Hepatic topographical changes of endoplasmic reticulum stress and unfolded protein response signaling after hemorrhagic shock and reperfusion

Endoplasmic reticulum (ER) stress plays a crucial role in cell death decisions in context of various diseases. Although it is known that ER stress occurs in livers subjected to hemorrhagic shock and reperfusion (HS/R), there is no understanding about the influence of the liver architecture on ER stress and the activation of the unfolded protein response (UPR). Materials and

These findings show that the liver architecture must be taken into account when investigating the role of ER stress and the UPR in ischemia-reperfusion injury after HS/R.

Mice were subjected to a pressure-controlled HS (30 ± 5 mmHg) for 90 min. Mice were sacrificed 2, 4, 6, 8, 10, 14, 18, and 24 h after shock induction. Plasma levels of inflammatory cytokines (IL-6, CXCL1, CXCL9, CXCL10, CCL2, CCL3) and transaminases were measured. Hematoxylin and eosin stains of paraffin-embedded liver tissue sections were evaluated for liver damage. Immunohistochemistry was used to analyze the hepatic topography of ER stress marker binding immunoglobulin protein and the activation of the three major pathways of the UPR.

Compared with sham-operated mice, HS/R led to profound liver damage and an elevation of inflammatory cytokines. We found time-dependent topographical changes of ER stress in the livers. Furthermore, the three major pathways of the UPR represented by protein kinase RNA-like ER kinase, activating transcription factor 6, and inositol-requiring enzyme 1 were activated in differing ways dependent on the zonation within the liver acinus. Conclusions: These findings show that the liver architecture must be taken into account when investigating the role of ER stress and the UPR in ischemia-reperfusion injury after HS/R.