Preface - Ous-research.no

Surgical Intensive Care Medicine
CLP, and Sham. Animals were sacrificed 18 hours after
surgery. Studies in a unique long-term mouse model were
conducted in collaboration with professors Heniz Redl and
Soheyl Bahrami from the Ludwig Boltzmann Institute for
Experimental and Clinical Traumatology, Vienna. Mice were
divided in four groups and sacrificed at baseline or 18, 48, or
96 hours following CLP.
Figure 1. Tissue specific regulation of CCN2 mRNA expression in the
livers, lungs and hearts of rats subjected to 18 hours of CLP.
Expression levels of sham animals set to one. Relative ecpression levels
in CLP animals displayed.
Such stresses cause accumulation of unfolded proteins
in the ER leading to a condition called ER stress. Protein
aggregation is toxic for the cells and several pathological
conditions are thus associated with ER stress. Adaption
to altered environment and restoration of cell homeostasis
involve cell protective mechanisms, Figure 3. Cellular
responses to ER stress degrade misfolded proteins by the
ubiquitin proteasome system in the cytoplasm, and regulate
mRNA translation and assist protein folding by a pathway
called unfolded protein response (UPR). The adaptive
mechanisms during UPR are mediated through the three ER
transmembrane receptors; pancreatic ER kinase (PKR)-like
ER kinase (PERK), activating transcription factor 6 (ATF6) and
inositol-requiring enzyme 1 (IRE1). Initial signalling through
these receptors induces protein folding and degradation of
ER-associated proteins and inhibits mRNA translation thereby
reducing the influx of proteins to the ER. However, if ER
stress is prolonged and the adaption fails, the signalling will
become pro-apoptotic and the cell will go into programmed
cell death, apoptosis.
Figure 2. Time differential regulation of CCN1 and CCN3 mRNA
expression in mice subjected to CLP for 0, 18, 48 or 96 hours. Expression
levels standardized to 0 hour.
Preliminary data shows both a tissue-specific (Figure 1) and
time-differential regulation of CCN gene expression in the
models (Figure 2).
Furthermore, a specific gene expression profile during
sepsis for single CCN genes in different organs has been
documented.
This provides novel indications of involvement of the ECM
associated CCN proteins in sepsis-induced organ failure.
Endoplasmic reticulum (ER) stress and apoptosis – links to
development of organ failure in sepsis
The ER is the main site of protein modification and folding
and is highly sensitive to stresses that alter the cellular
energy level, the redox state or the Ca2+ concentration.
Figure 3.: Cellular responses to Endoplasmatic Reticulum (ER) stress.
Cellular responses to ER stress involve degradation of
misfolded proteins by the ubiquitin proteasome system (1),
induction of protein folding and inhibition of mRNA translation
by the UPR, unfolded protein response (2) or can lead
to apoptosis (3) if the stress is prolonged.
Two previous studies report a possible role of prolonged
ER stress in the development of organ dysfunction in septic
animals. These studies show an increased expression of
known markers of ER stress in spleen of CLP-operated mice
and in liver of LPS-treated rats. Initial data generated in
our group show similar results in liver of CLP-operated rats
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