Trauma-hemorrhage: Mitochondrial dysfunction, autophagy and apoptosis in pig liver 72 h post polytrauma

Fragestellung Hepatic dysfunction frequently occurs after trauma-hemorrhage (TH) and results in severe pathophysiological responses, including leukocyte shifting and self-mediated mechanisms of cells, such as autophagy and apoptosis. This in vivo study aimed to characterize mitochondrial morphology, leukocyte reaction, and the processes of autophagy and apoptosis after TH in a long-term large animal model.

Methodik Liver tissue was taken from a porcine polytrauma model (hemorrhagic shock, blunt chest trauma, tibia fracture, and liver laceration) with an intensive care unit follow-up of 72 h. The ultrastructural changes of cryo-conserved liver tissue and cells after TH were evaluated by transmission electron microscopy (TEM). The leukocyte phenotypes and the autophagy and apoptosis pathways were elucidated by immunohistofluorescence (IHF), western blot, and tTerminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL).

Ergebnisse und Schlussfolgerung In addition to posttraumatic changes in the mitochondrial morphology, biomarkers of anti-inflammatory macrophages (CD163) and reparative monocytes (CD11R3 and CD16) were upregulated, while the inducible nitric oxide synthase (iNOS) was downregulated after TH. Furthermore, the autophagy-related protein expressions of LC3 and Beclin-1 were upregulated, whereas the protein expression of pP62 was downregulated after TH. Costaining showed that macrophages were LC3 (or Beclin-1) positive and that CD163 was copositive and upregulated. Apoptosis biomarkers (cleaved-caspase-3/caspase-3 and Bcl-2) increased after TH, which is in keeping with TUNEL results.

In conclusion, the observed findings indicate that mitochondrial dysfunction might be one trigger of hepatic autophagy and apoptosis after TH. These processes occur together with the activation of anti-inflammatory leukocytes in liver tissue. Further studies are needed to elucidate the potential therapeutic effects of inhibiting mitochondrial swelling during autophagy or apoptosis.

Stichwörter Porcine polytrauma hemorrhagic model, macrophage activation and polarization, liver injury, autophagy, apoptosis, mitochondria damage

Publication History

Article published online:
15 October 2020