Investigating the role of the JAK/STAT and MAPK ... - UCL Discovery

1.2.1 Mechanisms of I/R Induced Cell Death
During I/R injury, cell death can occur through apoptosis, necrosis and autophagy. Necrosis
is uncontrolled cellular destruction; necrotic cells rapidly loose membrane integrity and
release their contents into the extracellular space. Among the proteins released from necrotic
cells are danger associated molecular patterns (DAMPs) such as high mobility group protein
B1, uric acid, heat shock proteins (HSPs) and genomic DNA which are recognised by
receptors on dendritic cells and lead to the mounting of an inflammatory response (Scaffidi et
al., 2002, Shi et al., 2003, Muruve et al., 2008). Apoptosis on the other hand is a form of
controlled cellular suicide, distinct from necrosis which does not lead to activation of the
immune system. During apoptosis, cells become rounded, retract from neighbouring cells,
undergo nuclear fragmentation and membrane blebbing and eventually are engulfed by
phagocytes (Taylor et al., 2008). Apoptosis is initiated and controlled through a precisely
ordered signalling cascade that contains multiple checks and balances; at the same time that
apoptosis is initiated, an anti-apoptotic programme is also induced. The significance of this is
that apoptosis is not irreversible, activation of the apoptotic cascade does not guarantee cell
death and thus apoptosis is a highly regulated fluidic process. Autophagy involves formation
of autophagosomes which degrade and recycle proteins and organelles allowing them to be
reused in order to maintain metabolic function. Autophagy has been shown to occur in the
myocardium during I/R injury, however the study of autophagy in this context is still at an
early stage and it is not yet fully understood how it contributes to cell survival following
reperfusion (Yan et al., 2005, Gustafsson and Gottlieb, 2008).
1.2.2 Caspases
Apoptosis is regulated by an ordered signalling cascade which converges on a family of
cysteine proteases called caspases which are responsible for controlling the organised cellular
destruction. Caspases are present in the cell as inactive precursors and are activated following
cleavage; caspase activation can occur through three main routes which are depicted in Fig
1.2. Apoptogenic mediators such as granzyme B released from cytotoxic T cells can induce
apoptosis in target cells by directly activating caspase-3, this is a common form of cell death
in virally infected cells which display viral epitopes on their MHC for recognition by
cytotoxic T cells (Darmon et al., 1995). The extrinsic pathway on the other hand involves
recognition of extracellular ligands such as FasL and TNF- by the corresponding death
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