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| IJCEM Copyright © 2008-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711 |
Int J Clin Exp Med 1(3),213-247;2008
Original Article
Prevention of Trauma and Hemorrhagic Shock-Mediated Liver Apoptosis by
Activation of STAT3α
Ana Moran, Ayse Akcan Arikan, Mary-Ann A. Mastrangelo, Yong Wu, Bi Yu, andValeria Poli and David J. Tweardy
Infectious Diseases Section and Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Critical Care Section and
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Department of Genetics, Biology and Biochemistry, University
of Turin, Turin, Italy; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
Received May 15, 2008; accepted June 6, 2008; available online June 12, 2008
Abstract: Trauma is a major cause of mortality in the United States. Death among those surviving the initial insult is caused by multiple
organ failure (MOF) with the liver among the organs most frequently affected. We previously demonstrated in rodents that trauma
complicated by hemorrhagic shock (trauma/HS) results in liver injury that can be prevented by IL-6 administration at the start of
resuscitation; however, the contribution of the severity of HS to the extent of liver injury, whether or not resuscitation is required
and the mechanism for the IL-6 protective effect have not been reported. In the experiments reported here, we demonstrated that the
extent of liver apoptosis induced by trauma/HS depends on the duration of hypotension and requires resuscitation. We established that
IL-6 administration at the start of resuscitation is capable of completely reversing liver apoptosis and is associated with increased
Stat3 activation. Microarray analysis of the livers showed that the main effect of IL-6 was to normalize the trauma/HS-induced apoptosis
transcriptome. Pharmacological inhibition of Stat3 activity within the liver blocked the ability of IL-6 to prevent liver apoptosis and to
normalize the trauma/HS-induced liver apoptosis transcriptome. Genetic deletion of a Stat3β, a naturally occurring, dominant-negative
isoform of the Stat3, attenuated trauma/HSinduced liver apoptosis, confirming a role for Stat3, especially Stat3α, in preventing
trauma/HS-mediated liver apoptosis. Thus, trauma/HS-induced liver apoptosis depends on the duration of hypotension and requires
resuscitation; IL-6 administration at the start of resuscitation reverses HS-induced liver apoptosis, through activation of Stat3α, which
normalizes the trauma/HS-induced liver apoptosis transcriptome. (IJCEM805005).
Key Words: Nucleosomes, TUNEL, expression microarray, transcriptome
Full Text PDF
Address all correspondence to: David J. Tweardy, MD, BCM 286, Room N1318, One Baylor Plaza, Phone 713-798-8908, Fax 713-798-
8948, Email: dtweardy@bcm.tmc.edu
Original Article
Prevention of Trauma and Hemorrhagic Shock-Mediated Liver Apoptosis by
Activation of STAT3α
Ana Moran, Ayse Akcan Arikan, Mary-Ann A. Mastrangelo, Yong Wu, Bi Yu, andValeria Poli and David J. Tweardy
Infectious Diseases Section and Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Critical Care Section and
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Department of Genetics, Biology and Biochemistry, University
of Turin, Turin, Italy; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
Received May 15, 2008; accepted June 6, 2008; available online June 12, 2008
Abstract: Trauma is a major cause of mortality in the United States. Death among those surviving the initial insult is caused by multiple
organ failure (MOF) with the liver among the organs most frequently affected. We previously demonstrated in rodents that trauma
complicated by hemorrhagic shock (trauma/HS) results in liver injury that can be prevented by IL-6 administration at the start of
resuscitation; however, the contribution of the severity of HS to the extent of liver injury, whether or not resuscitation is required
and the mechanism for the IL-6 protective effect have not been reported. In the experiments reported here, we demonstrated that the
extent of liver apoptosis induced by trauma/HS depends on the duration of hypotension and requires resuscitation. We established that
IL-6 administration at the start of resuscitation is capable of completely reversing liver apoptosis and is associated with increased
Stat3 activation. Microarray analysis of the livers showed that the main effect of IL-6 was to normalize the trauma/HS-induced apoptosis
transcriptome. Pharmacological inhibition of Stat3 activity within the liver blocked the ability of IL-6 to prevent liver apoptosis and to
normalize the trauma/HS-induced liver apoptosis transcriptome. Genetic deletion of a Stat3β, a naturally occurring, dominant-negative
isoform of the Stat3, attenuated trauma/HSinduced liver apoptosis, confirming a role for Stat3, especially Stat3α, in preventing
trauma/HS-mediated liver apoptosis. Thus, trauma/HS-induced liver apoptosis depends on the duration of hypotension and requires
resuscitation; IL-6 administration at the start of resuscitation reverses HS-induced liver apoptosis, through activation of Stat3α, which
normalizes the trauma/HS-induced liver apoptosis transcriptome. (IJCEM805005).
Key Words: Nucleosomes, TUNEL, expression microarray, transcriptome
Full Text PDF
Address all correspondence to: David J. Tweardy, MD, BCM 286, Room N1318, One Baylor Plaza, Phone 713-798-8908, Fax 713-798-
8948, Email: dtweardy@bcm.tmc.edu
