40
U N I T 1
Cell and Tissue Function
chemical and radiation injury, toxicity from oxygen and
other gases, cellular aging, responses to microbial infec-
tions, and tissue injury caused by inflammation.
Free radicals are highly reactive chemical species with
an unpaired electron in the outer orbit (valence shell) of
the molecule. In the literature, the unpaired electron is
denoted by a dot, for example, NO
·
. The unpaired elec-
tron causes free radicals to be unstable and highly reac-
tive, so that they react nonspecifically with molecules in
the vicinity. Moreover, free radicals can establish chain
reactions consisting of many events that generate new
free radicals. In cells and tissues, free radicals react with
proteins, lipids, and carbohydrates, thereby damaging
cell membranes, inactivating enzymes, and damaging
nucleic acids that make up DNA.
Many free radicals that are harmful in human physi-
ology are derived from oxygen. These
reactive oxygen
species
(ROS) include free radicals, such as superoxide
anion (O
2
–
) and hydroxyl radical (OH
·
), as well as reac-
tive oxygen-containing species that are not free radicals,
such as hydrogen peroxide (H
2
O
2
). Reactive oxygen
species are normal products of mitochondrial respira-
tion and energy metabolism, and are typically removed
by cellular antioxidative systems. Exogenous causes,
including ionizing and UV radiation, can also cause ROS
production in the body.
Oxidative stress
is a condition
that occurs when the generation of ROS exceeds the
ability of the body to neutralize and eliminate ROS.
Oxidative stress can lead to oxidation of cell compo-
nents, activation of signal transduction pathways, DNA
damage, and changes in gene expression. In addition to
focusing on nuclear DNA as a target of oxidative injury,
current studies are focusing on mitochondrial DNA as a
target of oxidation and subsequent cause of mitochon-
drial dysfunction.
16
Although ROS and oxidative stress are clearly asso-
ciated with cell and tissue damage, recent evidence
suggests that ROS are not always acting in a random
and damaging manner. Current studies find that ROS
are also important signaling molecules that are used in
healthy cells to regulate normal functions such as vas-
cular smooth muscle tone and vascular endothelial
growth factor (VEGF) signaling, and even function as
a preconditioning factor to protect cells from injury.
17
Antioxidants
are natural and synthetic molecules
that inhibit the reactions of ROS with biologic struc-
tures or that prevent the uncontrolled formation of ROS.
Antioxidants include enzymatic and nonenzymatic com-
pounds. Enzymes known to function as antioxidants
include superoxide dismutase (SOD), catalase, glutathi-
one peroxidase, and thioreductase. Superoxide dismutase
forms hydrogen peroxide from superoxide. Catalase,
ATP depletion
Ca
++
Injurious agents
Hypoxia/ischemia
Free radical formation
↑
Intracellular Ca
↑
Anaerobic metabolism
↑
Influx Na and H
2
O
Accumulation of intracellular fluids,
dilation of endoplasmic reticulum,
increased membrane permeability,
decreased mitochondrial function
↓
Na
+
/K
+
-ATPase pump
↓
Glycogen stores and
intracellular pH
Detachment of ribosomes,
decreased protein synthesis,
and lipid deposition
Other effects
Inappropriate activation of
enzymes that damage cell
organelles, cytoskeleton,
and cell membranes;
hasten ATP depletion; and
fragment chromatin
Mitochondrion
Oxidation of cell
structures and nuclear
and mitochondrial DNA
O
2
–
, H
2
O
2
, OH•
FIGURE 2-6.
Mechanisms of cell injury.
ATP, adenosine triphosphate.
