探討轉化生長激素β對增加K他命潰瘍性膀胱炎大白鼠間質纖維化的角色

The Role of Transforming Growth Factor-β and Enhanced Interstitial Fibrosis in Ketamine-Induced Ulcerative Cystitis in a Rat Model

目的：探討轉化生長激素β（TGF-β）的表現是否會正向調節K他命注射後膀胱間質纖維化的反應，並以大白鼠K他命藥物成癮模式評估K他命注射後需多少時間引發明顯變化。方法：將30隻Sprague-Dawley大白鼠分成三組，每組之大白鼠會接受14到28天的生理食鹽水或K他命（25毫克／公斤／天）腹膜內注射。每組每周檢測膀胱壓力及代謝籠之解尿型態。以西方墨點分析膀組織發炎蛋白TGF-β，纖維化蛋白如纖連蛋白（fibronectin）和第一型膠原蛋白（type I collagen）及細胞外序號調節激活酶（ERK1/2）的表現。結果：K他命明顯造成頻尿及不自主膀胱收縮之膀胱過動症狀。Masson's trichrome染色顯示K他命會減少尿路上皮厚度但會增加膠原蛋白比平滑肌纖維的比率，並且惡化間質纖維化的現象。K他命注射後會有發炎及纖維化標記如TGF-β，fibronectin和type I collagen表現增加的變化。ERK1/2的密度也會隨著K他命注射而增加。結論: K他命注射28天後會造成膀胱的頻繁收縮並減少膀胱適應性。K他命會誘導ERK/1/2活化及TGF-β的過度表現，可能藉此調結K他命所引發膀胱纖維化的病理生理作用。

Objectives. To investigate whether the expression of transforming growth factor-β (TGF-β) is up-regulated in interstitial fibrosis and further evaluate the progression of this disease in rats addicted to ketamine and how long it would take for ketamine affect this change. Methods. Thirty Sprague-Dawley (SD) rats were classified into three groups, each receiving either saline or ketamine (25 mg/kg/day) by intraperitoneal injection over a period of 14 or 28 days. In each group, cystometry and metabolic cage micturition pattern study were performed weekly. The expressions of transforming growth factor-β (TGF-β), fibrosis proteins (fibronectin and type I collagen) and extracellular signal-regulated kinase 1/2 (ERK 1/2) in bladder tissues were examined by Western blot analysis. Results. Ketamine treatment resulted in bladder hyperactivity with a significant increase in micturition frequency and non voiding contraction. Masson's trichrome stain showed ketamine treatment decreased urothelium thickness while increasing collagen to smooth muscle ratio and exacerbated interstitial fibrosis. These alterations were accompanied by increases in the expressions of inflammatory and fibrosis markers, TGF-β, fibronectin and type I collagen after ketamine treatment. The density of the phosphorylated ERK 1/2 was also increased. Conclusion. Ketamine administration resulted in frequent bladder contractions and decreased bladder compliance after 28 days ketamine treatment. Ketamine induced the activation of phosphorylated ERK 1/2 and overexpression of TGF-β, possibly regulating the pathophysiology of fibrosis in ketamine-induced cystitis.