Trauma-Hemorrhage Stimulates Immune Defense, Mitochondrial Dysfunction, Autophagy and Apoptosis in Pig Liver at 72 H

Shi, Yulong; Greven, Johannes; Guo, Weijun; Luo, Peng; Xu, Ding; Wang, Weikang; Relja, Borna; Vollrath, Jan T.; Buhl, Eva Miriam; Horst, Klemens; Bolierakis, Eftychios; Bläsius, Felix; Hildebrand, Frank

doi:10.1097/SHK.0000000000001556

by Yulong Shi, Johannes Greven, Weijun Guo, Peng Luo, Ding Xu, Weikang Wang, Borna Relja, Jan T. Vollrath, Eva Miriam Buhl, Klemens Horst, Eftychios Bolierakis, Felix Bläsius, Frank Hildebrand

Abstract:

Hepatic dysfunction frequently occurs after trauma-hemorrhage, resulting in severe pathophysiological responses that include 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.Liver tissue was taken from a porcine polytrauma hemorrhage (TH) 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 the liver tissue after TH were evaluated by transmission electron microscopy (TEM). The leukocyte phenotypes and autophagy and apoptosis pathways were elucidated by immunohistofluorescence (IHF), Western blot, and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL).In addition to post-traumatic changes in the mitochondrial morphology, the 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 P62 was downregulated after TH. Costaining showed that the 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 line 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.

Reference:

Trauma-Hemorrhage Stimulates Immune Defense, Mitochondrial Dysfunction, Autophagy and Apoptosis in Pig Liver at 72 H (Yulong Shi, Johannes Greven, Weijun Guo, Peng Luo, Ding Xu, Weikang Wang, Borna Relja, Jan T. Vollrath, Eva Miriam Buhl, Klemens Horst, Eftychios Bolierakis, Felix Bläsius, Frank Hildebrand), In Shock (Augusta, Ga.), 2020.

Bibtex Entry:

@article{shi_trauma-hemorrhage_2020,
	title = {Trauma-{Hemorrhage} {Stimulates} {Immune} {Defense}, {Mitochondrial} {Dysfunction}, {Autophagy}  and {Apoptosis} in {Pig} {Liver} at 72 {H}},
	issn = {1540-0514 1073-2322},
	doi = {10.1097/SHK.0000000000001556},
	abstract = {Hepatic dysfunction frequently occurs after trauma-hemorrhage, resulting in severe  pathophysiological responses that include 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.Liver tissue was  taken from a porcine polytrauma hemorrhage (TH) 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 the liver tissue after TH were  evaluated by transmission electron microscopy (TEM). The leukocyte phenotypes and  autophagy and apoptosis pathways were elucidated by immunohistofluorescence (IHF),  Western blot, and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling  (TUNEL).In addition to post-traumatic changes in the mitochondrial morphology, the  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 P62 was  downregulated after TH. Costaining showed that the 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  line 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.},
	language = {eng},
	journal = {Shock (Augusta, Ga.)},
	author = {Shi, Yulong and Greven, Johannes and Guo, Weijun and Luo, Peng and Xu, Ding and Wang, Weikang and Relja, Borna and Vollrath, Jan T. and Buhl, Eva Miriam and Horst, Klemens and Bolierakis, Eftychios and Bläsius, Felix and Hildebrand, Frank},
	month = aug,
	year = {2020},
	pmid = {32826806}
}