Mandatory role of proteinase-activated receptor 1 in experimental bladder inflammation.
Mandatory role of proteinase-activated receptor 1 in experimental bladder inflammation.
复制标题
蛋白酶激活受体1在实验性膀胱炎症中的强制性作用。
DOI：
10.1186/1472-6793-7-4
复制
发表时间：
2007-03-30
期刊：
影响因子：
--
通讯作者：
Saban, Marcia R
中科院分区：
文献类型：
--
作者：
Saban, Ricardo;D'Andrea, Michael R;Andrade-Gordon, Patricia;Derian, Claudia K;Dozmorov, Igor;Ihnat, Michael A;Hurst, Robert E;Davis, Carole A;Simpson, Cindy;Saban, Marcia R
一般来说，炎症在大多数膀胱病理中起作用，并且代表对损伤的防御反应，通常是双刃剑。特别是，膀胱神经源性炎症涉及肥大细胞和感觉神经的参与。肥大细胞数量增加和类胰蛋白酶释放代表了间质性膀胱炎和其他膀胱炎性疾病的流行病因学理论之一。肥大细胞衍生的类胰蛋白酶以及凝血酶的活性在炎症期间显著增加。这些酶激活特定的G蛋白偶联蛋白酶激活受体（PAR）。到目前为止，已经克隆了四种PAR，不仅所有四种受体在小鼠膀胱的不同细胞类型中高度表达，而且它们的表达在实验性膀胱炎症期间发生改变。我们推测PAR可能将肥大细胞衍生的蛋白酶与膀胱炎症联系起来，因此在膀胱炎的发病机制中起着重要作用。在这里，我们证明，除了小鼠膀胱，所有四个PA受体也表达在J82人尿路上皮细胞系。在小鼠中膀胱内施用PAR活化肽导致以水肿和粒细胞浸润为特征的炎性反应。此外，膀胱内灌注已知的促炎刺激物如E。大肠杆菌脂多糖（LPS），P物质，和抗原的强烈减弱PAR 1，并在较小程度上，由PAR 2缺陷。我们的研究结果揭示了PAR1在膀胱炎症中的压倒性参与，为下游信号转导的参与提供了一个工作模型，并引发了关于PARs在膀胱炎症中作用的可检验的假设。靶向PAR1基因沉默或PAR1阻断的机制是否会改善膀胱炎的临床表现仍有待确定。
In general, inflammation plays a role in most bladder pathologies and represents a defense reaction to injury that often times is two edged. In particular, bladder neurogenic inflammation involves the participation of mast cells and sensory nerves. Increased mast cell numbers and tryptase release represent one of the prevalent etiologic theories for interstitial cystitis and other urinary bladder inflammatory conditions. The activity of mast cell-derived tryptase as well as thrombin is significantly increased during inflammation. Those enzymes activate specific G-protein coupled proteinase-activated receptors (PAR)s. Four PARs have been cloned so far, and not only are all four receptors highly expressed in different cell types of the mouse urinary bladder, but their expression is altered during experimental bladder inflammation. We hypothesize that PARs may link mast cell-derived proteases to bladder inflammation and, therefore, play a fundamental role in the pathogenesis of cystitis. Here, we demonstrate that in addition to the mouse urinary bladder, all four PA receptors are also expressed in the J82 human urothelial cell line. Intravesical administration of PAR-activating peptides in mice leads to an inflammatory reaction characterized by edema and granulocyte infiltration. Moreover, the inflammatory response to intravesical instillation of known pro-inflammatory stimuli such as E. coli lipopolysaccharide (LPS), substance P, and antigen was strongly attenuated by PAR1-, and to a lesser extent, by PAR2-deficiency. Our results reveal an overriding participation of PAR1 in bladder inflammation, provide a working model for the involvement of downstream signaling, and evoke testable hypotheses regarding the role of PARs in bladder inflammation. It remains to be determined whether or not mechanisms targeting PAR1 gene silencing or PAR1 blockade will ameliorate the clinical manifestations of cystitis.