title: Chemotherapy-associated steatohepatitis induced by irinotecan: a novel animal model.
abstract: OBJECTIVE
  Nonalcoholic steatohepatitis (NASH) has been associated with irinotecan (IRI)-based cancer chemotherapy regimens. The purpose of this study was to propose and test a consistent model of IRI-induced NASH, filling a gap in the medical literature.
  
  
  METHODS
  Swiss male mice were distributed in groups (n = 8) and injected with saline (5 mL/kg, i.p.; control) or IRI (25, 50, 75 or 100 mg/kg, i.p.) thrice a week for 7 weeks. Blood samples were collected to measure the serum concentrations of proteins, alanine and aspartate aminotransferases (ALT and AST). Each week animals were euthanized, and the livers were submitted to myeloperoxidase (MPO) assay, lipid dosage, immunohistochemistry for inducible nitric oxide synthase (iNOS), TNF-α and interleukin-1β (IL-1β), and histopathological analysis. Survival rates were also determined.
  
  
  RESULTS
  Mice treated with IRI had a significantly (p < 0.05) lower survival rate than controls and time- and dose-dependent body weight loss. ALT and AST plasma levels increased in relation to controls only in mice receiving IRI 50 mg/kg (p < 0.05). The histopathological features characteristic of NASH was observed, including steatosis, lobular neutrophil infiltration and ballooning hepatocytic degeneration. Additional findings included increased MPO, lipid accumulation, portal neutrophil infiltration, IL-1β and iNOS expression and fibrosis in liver tissues and low serum protein levels compared to controls.
  
  
  CONCLUSIONS
  This is the first report of a consistent model of IRI-induced NASH capable of mimicking clinical findings.
authors.affiliation: Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará (UFC), Rua Cel. Nunes de Melo, 1127-Rodolfo Teófilo, 60430-270, Fortaleza, Ceará, Caixa-Postal: 3157, Brazil, marcelolvcosta@gmail.com.
authors.forename: Marcelo Leite Vieira
authors.initials: ML
authors.lastname: Costa
authors.forename: Roberto César Pereira
authors.initials: RC
authors.lastname: Lima-Júnior
authors.forename: Karoline Sabóia
authors.initials: KS
authors.lastname: Aragão
authors.forename: Raul Pinheiro
authors.initials: RP
authors.lastname: Medeiros
authors.forename: Raphael Dias
authors.initials: RD
authors.lastname: Marques-Neto
authors.forename: Lucas
authors.initials: L
authors.lastname: de Sá Grassi
authors.forename: Leandro Linhares
authors.initials: LL
authors.lastname: Leite
authors.forename: Lorena Guimaraes
authors.initials: LG
authors.lastname: Nunes
authors.forename: José Wilson Benevides
authors.initials: JW
authors.lastname: de Mesquita Neto
authors.forename: Gerly Anne
authors.initials: GA
authors.lastname: de Castro Brito
authors.forename: Marcellus Henrique Loiola Pontes
authors.initials: MH
authors.lastname: de Souza
authors.forename: Paulo Roberto Carvalho
authors.initials: PR
authors.lastname: de Almeida
authors.forename: Ronaldo Albuquerque
authors.initials: RA
authors.lastname: Ribeiro
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism; D001219:Aspartate Aminotransferases / Q000097:blood; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D000077146:Irinotecan; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009195:Peroxidase / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D000077146:Irinotecan; D009195:Peroxidase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D002166:Camptothecin