5.3 Cell death
The I/R process of organisms is dynamic, and the mechanism for producing
ROS is also complex. The ROS produced by the above pathways may
accumulate in cells during the ischemic stage and inhibit antioxidants.
However, after tissue restoration of blood supply, if ischemia is
severe, ROS induced oxidative stress may further cause cell damage and
even cell death[94].
Apoptosis is a process of programmed cell death, mainly caused by
calcium overload and ROS activation in I/R. There are two pathways of
cell apoptosis that can interact with each other: endogenous apoptosis
pathway and exogenous apoptosis pathway. Endogenous pathway, also known
as mitochondrial pathway. In the cells injured by ischemia/reperfusion,
a large amount of calcium influx and ROS production will cause the
opening of mitochondrial mPT pore and the activation of apoptosis
promoting Bcl-2 family, increase the permeability of mitochondrial
membrane, release cytochrome C into the cytoplasm, and then combine with
apoptosis protease activating factor 1 (APAF-1) to activate Caspase-9
and form a complex, and then trigger the apoptosis cascade reaction to
promote apoptosis[95].The exogenous pathway, also
known as the death receptor pathway, is mainly activated by death
factors or receptors. Important death factors mainly include TNF-α,Fas
ligands, TRAIL, and TL1A. As mentioned earlier, during I/R, reperfusion
cells release TNF-α,Activate the JNK pathway to stimulate the
production of ROS. The accompanying oxidative stress will further
stabilize the phosphorylation of c-JunN-terminal kinase and accelerate
cell death[96]. If TNF-α Persistent increase will
induce the TNFR related death domain (TRADD) to combine with it to
synthesize TNF α- TRADD. TNF α- TRADD and Fas FADD can induce and
activate caspase 8 and 10, then enzymolysis activates downstream caspase
3, 6 and 10, and then starts the process of cell
apoptosis[97]. However, in ischemia-reperfusion
injury, cell apoptosis is not as common as necrosis mentioned below.
Necrotizing apoptosis is also a type of programmed cell death, but its
impact on organisms is completely different from previous cell
apoptosis. The main characteristics of necrotic apoptosis are cell
swelling, disintegration of organelle and leakage of intracellular
components, which often cause severe inflammatory reaction in ischemic
tissues[98, 99]. As a regulatory mode of death,
the main factors triggering necrotic apoptosis are the interacting
serine threonine kinase 3 (RIPK3) and mixed lineage kinase like domain
(MLKL)[100]. RIP3 can enable TNF-α driven cell
death changes from apoptosis to necrotic apoptosis. When Caspase-8 is
depleted or cIAP is deficient, TNFR1 will promote necrotic
apoptosis[99]. The assembly of necrotic complex is
mainly related to RIPK1/RIPK3 interaction and MLKL activation. RIPK3
induces phosphorylation of MLKL, leading to oligomerization and
translocation of MLKL to the lobules within the plasma membrane,
ultimately increasing plasma membrane permeability and cell
death[100]. ROS induced DNA damage also promotes
the formation of necrotic complex by activating
poly(ADP-ribose)polymerase (PARP), further accelerating cell death. Due
to the close relationship between necrotic apoptosis and the occurrence
of inflammation in the human body, understanding the molecular mechanism
and pathophysiological significance of necrotic apoptosis remains an
important goal of therapeutic I/R research.
The role of autophagy in I/R is bidirectional, which can both protect
cells and disrupt them. During ischemia, appropriate mitochondrial
autophagy can clear partially damaged mitochondria and reduce subsequent
damage[101].During the reperfusion phase, the
levels of Ca2+and ROS increase in the cells, while
oxidative stress inhibits the activity of rapamycin mTOR, leading to the
formation of ULK-1 complexes and PI3K III class, which induce autophagy.
However, autophagy cannot clear all damaged mitochondria, and when
autophagy clearance capacity is exceeded, it can lead to cell
death[102, 103].