title: Early propranolol treatment induces lung heme-oxygenase-1, attenuates metabolic dysfunction, and improves survival following experimental sepsis.
abstract: BACKGROUND
  Pharmacological agents that block beta-adrenergic receptors have been associated with improved outcome in burn injury. It has been hypothesized that injuries leading to a hypermetabolic state, such as septic shock, may also benefit from beta-blockade; however, outcome data in experimental models have been contradictory. Thus, we investigated the effect of beta-blockade with propranolol on survival, hemodynamics, lung heat shock protein (HSP) expression, metabolism and inflammatory markers in a rat cecal ligation and puncture (CLP) model of sepsis.
  
  
  METHODS
  Sprague-Dawley rats receiving either repeated doses (30 minutes pre-CLP and every 8 hours for 24 hours postoperatively) of propranolol or control (normal saline), underwent CLP and were monitored for survival. Additionally, lung and blood samples were collected at 6 and 24 hours for analysis. Animals also underwent monitoring to evaluate global hemodynamics.
  
  
  RESULTS
  Seven days following CLP, propranolol improved survival versus control (P < 0.01). Heart rates in the propranolol-treated rats were approximately 23% lower than control rats (P < 0.05) over the first 24 hours, but the mean arterial blood pressure was not different between groups. Metabolic analysis of lung tissue demonstrated an increase in lung ATP/ADP ratio and NAD+ content and a decreased ratio of polyunsaturated fatty acids to monounsaturated fatty acids (PUFA/MUFA). Cytokine analysis of the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) demonstrated decreased expression of TNF-alpha in both lung and plasma at 24 hours post CLP induced sepsis. Finally, propranolol led to a significant increase in lung hemeoxygenase-1 expression, a key cellular protective heat shock protein (HSP) in the lung. Other lung HSP expression was unchanged.
  
  
  CONCLUSIONS
  These results suggest that propranolol treatment may decrease mortality during sepsis potentially via a combination of improving metabolism, suppressing aspects of the inflammatory response and enhancing tissue protection.
authors.forename: Joel
authors.initials: J
authors.lastname: Wilson
authors.forename: David
authors.initials: D
authors.lastname: Higgins
authors.forename: Haley
authors.initials: H
authors.lastname: Hutting
authors.forename: Natalie
authors.initials: N
authors.lastname: Serkova
authors.forename: Christine
authors.initials: C
authors.lastname: Baird
authors.forename: Ludmila
authors.initials: L
authors.lastname: Khailova
authors.forename: Kelly
authors.initials: K
authors.lastname: Queensland
authors.forename: Zung
authors.initials: Z
authors.lastname: Vu Tran
authors.forename: Lindsay
authors.initials: L
authors.lastname: Weitzel
authors.forename: Paul E
authors.initials: PE
authors.lastname: Wischmeyer
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage*; D000818:Animals; D004334:Drug Administration Schedule; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D008168:Lung / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008659:Metabolic Diseases / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D011433:Propranolol / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D015996:Survival Rate / Q000639:trends; D016896:Treatment Outcome
chemical_list: D000319:Adrenergic beta-Antagonists; D011433:Propranolol; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat
references.citation: Free Radic Biol Med. 2000 Apr 15;28(8):1191-6
references.pmid: 10889448
references.citation: Crit Care Med. 2010 Feb;38(2):688-9
references.pmid: 20083925
references.citation: Curr Med Chem. 2009;16(9):1082-90
references.pmid: 19275613
references.citation: Crit Care Med. 2007 Sep;35(9 Suppl):S616-20
references.pmid: 17713418
references.citation: Surg Clin North Am. 1975 Jun;55(3):721-8
references.pmid: 1135753
references.citation: Am J Physiol Endocrinol Metab. 2003 Oct;285(4):E783-9
references.pmid: 12812919
references.citation: Crit Care Med. 2005 Oct;33(10):2294-301
references.pmid: 16215384
references.citation: Mol Pharmacol. 2009 Jul;76(1):173-82
references.pmid: 19366789
references.citation: Kidney Int Suppl. 2001 Feb;78:S148-54
references.pmid: 11169001
references.citation: Crit Care Med. 2005 Jun;33(6):1206-13
references.pmid: 15942332
references.citation: J Hepatol. 2006 May;44(5):956-62
references.pmid: 16223541
references.citation: JPEN J Parenter Enteral Nutr. 2012 Sep;36(5):551-5
references.pmid: 22544840
references.citation: Crit Care Med. 2012 Oct;40(10):2768-72
references.pmid: 22824934
references.citation: Crit Care Med. 2010 Feb;38(2):388-94
references.pmid: 19829100
references.citation: Eur Surg Res. 2003 Nov-Dec;35(6):486-91
references.pmid: 14593232
references.citation: Intensive Care Med. 2011 Nov;37(11):1849-56
references.pmid: 21847651
references.citation: Int J Hypertens. 2012;2012:859235
references.pmid: 22518295
references.citation: J Pediatr Surg. 1989 Aug;24(8):806-10; discussion 810-1
references.pmid: 2769550
references.citation: Shock. 2009 Feb;31(2):113-9
references.pmid: 18636043
references.citation: J Endotoxin Res. 2006;12(3):151-70
references.pmid: 16719987
references.citation: J Trauma. 2007 Mar;62(3):676-81
references.pmid: 17414346
references.citation: Resuscitation. 2007 Feb;72(2):286-94
references.pmid: 17118511
references.citation: Am J Physiol. 1999 Mar;276(3):L443-51
references.pmid: 10070108
references.citation: Ann Surg. 1988 Oct;208(4):484-92
references.pmid: 3052328
references.citation: Crit Care Med. 2010 Oct;38(10 Suppl):S608-12
references.pmid: 21164404
references.citation: Burns. 1990 Aug;16(4):259-64
references.pmid: 2257068
references.citation: Crit Care. 2009;13(5):230
references.pmid: 19863760
references.citation: Shock. 2009 May;31(5):515-20
references.pmid: 18791493
references.citation: J Trauma. 2008 Feb;64(2):477-86
references.pmid: 18301218
references.citation: J Burn Care Rehabil. 1997 May-Jun;18(3):223-7
references.pmid: 9169945