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Protective Effect of Synthetic Transforming Growth Factor-β Antagonist on Cyclophosphamide-induced Hemorrhagic Cystitis in Rat
|關鍵字:||TGF-β antagonist;TGF-β拮抗劑;Cyclophosphamide;Hemorrhagic Cystitis;環磷醯胺;出血性膀胱炎||出版社:||生命科學院碩士在職專班||摘要:||
環磷醯胺(CYP)在臨床上常和其他抗腫瘤藥物一起用於腫瘤疾病之治療，但CYP之代謝產物丙烯醛會造成泌尿上皮細胞的受損，誘發膀胱產生出血性發炎的現象。近年研究發現一個新近合成的TGF-β拮抗劑可加速皮膚發炎傷口之癒合及減少疤痕組織的形成。本論文因此以CYP誘發出血性膀胱炎做為研究模式，探討TGF-β拮抗劑是否可降低CYP對膀胱所造成之發炎性傷害及其可能的保護機轉，以做為日後治療出血性膀胱炎之新選擇。實驗中，以hematoxylin and eosin (HE)染色法、膀胱與體重測量法、Evans blue外滲檢測法、亞硝酸釋放法、西方墨點法及免疫組織化學染色法分別針對膀胱組織層之病變程度、膀胱水腫之程度、血漿蛋白外滲之情形、尿液中NO之濃度、iNOS及TGF-β在膀胱組織中之表現等變化做逐項分析，以評估CYP對膀胱所造成之發炎傷害及TGF-β拮抗劑之可能保護性。結果顯示大白鼠膀胱組織因CYP所造成之出血、黏膜層剝落、嗜中性白血球浸潤、膀胱水腫及血漿蛋白外滲等情形，均可因TGF-β拮抗劑之存在而減緩。同時發現因CYP而誘發之TGF-β與iNOS的蛋白表現，以及尿液中NO之濃度亦因此拮抗劑的存在有更加提升之現象。上述結果顯示TGF-β拮抗劑的確對CYP誘發之出血性膀胱炎具保護作用。兩者雖然均可提升TGF-β及NO之表現，但卻對膀胱造成完全相反之影響。目前推論可能和TGF-β及NO被提升的程度大小有關，詳細作用機轉仍有待日後進一步之探討。
Cyclophosphamide (CYP) has widely been used in treating various neoplastic diseases. Treatment with CYP however, often causes serious side effect, the hemorrhagic cystitis. To solve this problem a new drug, synthetic TGF-β antagonist, was investigated in this study to block the CYP-induced hemorrhagic cystitis. This drug has previously been demonstrated to be effective in would healing and scar inhibition. In the meanwhile, the molecular mechanism responsible for TGF-β antagonist-mediated protection was also under the investigation by targeting at the changes of TGF-β and nitric oxide (NO). In the study, a CYP-induced hemorrhagic cystitis was first induced in the SD rats and used as an animal model for evaluating the protective value of TGF-β antagonist. Various techniques including the hematoxylin and eosin (HE) staining, weight (bladder/whole body) measurement, Evans blue extravasation assay, Western blotting, nitrite release assay and immunohistochemical staining technique were applied to determine the CYP-induced alterations in bladder tissue and whether these pathologic alterations could be prevented by TGF-β antagonist. Results showed that CYP at a dose of 200 mg/kg, significantly eroded the epithelial cells of the mucosa layer, increased the blood vessel permeability by promoting the tissue edema and infiltration of red blood cells, neutrophils and blood bound albumins into the bladder tissue. The expression of TGF-βand iNOS and the urinary NO release were all significantly increased by CYP. Co-treatment with TGF-βantagonist (0.8 mg/kg/day) not only significantly reduced the above phenomena (except the swell of the submucosa layer) but further increased the expression of TGF-β and iNOS in the bladder tissue and the urinary release of NO. In overall, the protective value of TGF-β antagonist against CYP-induced hemorrhagic cystitis has been demonstrated. The protective mechanism underlying was proved to be TGF-βand NO related but details require further investigation.
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