Page 310 - Read Online

Page 4 of 11 Kumar et al. Plast Aesthet Res 2020;7:29 I http://dx.doi.org/10.20517/2347-9264.2019.71

lipases, proteases and cathepsins, are contained within the lysosomal complex by the lysosomal membrane.
In theory, externalization of lysosomal enzymes to the neutral pH of the cytoplasm would render these
enzymes inactive. However, it is now known that a few forms of cathepsins remain active even at neutral
[8]
pH and can trigger a cascade of events that lead to cell death from the lysosomal pathway . The acidity of
the local microenvironment can further activate the lysosomal enzymes released due to lysosomal damage.

There are various stimuli that can lead to increased permeability of the lysosomal membrane and
externalization of catalytic enzymes. Lysosomal membrane permeabilization may be caused by various
stimuli but the most common mechanism is by destruction of the lipid organization and oxidative damage
to membrane bound proteins. Ischemic-reperfusion injury following acute trauma may lead to oxidative
stress and membrane damage and destabilization from reactive oxygen species. The hydroxyl radical can
cause lipid peroxidation and damage to membrane bound proteins. In addition, reactive oxygen species
[9]
may also contribute by altering the lysosomal mechanism and activating calcium channels .
By releasing highly destructive enzymes (e.g., phospholipase A, cathepsin B) following trauma, cell
membranes and cellular proteins are damaged. Lysosomal enzymes cause intracellular cell death when
released but when the enzymes become extracellular, secondary damage to adjacent tissue occurs. The
normal extracellular pH (approximately 7.2) hampers the action of the majority of lysosomal enzymes
but acidic environments (pH ≤ 5) provide optimal conditions for their functioning. Experimentally, it has
also been shown that inhibitors of lysosomal proteolytic pathways produce beneficial effects on injured
[2]
musculoskeletal tissue .

Protein/enzyme denaturation mechanisms
[5]
Metabolic failure leads to low pH that can cause denaturation of cellular proteins (enzymes) . Denaturation
of enzymes leads to loss of cellular functionality with the end-result of cell death. Although denaturation
seems like an ultimate step in cell death, multiple factors can cause denaturation. Also, a low pH activates
many lysosomal enzymes, leading to secondary damage by enzymatic mechanisms. Hence, there is an
overlap of enzymatic and denaturation mechanisms that act together to produce secondary damage.

Membrane permeability mechanisms
Changes in membrane permeability cause: (1) oncosis (cellular swelling) leading to cells bursting; and (2)
failure of ion pumps (sodium-potassium-ATPase pump)/changes in voltage gradient and the resulting
2+
2+
+
2+
uncontrolled influx of ions (Na and Ca ) leads to cellular death. Increased intracellular Ca following Ca
influx causes activation of enzyme phospholipase, leading to disruption of the phospholipid membrane and
[10]
cell death .
Mitochondrial mechanisms
Metabolic failure through mitochondrial (power plant of the cell) damage is one of the leading causes of
[11]
cell death. Mitochondrial failure resulting in insufficient ATP may trigger other lethal pathophysiological
processes leading to cell death. This indicates overlap of various theories in this regard.

Causes of mitochondrial injury are: (1) hypoxic or ischemic injury, the oxidative production of ATP is
reduced in hypoxia and becomes inadequate for mitochondrial or cellular homeostasis [2,5,7,11] . Hypoxia
activates a number of phospholipases and proteases that cause progressive failure of mitochondrial ion
pumps and damage to the mitochondrial membrane. Also, a number of (intracellular) proteins (stress
proteins-heat shock protein 70 family; ubiquitin) that are expressed induce protein catabolism within
[12]
the injured cells; (2) oxidative or reperfusion injury, post-hypoxia reperfusion [5,11,13] produces enormous
amounts of oxygen-derived free radicals that exceed normal antioxidant defenses and tissue damage results.
Re-perfusion free radical damage of the mitochondrial membrane leads to cell powerhouse (mitochondria)