Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil.
Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil.
Int Immunopharmacol. 2018 Sep;62:96-108. doi: 10.1016/j.intimp.2018.06.031. Epub 2018 Jul 6.
Ifosfamide (IFO) is an antineoplastic drug that is commonly used to treat gynecological and breast cancers. Hemorrhagic cystitis (HC) is a common side effect associated with IFO injection, which courses with neutrophil accumulation and affects 6-50% of patients depending on dose intensity. Here, we investigated the role of neutrophils in this inflammatory process. Female Swiss mice (n = 8/group) were injected with saline, IFO (400 mg/kg, i.p.), fucoidan (a P- and L-selectins inhibitor, 100 mg/kg, i.v.) or IFO + fucoidan (1-100 mg/kg) alone or combined with mesna (80 mg/kg i.p.). Another group of mice received anti-Ly6G antibody (500 μg/mouse, once daily for 2 days) for neutrophil depletion before IFO injection. In another experimental setting, animals received granulocyte colony-stimulating factor (G-CSF, 400 μg/kg), IFO (200 mg/kg), G-CSF (25-400 μg/kg, for 5 days) + IFO (200 mg/kg, i.p.) or fucoidan + G-CSF + IFO. Bladder injury was evaluated 12 h after IFO injection. IFO 400 mg/kg significantly increased visceral hyperalgesia, bladder edema, hemorrhage, vascular permeability, MPO, IL-1β and IL-6 tissue levels, and COX-2 immunostaining and expression versus the saline group (P < 0.05). Conversely, fucoidan (100 mg/kg) significantly attenuated these parameters compared to IFO-injected mice (P < 0.05). Additionally, fucoidan potentiated mesna protective effect when compared with IFO + mesna group (P < 0.05). Accordingly, neutrophil depletion with anti-Ly6G reduced inflammatory parameters and bladder injury compared to IFO (P < 0.05). In contrast, G-CSF enhanced IFO (200 mg/kg)-induced HC, which was significantly attenuated by treatment with fucoidan (P < 0.05). Therefore, neutrophils contribute to the pathogenesis of HC.
异环磷酰胺（IFO）是一种常用的抗肿瘤药物，用于治疗妇科和乳腺癌。出血性膀胱炎（HC）是 IFO 注射的常见副作用，其伴随中性粒细胞积累，根据剂量强度影响 6-50%的患者。在这里，我们研究了中性粒细胞在这个炎症过程中的作用。雌性瑞士小鼠（每组 8 只）注射生理盐水、IFO（400mg/kg，腹腔注射）、褐藻糖胶（P 和 L 选择素抑制剂，100mg/kg，静脉注射）或 IFO 单独或与美司钠（80mg/kg，腹腔注射）联合使用。另一组小鼠在 IFO 注射前接受抗 Ly6G 抗体（500μg/只，每天一次，连用 2 天）以耗尽中性粒细胞。在另一个实验环境中，动物接受粒细胞集落刺激因子（G-CSF，400μg/kg）、IFO（200mg/kg）、G-CSF（25-400μg/kg，连用 5 天）+IFO（200mg/kg，腹腔注射）或褐藻糖胶+G-CSF+IFO。IFO 注射后 12 小时评估膀胱损伤。与生理盐水组相比，IFO 400mg/kg 显著增加内脏痛觉过敏、膀胱水肿、出血、血管通透性、MPO、IL-1β 和 IL-6 组织水平以及 COX-2 免疫染色和表达（P<0.05）。相反，褐藻糖胶（100mg/kg）与 IFO 注射小鼠相比显著减弱这些参数（P<0.05）。此外，与 IFO+mesna 组相比，褐藻糖胶增强了美司钠的保护作用（P<0.05）。因此，与 IFO 相比，抗 Ly6G 耗尽中性粒细胞可减少炎症参数和膀胱损伤（P<0.05）。相反，G-CSF 增强了 IFO（200mg/kg）诱导的 HC，褐藻糖胶可显著减弱其作用（P<0.05）。因此，中性粒细胞有助于 HC 的发病机制。
