title: Target Inhibition of IL-1 Receptor Prevents Ifosfamide Induced Hemorrhagic Cystitis in Mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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, muscle contractility, and for cystometrography. Inflammatory cell infiltration was assessed by myeloperoxidase assay and flow cytometry.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Caio A V G
authors.initials: CA
authors.lastname: Leite
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, São Paulo, Brazil.
authors.forename: Viviane T L
authors.initials: VT
authors.lastname: Alencar
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, São Paulo, Brazil.
authors.forename: Davi L R
authors.initials: DL
authors.lastname: Melo
authors.affiliation: Department of Clinics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: José M S C
authors.initials: JM
authors.lastname: Mota
authors.affiliation: Department of Immunology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: Paulo H
authors.initials: PH
authors.lastname: Melo
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, São Paulo, Brazil.
authors.forename: Lívia T C
authors.initials: LT
authors.lastname: Mourão
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, São Paulo, Brazil.
authors.forename: Deysi V T
authors.initials: DV
authors.lastname: Wong
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, São Paulo, Brazil.
authors.forename: Pedro J C
authors.initials: PJ
authors.lastname: Magalhães
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, São Paulo, Brazil.
authors.forename: Armênio A
authors.initials: AA
authors.lastname: Santos
authors.affiliation: Department of Morphology, Faculty of Medicine, Federal University of Ceará, São Paulo, Brazil.
authors.forename: Gerly A C
authors.initials: GA
authors.lastname: Brito
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, São Paulo, Brazil.
authors.forename: Roberto C P
authors.initials: RC
authors.lastname: Lima-Júnior
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.affiliation: 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. Electronic address: ribeiror21@gmail.com.
authors.forename: Ronaldo A
authors.initials: RA
authors.lastname: Ribeiro
mesh_terms: D000818:Animals; D003556:Cystitis / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006470:Hemorrhage / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D007069:Ifosfamide / Q000633:toxicity*; D000069285:Infliximab / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D001743:Urinary Bladder / Q000187:drug effects / Q000473:pathology
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D007069:Ifosfamide
keywords: antibodies; cystitis; interleukin 1 receptor antagonist protein; interstitial; monoclonal; tumor necrosis factor-alpha; urinary bladder