FASEB J. Avanti Polar Lipids
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text Free
Right arrow Full Text (PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by SCHÄFER, T.
Right arrow Articles by VOLLMAR, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by SCHÄFER, T.
Right arrow Articles by VOLLMAR, B.
(The FASEB Journal. 2003;17:660-667.)
© 2003 FASEB

Inhibition of p53 protects liver tissue against endotoxin-induced apoptotic and necrotic cell death

SCHÄFERT. , SCHEUERC. , ROEMERK. *, MENGERM. D. and VOLLMARB. {dagger},1

Institute for Clinical and Experimental Surgery,
* Department of Virology, University of Saarland, D-66421 Homburg/Saar; and
{dagger} Department of Experimental Surgery, University of Rostock, 18055 Rostock, Germany

1Correspondence: Department of Experimental Surgery, University of Rostock, D-18055 Rostock, Germany. E-mail: brigitte.vollmar{at}med.uni-rostock.de

There is increasing evidence that apoptotic and necrotic hepatocyte death following endotoxin-induced liver injury act as signals for leukocyte sequestration in the liver vasculature. p53 has been implicated to promote apoptosis through trans-activation and down-regulation of specific pro- and anti-apoptotic genes. Here, we report that inhibition of p53 decreases apoptotic and necrotic tissue injury as well as inflammatory cell response. Sprague-Dawley rats were injected intraperitoneally with 2.2 mg/kg pifithrin-{alpha} (PFT), a p53-inactivating agent, or the vehicle DMSO 30 min before intravenous exposure to lipopolysaccharide (LPS). In vehicle-pretreated animals, LPS induced significant apoptosis and necrosis of hepatocytes, which was associated with intrahepatic leukocyte recruitment, microvascular dysfunction, and enzyme release. Inhibition of p53 effectively attenuated (P<0.05) hepatocellular apoptosis and necrosis, but also reduced leukocyte recruitment and microvascular dysfunction. Western blot analysis revealed that PFT lowered the nuclear-to-cytoplasmic p53 ratio and reduced both activation of NF-{kappa}B and cleavage of procaspase 3 (P<0.05). In parallel, immunohistochemistry of PFT-pretreated, but not vehicle-pretreated, endotoxic animals exhibited nuclear p53 exclusion and reduced NF-{kappa}B p65 staining. This indicates that p53 mediates, at least in part, LPS-associated apoptosis and contributes to inflammatory endotoxic tissue injury through leukocyte activation and intraorgan sequestration.—Schäfer, T., Scheuer, C., Roemer, K., Menger, M. D., Vollmar, B. Inhibition of p53 protects liver tissue against endotoxin-induced apoptotic and necrotic cell death.


Key Words: apoptosis • necrosis • pifithrin-alpha • LPS • microcirculation • caspase 3 • NF-{kappa}B • ICAM-1 • intravital fluorescence microscopy • bisbenzimide




This article has been cited by other articles:


Home page
 Physiol. Rev.Home page
B. Vollmar and M. D. Menger
The Hepatic Microcirculation: Mechanistic Contributions and Therapeutic Targets in Liver Injury and Repair
Physiol Rev, October 1, 2009; 89(4): 1269 - 1339.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
X.L. Jin, V. Chandrakanthan, H.D. Morgan, and C. O'Neill
Preimplantation Embryo Development in the Mouse Requires the Latency of TRP53 Expression, Which Is Induced by a Ligand-Activated PI3 Kinase/AKT/MDM2-Mediated Signaling Pathway (Reprinted with Correction)
Biol Reprod, July 1, 2009; 81(1): 233 - 242.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
A. Kuhla, C. Eipel, K. Abshagen, N. Siebert, M. D. Menger, and B. Vollmar
Role of the perforin/granzyme cell death pathway in D-Gal/LPS-induced inflammatory liver injury
Am J Physiol Gastrointest Liver Physiol, May 1, 2009; 296(5): G1069 - G1076.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
X.L. Jin, V. Chandrakanthan, H.D. Morgan, and C. O'Neill
Preimplantation Embryo Development in the Mouse Requires the Latency of TRP53 Expression, Which Is Induced by a Ligand-Activated PI3 Kinase/AKT/MDM2-Mediated Signaling Pathway
Biol Reprod, February 1, 2009; 80(2): 286 - 294.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
A. J. Steele, A. G. Prentice, A. V. Hoffbrand, B. C. Yogashangary, S. M. Hart, E. P. Nacheva, J. D. Howard-Reeves, V. M. Duke, P. D. Kottaridis, K. Cwynarski, et al.
p53-mediated apoptosis of CLL cells: evidence for a transcription-independent mechanism
Blood, November 1, 2008; 112(9): 3827 - 3834.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
O. Kollmar, M. Corsten, C. Scheuer, B. Vollmar, M. K. Schilling, and M. D. Menger
Portal branch ligation induces a hepatic arterial buffer response, microvascular remodeling, normoxygenation, and cell proliferation in portal blood-deprived liver tissue
Am J Physiol Gastrointest Liver Physiol, June 1, 2007; 292(6): G1534 - G1542.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
K. Le Minh, K. Klemm, K. Abshagen, C. Eipel, M. D. Menger, and B. Vollmar
Attenuation of Inflammation and Apoptosis by Pre- and Posttreatment of Darbepoetin-{alpha} in Acute Liver Failure of Mice
Am. J. Pathol., June 1, 2007; 170(6): 1954 - 1963.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
A. V. Gudkov and E. A. Komarova
Dangerous habits of a security guard: the two faces of p53 as a drug target
Hum. Mol. Genet., April 15, 2007; 16(R1): R67 - R72.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
D. Marsolais, C. H. Cote, and J. Frenette
Pifithrin-{alpha}, an inhibitor of p53 transactivation, alters the inflammatory process and delays tendon healing following acute injury
Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2007; 292(1): R321 - R327.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. S. Hoagland, E. M. Hoagland, and H. I. Swanson
The p53 Inhibitor Pifithrin-{alpha} Is a Potent Agonist of the Aryl Hydrocarbon Receptor
J. Pharmacol. Exp. Ther., August 1, 2005; 314(2): 603 - 610.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
P. J. M. Murphy, M. D. Galigniana, Y. Morishima, J. M. Harrell, R. P. S. Kwok, M. Ljungman, and W. B. Pratt
Pifithrin-{alpha} Inhibits p53 Signaling after Interaction of the Tumor Suppressor Protein with hsp90 and Its Nuclear Translocation
J. Biol. Chem., July 16, 2004; 279(29): 30195 - 30201.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
N. Yahagi, H. Shimano, T. Matsuzaka, M. Sekiya, Y. Najima, S. Okazaki, H. Okazaki, Y. Tamura, Y. Iizuka, N. Inoue, et al.
p53 Involvement in the Pathogenesis of Fatty Liver Disease
J. Biol. Chem., May 14, 2004; 279(20): 20571 - 20575.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
C. Eipel, R. Bordel, R. M. Nickels, M. D. Menger, and B. Vollmar
Impact of leukocytes and platelets in mediating hepatocyte apoptosis in a rat model of systemic endotoxemia
Am J Physiol Gastrointest Liver Physiol, May 1, 2004; 286(5): G769 - G776.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2003 by The Federation of American Societies for Experimental Biology.