Bloqueio do receptor da interleucina-1 com Anakinra Inibe a cistite hemorrágica induzida por ifosfamida

Abstract

Hemorrhagic cystitis (HC) induced by ifosfamide (IFO) is an important clinical complication in patients with cancer. Despite prophylaxis, HC is observed. The role of interleukin-1 (IL-1) and tumor necrosis factor (TNF) in the pathogenesis of HC provides targets for treatment. Thus, this study aimed to evaluate the protective effect of the IL-1 receptor antagonist (anakinra) and anti-TNF-alpha antibody (infliximab) in experimental HC-induced by IFO in mice. Swiss , C57BL6 , IL -1R-/-, CASP1-/-, TNFR1-/-, TNFR1/R2-/- mice were used. Animals were submitted to pre- treatment with anakinra 100 mg/ kg, ip or infliximab 5 mg/ Kg, ip, or saline ip, 1h after, they were treated with IFO 400 mg/ kg ip, and 12 h after IFO injection they were killed. Then, it was performed resection of the bladder for macroscopic and histopathological evaluation, vascular permeability assay, myeloperoxidase assay, muscle contractility, cistometrogram and flow cytometry to neutrophils and macrophages. Some animals prior to death, were subjected to evaluation of visceral nociception. Anakinra was able to attenuate hemorrhage, edema, neutrophil infiltration, visceral hypernociception and bladder dysfunction. In addition, it was observed reduction of inflammatory parameters and bladder infiltration of neutrophils and macrophages in IL -1R-/- mice, when compared to wild type animals. In contrast, caspase-1-/- mice did not change the inflammatory pattern when compared to wild type animals. Conversely, infliximab inhibited bladder edema and visceral hypernociception, but did not inhibit hemorrhage, infiltration of neutrophils and macrophages and bladder dysfunction. A reduction in bladder edema was also observed in TNFR1-/- mice, when compared with wild type animals, although TNFR1-/- mice did not block infiltration of neutrophils and macrophages. In other hand, TNFR1/R2-/- mice treated with IFO showed a deterioration of HC. Thus, this study shows the efficacy of anakinra in preventing the HC syndrome induced by IFO, and efficacy of infliximab in inhibiting hypernociception. In addition, the pathogenesis of HC appears to be independent of IL- 1β produced by caspase-1 or IL-1α dependent. Furthermore, HC appears to be partially dependent of TNFR1, but possibly arising from a physiological protection TNFR2.