A peptide inhibitor of C-jun N-terminal kinase modulates hepatic damage and the inflammatory response after hemorrhagic shock and resuscitation.
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.
Lehnert
Mark
M
Department of Trauma Surgery, JW Goethe University, Frankfurt, Germany.
Relja
Borna
B
Sun-Young Lee
Veronika
V
Schwestka
Birgit
B
Henrich
Dirk
D
Czerny
Christoph
C
Froh
Matthias
M
Borsello
Tiziana
T
Marzi
Ingo
I
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000627:therapeutic use*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D008099:Liver / Q000098:blood supply / Q000201:enzymology / Q000473:pathology*; D008297:Male; D010455:Peptides / Q000008:administration & dosage / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation / Q000379:methods; D012771:Shock, Hemorrhagic / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*
D018836:Inflammation Mediators; D010455:Peptides; D048031:JNK Mitogen-Activated Protein Kinases; C478085:D-JNKI-1