5.2 ROS
When ischemic tissue undergoes reperfusion, blood brings oxygen and
nutrients to the tissue. At the same time, due to the low concentration
of antioxidants in cells, the production of reactive oxygen species
(ROS) increases. In the I /R process of biology, ROS will be produced by
many ways, including mitochondrial electron transfer chain (ETC),
xanthine oxidase system (XOD), NADPH oxidase system and nitric oxide
synthase (NOS), etc[85]. The first three are
related to oxidative stress in multiple organs, such as the heart,
brain, lungs, liver, pancreas, kidneys, and gastrointestinal
tract[86]. NOS mainly acts as an oxidative stress
factor in vascular endothelial cells[87]. During
the metabolism of normal mitochondria, the respiratory chain complex on
the inner mitochondrial membrane can produce a small amount of
ROS[88]. As mentioned earlier, when I/R occurs,
due to hypoxia, changes in ATP, pH, and calcium overload occur in cells,
which can lead to mitochondrial damage and produce more ROS. However,
ROS further exacerbates oxidative stress, leading to a vicious cycle of
cells[82, 88].
The xanthine oxidase (XOD) system is an important pathway for ROS
production. Under ischemia, ATP synthesis is reduced and xanthine
dehydrogenase (XDH) is converted into xanthine oxidase (XOD). At the
same time, ATP degradation products (ADP, AMP, hypoxanthine) accumulate.
When reperfusion is resumed, a large amount of oxygen molecules enter
the tissue with the blood, and XOD catalyzes the conversion of
hypoxanthine into xanthine and uric acid, producing a large amount of
ROS[89]. The oxygen free radicals generated by
this pathway have chemotactic effects, attracting and activating a large
number of white blood cells to aggregate. When the tissue resumes oxygen
supply, the activated white blood cells’ oxygen consumption increases
sharply, further producing a large amount of oxygen free radicals,
causing cell damage.
The NOx/Deox family of NADPH oxidase mainly includes 7 subtypes, such as
Nox-1, Nox-2, Nox-3, Nox-4, Nox-5, Duox-1 and Duox-2, these enzymes have
the ability to produce ROS[90]. Under hypoxic
conditions, hypoxia inhibitory factor-1α (HIF-1α). Promote the
activation of NOX enzyme, and after reperfusion, cells will release some
chemical factors to further activate NADPH oxidase, such as
phospholipase A2 (PLA2), TNF-α, IL-1β, IFN-γ and angiotensin II(Ang II),
etc. Overexpression of NADPH oxidase after activation enhances ROS
production[91, 92].
In addition to the aforementioned pathways, NOS is also an important
pathway for generating ROS. Tetrahydrobiopterin (BH4) is a cofactor of
NOS enzyme. In I/R, oxidative stress oxidizes BH4 to BH2, leading to a
decrease in BH4 cell level and uncoupling of NOS, thereby promoting ROS
production[93].