Lehnert, Mark and Relja, Borna and Lee, Veronika Sun-Young and Schwestka, Birgit and Henrich, Dirk and Czerny, Christoph and Froh, Matthias and Borsello, Tiziana and Marzi, Ingo (2008) A peptide inhibitor of c-JUN N-terminal kinase modulates hepatic damage and the inflammatory response after hemorrhagic shock and resuscitation. SHOCK, 30 (2). pp. 159-165. ISSN 1073-2322,
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HEME OXYGENASE-1 GENE; ORGAN INJURY; TRANSCRIPTION FACTORS; ISCHEMIA-REPERFUSION; IN-VIVO; LIVER; PROTEIN; JNK; DYSFUNCTION; APOPTOSIS; hemorrhage/resuscitation; mitogen-activated protein kinase; in vivo JNK inhibition; inflammation |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin I |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 28 Oct 2020 06:40 |
| Last Modified: | 28 Oct 2020 06:40 |
| URI: | https://pred.uni-regensburg.de/id/eprint/30570 |
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