Hemorrhagic cystitis is an important dose limiting side effect of ifosfamide based cancer chemotherapy. Despite chemoprophylaxis inflammation can still be found in cystoscopy guided biopsies. Previous studies confirmed the role of TNF-α and IL-1β.
We evaluated the protective effect of the IL-1R antagonist anakinra and the anti-TNF-α antibody infliximab in experimental ifosfamide induced hemorrhagic cystitis.
Hemorrhagic cystitis was induced by an injection of ifosfamide (400 mg/kg intraperitoneally) in Swiss wild-type C57Bl/6, IL-1R(-/-), TNFR1(-/-) or TNFR1/R2(-/-) mice. Mice were treated 30 minutes before ifosfamide with anakinra (100 mg/kg intraperitoneally), infliximab (5 mg/kg intraperitoneally) or vehicle. Visceral nociception was evaluated after hemorrhagic cystitis induction. At 12 hours the animals were sacrificed. Bladders were harvested to assess bladder wet weight, vascular permeability, macroscopic and microscopic findings and muscle contractility, and for cystometrography. Inflammatory cell infiltration was assessed by myeloperoxidase assay and flow cytometry.
Anakinra attenuated hemorrhage, edema, neutrophil infiltration, visceral hyperalgesia and bladder dysfunction. IL-1R(-/-) mice also showed milder hemorrhagic cystitis. Infliximab inhibited bladder edema and visceral hyperalgesia without preventing hemorrhage, bladder dysfunction, neutrophils or accumulation. Additionally, the lack of TNFR1 decreased bladder edema but not cell infiltration whereas concomitant deficiency of TNFR1 and TNFR2 resulted in worse hemorrhagic cystitis.
Anakinra is effective for preventing experimentally ifosfamide induced hemorrhagic cystitis. It seems that neutrophil and macrophage infiltration in this circumstance depends on IL-1 signaling through IL1R. Possibly TNFR2 has a protective role in hemorrhagic cystitis.
The Journal of urology. 2015 Jul 26 [Epub ahead of print]
Caio A V G Leite, Viviane T L Alencar, Davi L R Melo, José M S C Mota, Paulo H Melo, Lívia T C Mourão, Deysi V T Wong, Pedro J C Magalhães, Armênio A Santos, Gerly A C Brito, Roberto C P Lima-Júnior, Fernando Q Cunha, Ronaldo A Ribeiro
Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, São Paulo, Brazil; Department of Clinical Oncology, Haroldo Juaçaba Hospital, Cancer Institute of Ceará, Fortaleza, Brazil. , Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, São Paulo, Brazil. , Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, São Paulo, Brazil. , Department of Clinics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil. , Department of Immunology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil. , Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, São Paulo, Brazil. , Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, São Paulo, Brazil. , Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, São Paulo, Brazil. , Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, São Paulo, Brazil. , Department of Morphology, Faculty of Medicine, Federal University of Ceará, São Paulo, Brazil. , Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, São Paulo, Brazil. , Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil. , Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, São Paulo, Brazil; Department of Clinical Oncology, Haroldo Juaçaba Hospital, Cancer Institute of Ceará, Fortaleza, Brazil.