Porth's Essentials of Pathophysiology, 4e

40

Cell and Tissue Function

U N I T 1

Injurious agents

Hypoxia/ischemia

Ca ++

– , H 2

O 2

O 2

, OH•

↑ Intracellular Ca

Free radical formation

Inappropriate activation of enzymes that damage cell organelles, cytoskeleton, and cell membranes; hasten ATP depletion; and fragment chromatin

Oxidation of cell structures and nuclear and mitochondrial DNA

Mitochondrion

ATP depletion

↓ Na + /K + -ATPase pump

↑ Anaerobic metabolism

Other effects

↓ Glycogen stores and intracellular pH

↑ Influx Na and H 2 O

Detachment of ribosomes, decreased protein synthesis, and lipid deposition

Accumulation of intracellular fluids, dilation of endoplasmic reticulum, increased membrane permeability, decreased mitochondrial function

FIGURE 2-6. Mechanisms of cell injury. ATP, adenosine triphosphate.

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,