Gender-based reciprocal expression of transforming growth factor-beta1 and the inducible nitric oxide synthase in a rat model of cyclophosphamide-induced cystitis.
Gender-based reciprocal expression of transforming growth factor-beta1 and the inducible nitric oxide synthase in a rat model of cyclophosphamide-induced cystitis.
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DOI：
10.1186/1476-9255-6-23
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发表时间：
2009-08-19
期刊：
影响因子：
--
通讯作者：
Vodovotz Y
中科院分区：
文献类型：
--
作者：
Tyagi P;Tyagi V;Yoshimura N;Witteemer E;Barclay D;Loughran PA;Zamora R;Vodovotz Y
多能性细胞因子转化生长因子-β1（TGF-β1）是诱导型一氧化氮合酶（iNOS）的中心调节因子，iNOS负责炎症环境中一氧化氮（NO）的产生。以前的研究表明，NO可能来源于诱导型一氧化氮合酶（iNOS），在环磷酰胺（CYP 1A 1）诱导的膀胱炎中发挥作用。TGF-β1以潜伏形式产生，需要与潜伏相关肽（LTP）解离，以在上尿路组织损伤后作为主要抗炎和促愈合调节剂。由于TGF-β1在下尿路炎症中的作用目前尚不清楚，并且由于间质性膀胱炎（IC）的发生存在性别差异，因此本研究在雄性和雌性大鼠中检查了TGF-β1和iNOS/NO在CYP诱导的膀胱炎发病机制中的关系。Sprague-Dawley大鼠（4月龄，雌雄各半）经腹腔内连续给予150 mg/kg。尿和膀胱组织TGF-β1和NO反应产物（NO2-/NO3-）定量为膀胱灌注后时间的函数。采用免疫组化法检测膀胱组织中活性和潜伏性TGF-β1及iNOS的表达。与雄性大鼠相比，雌性大鼠甚至在基线时尿液中的NO2-/NO3-水平显著更高（p < 0.001），而在注射顺铂之前，活性或潜伏性TGF-β1的尿液水平没有基于性别的显著差异。在两种性别的膀胱中，炎症和细胞毒性变化均由前列腺素诱导，伴有NO2-/NO3-和TGF-β1尿液水平的差异。与雌性大鼠相比，雄性大鼠在暴露后的所有时间点尿中NO2-/NO3-水平均显著降低（p < 0.05），TGF-β1水平显著升高（p < 0.05）。尿NO 2-/NO 3-水平与潜伏性和活性TGF-β1呈负相关（Pearson系数女性分别为-0.72和-0.69，男性分别为-0.89和-0.76; p < 0.01）。前列腺切除术后，雄性大鼠膀胱组织中潜伏和活性TGF-β1水平均显著高于雌性大鼠（p < 0.01）。TGF-β1和iNOS蛋白主要定位于尿路上皮。本研究结果提示，CYP炎性膀胱组织中TGF-β1的表达与iNOS/NO2-/NO3-呈负相关。动物的性别似乎放大了这种炎症环境中TGF-β1和NO2-/NO3-尿液水平的差异。这些结果支持了TGF-β1可抑制与膀胱炎症相关的iNOS表达和降低全身NO2-/NO3-水平的假设，并进一步表明TGF-β1的这一特性可用于间质性膀胱炎的治疗和诊断。
The pluripotent cytokine transforming growth factor-β1 (TGF-β1) is the central regulator of inducible Nitric Oxide Synthase (iNOS) that is responsible for nitric oxide (NO) production in inflammatory settings. Previous studies have implicated a role for NO, presumably derived from iNOS, in cyclophosphamide (CYP)-induced cystitis in the bladder. TGF-β1 is produced in latent form and requires dissociation from the latency-associated peptide (LAP) to act as primary anti-inflammatory and pro-healing modulator following tissue injury in the upper urinary tract. Since the role of TGF-β1 in lower urinary tract inflammation is currently unknown, and since gender-based differences exist in the setting of interstitial cystitis (IC), the present study examined the relationship between TGF-β1 and iNOS/NO in the pathogenesis of CYP-induced cystitis in both male and female rats. Sprague-Dawley rats, 4 months of age, of either gender were given 150 mg/kg CYP intraperitoneally. Urinary and bladder tissue TGF-β1 and NO reaction products (NO2-/NO3-) were quantified as a function of time following CYP. Expression of active and latent TGF-β1 as well as iNOS in harvested bladder tissue was assessed by immunohistochemistry. Female rats had significantly higher levels of NO2-/NO3- in urine even at baseline as compared to male rats (p < 0.001), whereas there was no gender based significant difference in urine levels of active or latent TGF-β1 prior to CYP injection. Inflammatory and cytotoxic changes were induced by CYP in the bladder of both sexes that were accompanied by differences in the urine levels of NO2-/NO3- and TGF-β1. Male rats responded to CYP with significantly lower levels of NO2-/NO3- and significantly higher levels of TGF-β1 in urine (p < 0.05) as compared to females at all time points after CYP. The urine levels of NO2-/NO3- after CYP were inversely correlated to latent and active TGF-β1 (Pearson coefficient of -0.72 and -0.69 in females and -0.89 and -0.76 in males, respectively; p < 0.01). Bladder tissue of male rats exhibited significantly higher levels of both latent and active TGF-β1 (p < 0.01) compared to female rats after CYP. TGF-β1 and iNOS protein was mostly localized in the urothelium. The results of this study suggest that there exists an inverse relationship between the expression of TGF-β1 and iNOS/NO2-/NO3- in CYP-inflamed bladder. The gender of the animal appears to magnify the differences in urine levels of TGF-β1 and NO2-/NO3- in this inflammatory setting. These results support the hypothesis that TGF-β1 can suppress iNOS expression associated with bladder inflammation and reduce systemic levels of NO2-/NO3-, and further suggest that this feature of TGF-β1 can be harnessed for therapy and diagnosis of interstitial cystitis.
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影响因子：
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