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Abstract
The mismatch of oxygen supply and demand during hemorrhagic shock disturbs endoplasmic reticulum (ER) homeostasis. The resulting accumulation of unfolded proteins in the ER lumen, which is a condition that is defined as ER stress, triggers the unfolded protein response (UPR). Since the UPR influences the extent of organ damage following hemorrhagic shock/reperfusion (HS/R) and mediates the protective effects of stress preconditioning before ischemia-reperfusion injury, the current study investigated the mechanisms of ER stress preconditioning and its impact on post-hemorrhagic liver damage. Male C56BL/6-mice were injected intraperitoneally with the ER stress inductor tunicamycin (TM) or its drug vehicle 48 h prior to being subjected to a 90 min pressure-controlled hemorrhagic shock (30±5 mmHg). A period of 14 h after hemorrhagic shock induction, mice were sacrificed. Hepatocellular damage was quantified by analyzing hepatic transaminases and hematoxylin-eosin stained liver tissue sections. Additionally, the topographic expression patterns of the ER stress marker binding immunoglobulin protein (BiP), UPR signaling pathways, and the autophagy marker Beclin1 were evaluated. TM injection significantly increased BiP expression and modified the topographic expression patterns of the UPR signaling proteins. In addition, immunohistochemical analysis of Beclin1 revealed an increased pericentral staining intensity following TM pretreatment. The histologic analysis of hepatocellular damage demonstrated a significant reduction in cell death areas in HS/R+TM (P=0.024). ER stress preconditioning influences the UPR and alleviates post-hemorrhagic liver damage. The beneficial effects were, at least partially, mediated by the upregulation of BiP and autophagy induction. These results underscore the importance of the UPR in the context of HS/R and may help identify novel therapeutic targets.
Highlights
Trauma is the most common cause of death for all age groups below the age of 44 and the single largest cause for years of life lost in the United States [1,2,3]
As previously shown by Jian et al [16], endo‐ plasmic reticulum (ER) stress plays an important role in liver injury following hemor‐ rhagic shock/reperfusion (HS/R)
We confirmed this finding in our preceding study: The injection of the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) during reperfusion mitigated hepatocellular damage, whereas the administration of the ER stress inductor TM during reperfu‐ sion increased hepatocellular damage [18]
Summary
Trauma is the most common cause of death for all age groups below the age of 44 and the single largest cause for years of life lost in the United States [1,2,3]. One of the most dire consequences of severe trauma, and a leading cause of post‐injury death, is hemorrhagic shock as it may result in ischemia‐reperfusion injury (IRI), systemic inflammation, and multi‐organ failure [5]. Hemorrhagic shock is known to cause a mismatch between oxygen supply and demand. Protein maturation and folding in the endo‐ plasmic reticulum (ER) is a highly energy‐dependent cellular process [6]. Perturbations in the ER homeostasis result in an impaired ER function and an accumulation of unfolded proteins in the ER lumen‐a condition defined as ER stress [7]. The cell activates specific signaling pathways, which are collectively known as the unfolded protein response (UPR) consisting of three primary branches: Protein kinase RNA‐like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), and inositol‐requiring enzyme 1
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