C-Jun N-Terminal Kinase 2 Promotes Liver Injury via the Mitochondrial Permeability Transition after Hemorrhage and Resuscitation

Abstract EN

Hemorrhagic shock leads to hepatic hypoperfusion and activation of mitogen-activated stress kinases (MAPK) like c-Jun N-terminal kinase (JNK) 1 and 2.

Our aim was to determine whether mitochondrial dysfunction leading to hepatic necrosis and apoptosis after hemorrhage/resuscitation (H/R) was dependent on JNK2.

Under pentobarbital anesthesia, wildtype (WT) and JNK2 deficient (KO) mice were hemorrhaged to 30 mm Hg for 3 h and then resuscitated with shed blood plus half the volume of lactated Ringer’s solution.

Serum alanine aminotransferase (ALT), necrosis, apoptosis and oxidative stress were assessed 6 h after resuscitation.

Mitochondrial polarization was assessed by intravital microscopy.

After H/R, ALT in WT-mice increased from 130 U/L to 4800 U/L.

In KO-mice, ALT after H/R was blunted to 1800 U/l (P<0.05).

Necrosis, caspase-3 activity and ROS were all substantially decreased in KO compared to WT mice after H/R.

After sham operation, intravital microscopy revealed punctate mitochondrial staining by rhodamine 123 (Rh123), indicating normal mitochondrial polarization.

At 4 h after H/R, Rh123 staining became dim and diffuse in 58% of hepatocytes, indicating depolarization and onset of the mitochondrial permeability transition (MPT).

By contrast, KO mice displayed less depolarization after H/R (23%, P<0.05).

In conclusion, JNK2 contributes to MPT-mediated liver injury after H/R.