RESUMO
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 (nâ¯=â¯8/group) were injected with saline, IFO (400â¯mg/kg, i.p.), fucoidan (a P- and L-selectins inhibitor, 100â¯mg/kg, i.v.) or IFOâ¯+â¯fucoidan (1-100â¯mg/kg) alone or combined with mesna (80â¯mg/kg i.p.). Another group of mice received anti-Ly6G antibody (500⯵g/mouse, once daily for 2â¯days) for neutrophil depletion before IFO injection. In another experimental setting, animals received granulocyte colony-stimulating factor (G-CSF, 400⯵g/kg), IFO (200â¯mg/kg), G-CSF (25-400⯵g/kg, for 5â¯days)â¯+â¯IFO (200â¯mg/kg, i.p.) or fucoidanâ¯+â¯G-CSFâ¯+â¯IFO. Bladder injury was evaluated 12â¯h after IFO injection. IFO 400â¯mg/kg significantly increased visceral hyperalgesia, bladder edema, hemorrhage, vascular permeability, MPO, IL-1ß and IL-6 tissue levels, and COX-2 immunostaining and expression versus the saline group (Pâ¯<â¯0.05). Conversely, fucoidan (100â¯mg/kg) significantly attenuated these parameters compared to IFO-injected mice (Pâ¯<â¯0.05). Additionally, fucoidan potentiated mesna protective effect when compared with IFOâ¯+â¯mesna group (Pâ¯<â¯0.05). Accordingly, neutrophil depletion with anti-Ly6G reduced inflammatory parameters and bladder injury compared to IFO (Pâ¯<â¯0.05). In contrast, G-CSF enhanced IFO (200â¯mg/kg)-induced HC, which was significantly attenuated by treatment with fucoidan (Pâ¯<â¯0.05). Therefore, neutrophils contribute to the pathogenesis of HC.