Protection against hemorrhagic shock in mice genetically deficient in poly(ADP-ribose)polymerase
Details
Serval ID
serval:BIB_29950AB93F0A
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Protection against hemorrhagic shock in mice genetically deficient in poly(ADP-ribose)polymerase
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN
0027-8424 (Print)
Publication state
Published
Issued date
08/2000
Volume
97
Number
18
Pages
10203-8
Notes
In Vitro
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S. --- Old month value: Aug 29
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S. --- Old month value: Aug 29
Abstract
Hemorrhagic shock (HS) and resuscitation leads to widespread production of oxidant species. Activation of the enzyme poly(ADP-ribose) polymerase (PARP) has been shown to contribute to cell necrosis and organ failure in various disease conditions associated with oxidative stress. We tested the hypothesis whether PARP activation plays a role in the multiple organ dysfunction complicating HS and resuscitation in a murine model of HS and resuscitation by using mice genetically deficient in PARP (PARP(-/-)) and their wild-type littermates (PARP(+/+)). Animals were bled to a mean blood pressure of 45 mmHg (1 mmHg = 133 Pa) and resuscitated after 45 min with isotonic saline (2x volume of shed blood). There was a massive activation of PARP, detected by poly(ADP-ribose) immunohistochemistry, which localized to the areas of the most severe intestinal injury, i.e., the necrotic epithelial cells at the tip of the intestinal villi, and colocalized with tyrosine nitration, an index of peroxynitrite generation. Intestinal PARP activation resulted in gut hyperpermeability, which developed in PARP(+/+) but not PARP(-/-) mice. PARP(-/-) mice were also protected from the rapid decrease in blood pressure after resuscitation and showed an increased survival time, as well as reduced lung neutrophil sequestration. The beneficial effects of PARP suppression were not related to a modulation of the NO pathway nor to a modulation of signaling through IL-6, which similarly increased in both PARP(+/+) and PARP(-/-) mice exposed to HS. We propose that PARP activation and associated cell injury (necrosis) plays a crucial role in the intestinal injury, cardiovascular failure, and multiple organ damage associated with resuscitated HS.
Keywords
Acetylcholine/pharmacology
Animals
Aorta, Thoracic/drug effects/physiology/physiopathology
Blood Pressure
Blood Volume
Dinoprost/pharmacology
Enzyme Activation
*Hemodynamic Processes
Intestinal Mucosa/enzymology/*pathology
Liver/enzymology/pathology
Male
Mice
Mice, Knockout
Muscle Contraction/drug effects
Muscle Relaxation/drug effects
Muscle, Smooth, Vascular/drug effects/physiology/*physiopathology
Peroxidase/metabolism
Poly(ADP-ribose) Polymerases/deficiency/genetics/*metabolism
Resuscitation
Shock, Hemorrhagic/*genetics/physiopathology/therapy
Sodium Chloride/therapeutic use
Tyrosine/analogs & derivatives/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 17:01
Last modification date
20/08/2019 13:09