion iniury(group Ⅰ ). With a-tocopherol treatment, ischemia-reperfusion injury as well as Tacrolimus nephrotoxicity was decreased or healed 2 weel after transplantation, and the amount of MDA was markedly decreased after 1 week. In summary, Tacrolimus nephrotoxicity polonged the duration of acute tubular necrosis and caused tubulointerstitial nephritis in the rat r enal isograft model, which may be the result of aggravation of ischemia-reperfusion injury. That the renal damage due to cold ischemia-reperfu-sion and Tacrolimus administration was reduced by a- tocopherol, indicates that oxidative injury is a pathogenetic mechanism of Tacmlirnus nephrotoxicity in this model.
[영문] Tacrolimus(FK-506) is a Macrolide which possesses similar but more potent immunosuppessant properties than cyclosporine. However nephrotoxicity is the most common and important complication. Many authors have reported the morphologic similarity between Tacrolimus and Cyclosporin A(CyA) nephrotoxicity, but others have not agreed with this opinion. There have been many reports about oxygen tee radical injury as a pathogenetic mechanism of CyA nephrotoxicity, but few reports have investigated the relationship between Tacrolimus nephrotoxicity and oxygen free radical injury. Therefore, I decided to evaluate the relationship between Tacrolimus nephrotoxicity and oxygen free radicals, to examine the protective effect of a-tocopherol as an antioxidant, and finally to determine the histological changes of these injuries. En bloc resection of the left kidney, left renal artery including a portion of aorta, left renal vein with vena cave, and left ureter including a portion of bladder from male Lewis rats was done, and then preserved in UW solution and stored in the refrigerator at 4℃ for 24 hours. After right nephrectomy in the recipients, the harvested organs were transplanted into the right peritoneal cavity using anastomoses between the sides of the aorta and vena cave of recipients and the ends of the aorta and vena cave of donors under a microscope. Also, anastomosis was made between the bladder portion of donors and recipients after resection of a portion of the bladder from recipients. After transplantations, rats were divided into 4 groups( Ⅰ -Ⅳ). 2 mg of Tacrolimus per kilogram body weight was injected intramuscularly daily into groups Ⅱ and Ⅲ. a-Tocopherol was injected intraperitoneally daily in the amount of 20 mg/kg from 2 days prior to transplantation in groups Ⅲ andⅣ. The comtrol group( Ⅰ ) received the same amount of saline. 5 or 6 rats from each group were sacrificed at 3 days, 7 days, and 14 days after transplantation respectively. The grafted and native kidneys were removed far histopathologic examination and the measurement of malondialdehyde(MDA) using a modified TBA method(Ohkawa). Both morphologic renal tubular injury and the increase of MDA due to cold ischemia-reperfusion were highest at 3 days after transplantation, then were alleviated after 7 days. The inhibitory effect of a-tocopherol to renal tubular damage from cold ischemia-reperfusion began to appear after 1 week, and was distinct 2 weel after transplantation. The degree of renal tubular damage was the most severe in Tacrolimus nephrotoxicity, and the frequency of tubulointerstitial nephritis increased with the passage of time, as compared with the ischemia-reperfusion iniury(group Ⅰ ). With a-tocopherol treatment, ischemia-reperfusion injury as well as Tacrolimus nephrotoxicity was decreased or healed 2 weel after transplantation, and the amount of MDA was markedly decreased after 1 week. In summary, Tacrolimus nephrotoxicity polonged the duration of acute tubular necrosis and caused tubulointerstitial nephritis in the rat r enal isograft model, which may be the result of aggravation of ischemia-reperfusion injury. That the renal damage due to cold ischemia-reperfu-sion and Tacrolimus administration was reduced by a- tocopherol, indicates that oxidative injury is a pathogenetic mechanism of Tacmlirnus nephrotoxicity in this model.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/125845
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2. 학위논문 > 1. College of Medicine (의과대학) > 박사
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