Document Detail

Differential expression pattern of heme oxygenase-1/heat shock protein 32 and nitric oxide synthase-II and their impact on liver injury in a rat model of hemorrhage and resuscitation.
MedLine Citation:
PMID:  10628624     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: To investigate the role of the vasodilator systems heme oxygenase-1/heat shock protein 32 (HO-1/HSP32) and nitric oxide synthase-II (NOS-II), generating carbon monoxide and nitric oxide respectively, as modulators of liver injury in an experimental model of reversible hemorrhagic shock. DESIGN: Prospective controlled laboratory study. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rats weighing 250-350 g. INTERVENTIONS: Animals were anesthetized and assigned to a hemorrhagic shock (mean arterial pressure, 35-40 mmHg for 60 mins) or a sham protocol. On the basis of the time course of gene expression, HO-1/HSP32 or NOS-II was blocked 5 hrs after onset of resuscitation. To assess the role of the antioxidative properties of the heme oxygenase (HO) pathway in additional experiments, Trolox, a potent antioxidant, was administered at the time of blockade of HO. Liver injury was assessed morphometrically and by plasma alpha-glutathione-S-transferase (alpha-GST) release 11 hours after onset of resuscitation. MEASUREMENTS AND MAIN RESULTS: Hemorrhage and resuscitation increased HO-1/HSP32 messenger RNA and protein primarily in parenchymal cells, and a faint induction of NOS-II, restricted to nonparenchymal cells, was observed. Inhibition of the HO pathway with tin protoporphyrin-IX (SnPP-IX) increased the incidence of pericentral necrosis (intact acini: shock/vehicle 68.8%; shock/SnPP-IX 42.6%) and alpha-GST levels (sham 94+/-24 microg/L; shock/vehicle 377+/-139 microg/L; shock/SnPP-IX 1708+/-833 microg/L), whereas blockade of NOS-II with S-methylisothiourea did not affect liver injury. Coadministration of Trolox failed to attenuate the aggravation of necrosis associated with blockade of HO, whereas alpha-GST levels were reduced (intact acini: shock/vehicle/Trolox 82.1%, shock/SnPP-IX/Trolox 42.7%; alpha-GST: shock/vehicle/Trolox 202+/-55 microg/L; shock/SnPP-IX/Trolox 236+/-61 microg/L). CONCLUSIONS: These data suggest that HO-1/HSP32, but not the alternative cyclic guanosine monophosphate-generating enzyme NOS-II, is induced after hemorrhage and resuscitation and protects against hepatocellular injury. Both metabolites generated by the heme oxygenase pathway, e.g., carbon monoxide (a vasodilator) and biliverdin (an antioxidant) seem to contribute to the salutary effects of induction of HO-1/HSP32.
H Rensing; I Bauer; V Datene; C Pätau; B H Pannen; M Bauer
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Critical care medicine     Volume:  27     ISSN:  0090-3493     ISO Abbreviation:  Crit. Care Med.     Publication Date:  1999 Dec 
Date Detail:
Created Date:  2000-01-27     Completed Date:  2000-01-27     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0355501     Medline TA:  Crit Care Med     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2766-75     Citation Subset:  AIM; IM    
Department of Anesthesiology and Critical Care Medicine, University of the Saarland, Homburg, Germany.
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MeSH Terms
Analysis of Variance
Carbon Monoxide / metabolism
Gene Expression Regulation, Enzymologic
Glutathione Transferase / blood
Heat-Shock Proteins / metabolism*
Heme Oxygenase (Decyclizing) / genetics,  metabolism*
Hemodynamics / drug effects
Liver / enzymology*,  pathology
Nitric Oxide / biosynthesis
Nitric Oxide Synthase / genetics,  metabolism*
Rats, Sprague-Dawley
Shock, Hemorrhagic / metabolism*,  therapy
Reg. No./Substance:
0/Heat-Shock Proteins; 10102-43-9/Nitric Oxide; 630-08-0/Carbon Monoxide; EC Oxide Synthase; EC Oxygenase (Decyclizing); EC Transferase
Comment In:
Crit Care Med. 1999 Dec;27(12):2842-3   [PMID:  10628645 ]

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