title: Molecular changes induced in rat liver by hemorrhage and effects of melanocortin treatment.
abstract: BACKGROUND
  Melanocortin peptides improve hemodynamic parameters and prevent death during severe hemorrhagic shock. In the present research we determined influences of a synthetic melanocortin 1/4 receptor agonist on the molecular changes that occur in rat liver during hemorrhage.
  
  
  METHODS
  Controlled-volume hemorrhage was performed in adult rats under general anesthesia by a stepwise blood withdrawal until mean arterial pressure fell to 40 mmHg. Then rats received either saline or the synthetic melanocortin 1/4 receptor agonist Butir-His-D-Phe-Arg-Trp-Sar-NH2 (Ro27-3225; n = 6-8 per group). Hemogasanalysis was performed throughout a 60-min period. Gene expression in liver samples was determined at 1 or 3 h using quantitative real-time polymerase chain reaction.
  
  
  RESULTS
  At 1 h, in saline-treated shocked rats, there were significant increases in activating transcription factor 3 (Atf3), early growth response 1 (Egr1), heme oxygenase (decycling) 1 (Hmox1), FBJ murine osteosarcoma viral oncogene homolog (Fos), and jun oncogene (Jun). These changes were prevented by Ro27-3225 (mean ± SEM: Atf3 152.83 ± 58.62 vs. 579.00 ± 124.13, P = 0.002; Egr1 13.21 ± 1.28 vs. 26.63 ± 1.02, P = 0.001; Hmox1 3.28 ± 0.31 vs. 166.54 ± 35.03, P = 0.002; Fos 4.36 ± 1.03 vs. 14.90 ± 3.44, P < 0.001; Jun 6.62 ± 1.93 vs. 15.07 ± 2.09, P = 0.005; respectively). Increases in alpha-2-macroglobulin (A2m), heat shock 70kD protein 1A (Hspa1a), erythropoietin (Epo), and interleukin-6 (Il6) occurred at 3 h in shocked rats and were prevented by Ro27-3225 treatment (A2m 6.90 ± 0.82 vs. 36.73 ± 4.00, P < 0.001; Hspa1a 10.34 ± 3.28 vs. 25.72 ± 3.64, P = 0.001; Epo 0.49 ± 0.13 vs. 2.37 ± 0.73, P = 0.002; Il6 1.05 ± 0.15 vs. 1.88 ± 0.23, P < 0.001; respectively). Further, at 3 h in shocked rats treated with Ro27-3225 there were significant increases in tight junction protein 1 (Tjp1; 27.30 ± 2.43 vs. 5.03 ± 1.68, P < 0.001) and nuclear receptor subfamily 4, group A, member 1 (Nr4a1; 91.03 ± 16.20 vs. 30.43 ± 11.0, P = 0.01) relative to sham animals. Treatment with Ro27-3225 rapidly restored blood pressure, hemogasanalysis parameters, and lactate blood levels.
  
  
  CONCLUSIONS
  Melanocortin treatment significantly prevents most of the systemic and hepatic detrimental changes induced by hemorrhage.
authors.affiliation: Center for Surgical Research, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Lonati
authors.forename: Andrea
authors.initials: A
authors.lastname: Sordi
authors.forename: Daniela
authors.initials: D
authors.lastname: Giuliani
authors.forename: Luca
authors.initials: L
authors.lastname: Spaccapelo
authors.forename: Patrizia
authors.initials: P
authors.lastname: Leonardi
authors.forename: Andrea
authors.initials: A
authors.lastname: Carlin
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ottani
authors.forename: Maria
authors.initials: M
authors.lastname: Galantucci
authors.forename: Paolo
authors.initials: P
authors.lastname: Grieco
authors.forename: Anna
authors.initials: A
authors.lastname: Catania
authors.forename: Salvatore
authors.initials: S
authors.lastname: Guarini
mesh_terms: D000818:Animals; D053486:Melanocortins / Q000378:metabolism / Q000627:therapeutic use*; D010455:Peptides / Q000378:metabolism / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D044102:Receptor, Melanocortin, Type 1 / Q000819:agonists / Q000502:physiology; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists / Q000502:physiology; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D053486:Melanocortins; D010455:Peptides; D044102:Receptor, Melanocortin, Type 1; D044105:Receptor, Melanocortin, Type 4; C560214:butir-His-Phe-Arg-Trp-Sar-NH2