The Bay Pines VA Healthcare System, Bay Pines, Florida, USA.
Neurourol Urodyn. 2010 Nov;29(8):1451-7. doi: 10.1002/nau.20878.
Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine found pre-formed in the urothelium. During inflammation, MIF is released into the bladder lumen and bladder MIF mRNA is upregulated. Since MIF also has tautomerase activity and blocking tautomerase activity also blocks MIF's biological activity, we hypothesized that blocking MIF's tautomerase activity would prevent bladder inflammation. Therefore, we examined the effects of a MIF tautomerase inhibitor (ISO-1; also blocks biological activity) on cyclophosphamide (CYP)-induced cystitis in mice.
Mice receiving CYP (300 mg/kg; i.p.) to induce cystitis or saline (control) were treated either with ISO-1 (20 mg/kg; i.p.; daily) or vehicle (20% DMSO; i.p.; daily) for 2 days. After 2 days, micturition volume and frequency in awake mice were recorded and also mechanical sensitivity to abdominal stimulation using von Frey monofilaments. Bladders were collected under anesthesia and examined histologically, nerve growth factor levels were assayed in bladder homogenates, and production of inflammatory cytokines in the bladder was determined using a targeted array.
CYP treatment resulted in decreased micturition volume, increased frequency, decreased threshold, increased histological signs of cystitis, increased bladder NGF levels and production of inflammatory cytokines when compared to the control group. Treatment with ISO-1 prevented or greatly decreased all these changes.
Antagonizing MIF's activity with a systemic MIF tautomerase inhibitor was able to prevent or greatly reduced chemical cystitis in mice, thus indicating the MIF mediates bladder inflammation in this model. MIF represents a novel and important modulator of cystitis.
巨噬细胞移动抑制因子（MIF）是一种前炎症细胞因子，存在于尿路上皮细胞中。在炎症过程中，MIF 被释放到膀胱腔中，膀胱 MIFmRNA 上调。由于 MIF 还具有互变异构酶活性，并且阻断互变异构酶活性也可以阻止 MIF 的生物学活性，因此我们假设阻断 MIF 的互变异构酶活性将预防膀胱炎症。因此，我们研究了 MIF 互变异构酶抑制剂（ISO-1；同时阻断生物活性）对环磷酰胺（CYP）诱导的小鼠膀胱炎的影响。
用 CYP（300mg/kg；腹腔注射）诱导膀胱炎的小鼠或生理盐水（对照）接受 ISO-1（20mg/kg；腹腔注射；每天）或载体（20%DMSO；腹腔注射；每天）治疗 2 天。2 天后，在清醒的小鼠中记录排尿量和频率，并用冯弗雷单丝测量腹部刺激的机械敏感性。在麻醉下收集膀胱，进行组织学检查，测定膀胱匀浆中神经生长因子水平，并使用靶向阵列测定膀胱中炎症细胞因子的产生。
与对照组相比，CYP 处理导致排尿量减少、频率增加、阈值降低、膀胱炎组织学迹象增加、膀胱 NGF 水平升高和炎症细胞因子产生增加。用 ISO-1 治疗可预防或大大减少所有这些变化。
用系统的 MIF 互变异构酶抑制剂拮抗 MIF 的活性能够预防或大大减少小鼠的化学性膀胱炎，这表明 MIF 在该模型中介导了膀胱炎症。MIF 代表了一种新的和重要的膀胱炎调节剂。
