ABSTRACT
Title
Molecular changes in rat liver during hemorrhagic shock and effects of melanocortin treatment
Authors
C. Lonati1, L. Spaccapelo2, A. Sordi1, A. Carlin1, P. Leonardi1, M. Galantucci2, E. Ardimento2, A. Ottani2, D. Giuliani2, S. Guarini2, A. Catania1
1Center for Preclinical Investigation and Center for Surgical Research, Fondazione IRCCS Cà Granda - Ospedale Maggiore Policlinico, Milano, Italy
2Dept. of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, Modena, Italy
Abstract
Previous research indicates that treatment with melanocortin peptides improves hemodynamic parameters and prevents death during severe hemorrhagic shock in animals and humans (Guarini et al., 1990, 2004; Noera et al., 2001). The aim of the present research was to determine the molecular changes that occur in rat liver during hemorrhagic shock and influences of treatment with the synthetic melanocortin 1/4 receptor agonist RO27-3225 on such changes. Controlled-volume hemorrhagic shock was induced in adult rats under general anesthesia, by a stepwise (within 20-25 min) blood withdrawal until mean arterial pressure fell to and stabilized at 40 mmHg (Bowmann et al., 2005). Arterial blood pressure and respiratory rate were monitored until 1 and 3h after shock. Shocked rats received intravenously either saline or RO27-3225 at a dose (90 µg/kg) previously resulted to be maximally effective in reversing hemorrhagic shock (Giuliani et al., 2007). Gene expression in liver samples was determined at 1 and 3 h after shock using quantitative realtime PCR. Hemorrhagic shock altered liver expression profile. Indeed, hemorrhage induced expression of several genes including activating transcription factor 3 (Atf3), heme oxygenase 1 (Hmox1), alpha-2-macroglobulin (A2m), erythropoietin (Epo) and heat shock 70kD protein 1A (Hspa1a). Treatment with RO27-3225 almost completely restored arterial blood pressure and respiratory function, and broadly modulated gene expression. Hemorrhagic shock alters gene expression in the liver and melanocortin treatment significantly prevents most of these changes. Because blood replacement is not sufficient to prevent systemic inflammation and tissue injury caused by hemorrhagic shock, a melanocortin-based treatment could exert beneficial effects.
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Guarini et al. (1990). Crit Care Med.18:862-865.
Guarini et al. (2004). Cardiovasc Res. 63:357-365.
Noera et al. (2001). Lancet.358: 469-470.
Bowmann et al. (2005). Physiol Genomics. 23:275-286.
Giuliani et al.(2007). Br J Pharmacol. 150:595-603.
Guarini et al. (1990). Crit Care Med.18:862-865.
Guarini et al. (2004). Cardiovasc Res. 63:357-365.
Noera et al. (2001). Lancet.358: 469-470.