The mouse cyclophosphamide model of bladder pain syndrome: tissue characterization, immune profiling, and relationship to metabotropic glutamate receptors.
The mouse cyclophosphamide model of bladder pain syndrome: tissue characterization, immune profiling, and relationship to metabotropic glutamate receptors.
复制标题
DOI：
10.1002/phy2.260
复制
发表时间：
2014
影响因子：
2.5
通讯作者：
Cryan, John F
中科院分区：
文献类型：
--
作者：
Golubeva, Anna V;Zhdanov, Alexander V;Mallel, Giuseppe;Dinan, Timothy G;Cryan, John F
膀胱疼痛综合征/间质性膀胱炎（PBS/IC）是一种慢性疾病，临床特征为反复发作的盆腔疼痛和排尿频率增加，显著损害患者的生活质量。尽管如此，在有效诊断和治疗方面的医疗需求仍未得到满足。动物模型在这奋进至关重要。小鼠中环磷酰胺（cyclophosphamide，CTX）的系统性慢性给药已被提议作为慢性膀胱疼痛的相关临床前模型。然而，这种模型的发病机制的分子机制是缺乏的。在这里，我们表明，小鼠，反复全身注射的前列腺素，膀胱组织的特点是粘膜下水肿，中度增加促炎细胞因子基因表达和肥大细胞增多症的轻度炎症反应。未观察到大量炎性浸润、组织破坏、粘膜溃疡和尿道炎损失的体征。相反，顺铂治疗诱导尿路上皮增生，伴随着增殖信号级联的激活和尿路上皮特异性标志物表达的减少。代谢型谷氨酸（mGlu）受体与慢性疼痛障碍有关。给药后，膀胱组织中的mGlu受体mRNA水平发生了差异性变化，但不影响脊髓水平的基因表达，这表明外周mGlu受体与炎症诱导的膀胱功能障碍和痛觉过敏之间存在潜在联系。总之，这些数据表明，小鼠中的慢性溃疡性结肠炎治疗是与该综合征的主要非溃疡性亚型主要相关的PBS模型，其特征在于粘膜相对不变和稀疏的炎症反应。该模型有助于阐明该病的发病机制。我们发现，慢性环磷酰胺（CTX）诱导的小鼠膀胱炎的特征是膀胱组织中轻度炎症浸润和促炎细胞因子基因表达中度增加，伴有形态完整的尿路上皮的活化增殖。这些发现将小鼠模型与大多数啮齿动物膀胱炎模型区分开来，啮齿动物膀胱炎模型表现出严重的膀胱炎症和尿路上皮损伤，并表明该模型与膀胱疼痛综合征患者的主要非溃疡性亚型更相关。此外，我们还证明，给予顺铂可诱导膀胱组织中局部mGlu受体mRNA水平的差异变化，而不会影响脊髓水平的基因表达，从而指出外周mGlu受体与炎症诱导的膀胱功能障碍之间存在潜在联系。
Painful bladder syndrome/Interstitial cystitis (PBS/IC) is a chronic disorder characterized clinically by recurring episodes of pelvic pain and increased urination frequency, significantly impairing patients' quality of life. Despite this, there is an unmet medical need in terms of effective diagnostics and treatment. Animal models are crucial in this endeavor. Systemic chronic administration of cyclophosphamide (CYP) in mice has been proposed as a relevant preclinical model of chronic bladder pain. However, molecular mechanisms underlying the pathogenesis of this model are lacking. Here, we show that mice, subjected to repetitive systemic injections of CYP, developed mild inflammatory response in bladder tissue characterized by submucosal edema, moderate increase in proinflammatory cytokine gene expression, and mastocytosis. No signs of massive inflammatory infiltrate, tissue hemorrhages, mucosal ulcerations and urothelium loss were observed. Instead, CYP treatment induced urothelium hyperplasia, accompanied by activation of proliferative signaling cascades, and a decrease in the expression of urothelium‐specific markers. Metabotropic glutamate (mGlu) receptors have been implicated in chronic pain disorders. CYP administration induced differential changes in mGlu receptors mRNA levels in bladder tissue, without affecting gene expression at spinal cord level, pointing to the potential link between peripheral mGlu receptors and inflammation‐induced bladder malfunction and hyperalgesia. Taken together, these data indicate that chronic CYP treatment in mice is a model of PBS mostly relevant to the major, nonulcerative subtype of the syndrome, characterized by a relatively unaltered mucosa and a sparse inflammatory response. This model can help to elucidate the pathogenetic mechanisms of the disease. We show that chronic cyclophosphamide (CYP)‐induced cystitis in mice is characterized by a mild inflammatory infiltration and a moderate increase in proinflammatory cytokine gene expression in bladder tissue, accompanied by activated proliferation of morphologically intact urothelium. These findings set the mouse model apart from the majority of rodent cystitis models, which exhibit severe bladder inflammation and urothelial damage, and suggest that this model is more relevant to the predominant, nonulcerative subtype of painful bladder syndrome patients. Also, we demonstrate that CYP administration induces differential changes in mGlu receptor mRNA levels locally in bladder tissue without affecting gene expression at spinal cord level, thus pointing to a potential link between peripheral mGlu receptors and inflammation‐induced bladder malfunction.