Girard Beatrice M, Campbell Susan E, Vizzard Margaret A
The Larner College of Medicine at The University of Vermont, Department of Neurological Sciences, Burlington, VT, 05405.
Front Urol. 2023;3. doi: 10.3389/fruro.2023.1079790. Epub 2023 Mar 22.
Symptom exacerbation due to stress is prevalent in many disease states, including functional disorders of the urinary bladder (e.g., overactive bladder (OAB), interstitial cystitis/bladder pain syndrome (IC/BPS)); however, the mechanisms underlying the effects of stress on micturition reflex function are unclear. In this study we designed and evaluated a stress-induced symptom exacerbation (SISE) mouse model that demonstrates increased urinary frequency and somatic (pelvic and hindpaw) sensitivity. Cyclophosphamide (CYP) (35 mg/kg; i.p., every 48 hours for a total of 4 doses) or 7 days of repeated variate stress (RVS) did not alter urinary bladder function or somatic sensitivity; however, both CYP alone and RVS alone significantly (p ≤ 0.01) decreased weight gain and increased serum corticosterone. CYP treatment when combined with RVS for 7 days (CYP+RVS) significantly (p ≤ 0.01) increased serum corticosterone, urinary frequency and somatic sensitivity and decreased weight gain. CYP+RVS exposure in mice significantly (p ≤ 0.01) increased (2.6-fold) voiding frequency as we determined using conscious, open-outlet cystometry. CYP+RVS significantly (p ≤ 0.05) increased baseline, threshold, and peak micturition pressures. We also evaluated the expression of NGF, BDNF, CXC chemokines and IL-6 in urinary bladder in CYP alone, RVS alone and CYP+RVS mouse cohorts. Although all treatments or exposures increased urinary bladder NGF, BDNF, CXC and IL-6 content, CYP+RVS produced the largest increase in all inflammatory mediators examined. These results demonstrated that CYP alone or RVS alone creates a change in the inflammatory environment of the urinary bladder but does not result in a change in bladder function or somatic sensitivity until CYP is combined with RVS (CYP+RVS). The SISE model of CYP+RVS will be useful to develop testable hypotheses addressing underlying mechanisms where psychological stress exacerbates symptoms in functional bladder disorders leading to identification of targets and potential treatments.
应激导致的症状加重在许多疾病状态中都很常见，包括膀胱功能障碍（如膀胱过度活动症（OAB）、间质性膀胱炎/膀胱疼痛综合征（IC/BPS））；然而，应激对排尿反射功能影响的潜在机制尚不清楚。在本研究中，我们设计并评估了一种应激诱导的症状加重（SISE）小鼠模型，该模型表现出排尿频率增加和躯体（盆腔和后爪）敏感性增加。环磷酰胺（CYP）（35mg/kg；腹腔注射，每48小时一次，共4剂）或7天的重复可变应激（RVS）均未改变膀胱功能或躯体敏感性；然而，单独使用CYP和单独使用RVS均显著（p≤0.01）降低体重增加并增加血清皮质酮。CYP治疗与RVS联合7天（CYP+RVS）显著（p≤0.01）增加血清皮质酮、排尿频率和躯体敏感性，并降低体重增加。正如我们使用清醒、开放出口膀胱测压法所确定的，小鼠暴露于CYP+RVS显著（p≤0.01）增加（2.6倍）排尿频率。CYP+RVS显著（p≤0.05）增加基线、阈值和排尿峰值压力。我们还评估了单独使用CYP、单独使用RVS和CYP+RVS小鼠组膀胱中NGF、BDNF、CXC趋化因子和IL-6的表达。尽管所有治疗或暴露均增加了膀胱NGF、BDNF、CXC和IL-6含量，但CYP+RVS在所有检测的炎症介质中产生的增加最大。这些结果表明，单独使用CYP或单独使用RVS会改变膀胱的炎症环境，但在CYP与RVS联合（CYP+RVS）之前不会导致膀胱功能或躯体敏感性改变。CYP+RVS的SISE模型将有助于提出可检验的假设，以探讨心理应激加重功能性膀胱疾病症状的潜在机制，从而确定靶点和潜在治疗方法。
