A peptide inhibitor of C-JUN N-terminal kinase modulates hepatic damage and the inflammatory response after hemorrhagic shock and resuscitation

Mark Lehnert, Borna Relja, Veronika Sun-Young Lee, Birgit Schwestka, Dirk Henrich, Christoph Czerny, Matthias Froh, Tiziana Borsello, Ingo Marzi

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Hemorrhage and resuscitation (H/R) leads to phosphorylation of mitogen-activated stress kinases, an event that is associated with organ damage. Recently, a specific, cell-penetrating, protease-resistant inhibitory peptide of the mitogen-activated protein kinase c-JUN N-terminal kinase (JNK) was developed (D-JNKI-1). Here, using this peptide, we tested if inhibition of JNK protects against organ damage after H/R. Male Sprague-Dawley rats were treated with D-JNKI-1 (11 mg/kg, i.p.) or vehicle. Thirty minutes later, rats were hemorrhaged for 1 h to a MAP of 30 to 35 mmHg and then resuscitated with 60% of the shed blood and twice the shed blood volume as Ringer lactate. Tissues were harvested 2 h later. ANOVA with Tukey post hoc analysis or Kruskal-Wallis ANOVA on ranks, P <0.05, was considered significant. c-JUN N-terminal kinase inhibition decreased serum alanine aminotransferase activity as a marker of liver injury by 70%, serum creatine kinase activity by 67%, and serum lactate dehydrogenase activity by 60% as compared with vehicle treatment. The histological tissue damage observed was blunted after D-JNKI-1 pretreatment both for necrotic and apoptotic cell death. Hepatic leukocyte infiltration and serum IL-6 levels were largely diminished after D-JNKI-1 pretreatment. The extent of oxidative stress as evaluated by immunohistochemical detection of 4-hydroxynonenal was largely abrogated after JNK inhibition. After JNK inhibition, activation of cJUN after H/R was also reduced. Hemorrhage and resuscitation induces a systemic inflammatory response and leads to end-organ damage. These changes are mediated, at least in part, by JNK. Therefore, JNK inhibition deserves further evaluation as a potential treatment option in patients after resuscitated blood loss.

Original languageEnglish
Pages (from-to)159-165
Number of pages7
JournalShock
Volume30
Issue number2
DOIs
Publication statusPublished - Aug 2008

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Hemorrhagic Shock
Resuscitation
Phosphotransferases
Liver
Hemorrhage
Serum
Analysis of Variance
Peptides
polypeptide C
Creatine Kinase
Mitogen-Activated Protein Kinases
Blood Volume
Alanine Transaminase
Mitogens
L-Lactate Dehydrogenase
Sprague Dawley Rats
Interleukin-6
Oxidative Stress
Leukocytes
Peptide Hydrolases

Keywords

  • Hemorrhage/resuscitation
  • In vivo JNK inhibition
  • Inflammation
  • Mitogen-activated protein kinase

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Emergency Medicine

Cite this

A peptide inhibitor of C-JUN N-terminal kinase modulates hepatic damage and the inflammatory response after hemorrhagic shock and resuscitation. / Lehnert, Mark; Relja, Borna; Sun-Young Lee, Veronika; Schwestka, Birgit; Henrich, Dirk; Czerny, Christoph; Froh, Matthias; Borsello, Tiziana; Marzi, Ingo.

In: Shock, Vol. 30, No. 2, 08.2008, p. 159-165.

Research output: Contribution to journalArticle

Lehnert, M, Relja, B, Sun-Young Lee, V, Schwestka, B, Henrich, D, Czerny, C, Froh, M, Borsello, T & Marzi, I 2008, 'A peptide inhibitor of C-JUN N-terminal kinase modulates hepatic damage and the inflammatory response after hemorrhagic shock and resuscitation', Shock, vol. 30, no. 2, pp. 159-165. https://doi.org/10.1097/SHK.0b013e31815dd623
Lehnert, Mark ; Relja, Borna ; Sun-Young Lee, Veronika ; Schwestka, Birgit ; Henrich, Dirk ; Czerny, Christoph ; Froh, Matthias ; Borsello, Tiziana ; Marzi, Ingo. / A peptide inhibitor of C-JUN N-terminal kinase modulates hepatic damage and the inflammatory response after hemorrhagic shock and resuscitation. In: Shock. 2008 ; Vol. 30, No. 2. pp. 159-165.
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