Modulation of the Unfolded Protein Response During Hepatocyte and Cardiomyocyte Apoptosis In Trauma/Hemorrhagic Shock

Abstract

Trauma with hemorrhagic shock (T/HS), has been shown to result in liver injury marked by hepatocyte apoptosis and heart failure marked by cardiomyocyte apoptosis, both of which we have shown to be prevented by IL-6 administration at resuscitation, and Stat3 largely mediated this. As specific mediators have not been delineated, we investigated the unfolded protein response (UPR), which, with marked activation, can lead to apoptosis. Prior studies of hepatic and cardiac injury examined limited repertoires of UPR elements, making it difficult to assess the role of the UPR in T/HS. This study describes the first global examination of the UPR transcriptome in the liver and heart following T/HS, demonstrating organ-specific UPR transcriptome changes. The non-canonical UPR chaperone, Hsp70, was most dysregulated following T/HS and may contribute to hepatocyte protection via an IL-6-mediated pathway, identifying a potential new therapeutic strategy to prevent hepatocyte death and organ dysfunction in T/HS.

Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 to Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution

“…In addition, administration of a NO scavenger also resulted in reduced lung injury and reduced activation of NF-kB and STAT3 after resuscitated hemorrhagic shock (Hierholzer et al, 2002), presumably through downregulation of acute inflammation (Hierholzer et al, 2002). Importantly, resuscitation from hemorrhagic shock also resulted in apoptosis of lung type I alveolar endothelial cells (Moran et al, 2009), liver hepatocytes (Moran et al, 2008), and cardiomyocytes (Thacker et al, 2013), which resulted in increased susceptibility to pneumonia (Thacker et al, 2014) and sepsis following intraperitoneal bacterial challenge (Arikan et al, 2006). Importantly, apoptosis of these critical parenchymal cells in the lung, liver, and heart and the increased susceptibility to pneumonia and bacterial peritonitis could be reversed by administration of IL-6 at the start of resuscitation; this action of IL-6 was mediated by activation of STAT3.…”

Genomics of lipid-laden human hepatocyte cultures enables drug target screening for the treatment of non-alcoholic fatty liver disease

“…This pathway involves complex signaling cascades aimed at restoring cellular homeostasis. However, prolonged hepatic steatosis disrupts the ER and secretory pathway homeostasis and is predominantly associated with insulin resistance, inflammation and apoptosis [12, 13]. Moreover, ectopic LD formation perturbs physical and functional links between mitochondria and ER to influence hepatocellular metabolism [14].…”

Resveratrol Improves Survival and Prolongs Life Following Hemorrhagic Shock

“…Studies using animal models of hemorrhagic injury (HI) have demonstrated increased systemic inflammation, mitochondrial dysfunction and reduced endoplasmic reticulum stress with concomitant decrease in organ function including cardiac function, despite fluid resuscitation (8)(9)(10)(11).…”