Porth's Essentials of Pathophysiology, 4e

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Cellular Responses to Stress, Injury, and Aging

C h a p t e r 2

present in peroxisomes, catalyzes the reaction that forms water from hydrogen peroxide. Nonenzymatic antioxi- dants include carotenes (e.g., vitamin A), tocopherols (e.g., vitamin E), ascorbate (vitamin C), glutathione, and flavonoids, as well as micronutrients such as selenium and zinc. 18 Nonenzymatic antioxidants often directly react with oxidants to “disarm” them. For example, vitamin C directly scavenges superoxide and hydroxyl radicals. 19 Oxidative damage has been implicated in many diseases. Mutations in the gene for SOD are associ- ated with amyotrophic lateral sclerosis (ALS; so-called Lou Gehrig disease ). 20 Oxidative stress is thought to have an important role in the development of can- cer. 21 Reestablishment of blood flow following loss of perfusion, as occurs during heart attack and stroke, is associated with oxidative injury to vital organs. The endothelial dysfunction that contributes to the devel- opment, progression, and prognosis of cardiovascular diseases is thought to be caused in part by oxidative stress. 22 In addition, oxidative stress has been associated with age-related functional declines. 23 Hypoxic Cell Injury Hypoxia deprives the cell of oxygen and interrupts oxidative metabolism and the generation of ATP. The actual time necessary to produce irreversible cell dam- age depends on the degree of oxygen deprivation and the metabolic needs of the cell. Some cells, such as those in the heart, brain, and kidney, require large amounts of oxygen to provide the energy to perform their functions. Brain cells, for example, begin to undergo permanent damage after 4 to 6 minutes of oxygen deprivation. A thin margin of time exists between reversible and irre- versible cell damage. A classic study found that the epi- thelial cells of the proximal tubule of the kidney in the rat could survive 20 but not 30 minutes of ischemia. 24 Recent work has identified a group of proteins called hypoxia-inducible factors (HIFs). During hypoxic condi- tions, HIFs cause the expression of genes that stimulate red blood cell formation, manufacture glycolytic enzymes that produce ATP in the absence of oxygen, and increase angiogenesis 25 (i.e., the formation of new blood vessels). Hypoxia can result from an inadequate amount of oxy- gen in the air, respiratory disease, ischemia (i.e., decreased blood flow due to vasoconstriction or vascular obstruc- tion), anemia, edema, or inability of the cells to use oxy- gen. Ischemia is characterized by impaired oxygen delivery and impaired removal of metabolic end products such as lactic acid. In contrast to pure hypoxia, which depends on the oxygen content of the blood and affects all cells in the body, ischemia commonly depends on blood flow through limited numbers of blood vessels and produces local tissue injury. In some cases of edema, the distance for diffusion of oxygen may become a limiting factor in the delivery of oxygen. In hypermetabolic states, the cells may require more oxygen than can be supplied by normal respiratory function and oxygen transport. Hypoxia also serves as the ultimate cause of cell death in other injuries. For example, physical factors such as a cold temperature can cause severe constriction and impair blood flow.

Hypoxia causes a power failure in the cell, with wide- spread effects on the cell’s structural and functional components. As oxygen tension in the cell falls, oxida- tive metabolism ceases, and the cell reverts to anaero- bic metabolism, using its limited glycogen stores in an attempt to maintain vital cell functions. Cellular pH falls as lactic acid accumulates in the cell. This reduction in pH can have adverse effects on intracellular structures and biochemical reactions. Low pH can alter cell mem- branes and cause chromatin clumping and cell volume changes. An important effect of reduced ATP is acute cell swell- ing caused by failure of the energy-dependent sodium/ potassium (Na + /K + )-adenosine triphosphatase (ATPase) membrane pump, which extrudes sodium from and returns potassium to the cell. With impaired function of this pump, intracellular potassium levels decrease, and sodium and water accumulate in the cell. The movement of water and ions into the cell is associated with dila- tion of the endoplasmic reticulum, increased membrane permeability, and decreased mitochondrial function. 2 To a point, the cellular changes due to hypoxia are revers- ible if oxygenation is restored. However, if the oxygen supply is not restored there is continued loss of enzymes, proteins, and ribonucleic acid through the hyperperme- able cell membrane. Injury to the lysosomal membranes results in the leakage of destructive lysosomal enzymes into the cytoplasm and enzymatic digestion of cell com- ponents. Leakage of intracellular enzymes through the permeable cell membrane into the extracellular fluid provides an important clinical indicator of cell injury and death. These enzymes enter the blood and can be measured by laboratory tests. Impaired Calcium Homeostasis Calcium functions as an important second messenger and cytosolic signal for many cell responses. Various calcium- binding proteins, such as troponin and calmodulin, act as transducers for cytosolic calcium signaling. Calcium/ calmodulin–dependent kinases indirectly mediate the effects of calcium on responses such as smooth muscle contraction and glycogen breakdown. Normally, intracel- lular calcium ion levels are kept extremely low compared with extracellular levels. These low intracellular levels are maintained by energy-dependent membrane-associ- ated calcium/magnesium (Ca ++ /Mg ++ )-ATPase exchange systems 2 and sequestration of calcium ions within organ- elles such as the mitochondria and smooth endoplasmic reticulum. Ischemia and certain toxins lead to an increase in cytosolic calcium because of the increased influx across the cell membrane and the release of calcium from intra- cellular stores. The increased calcium level may inappro- priately activate a number of enzymes with potentially damaging effects. These enzymes include phospholipases that can damage the cell membrane, proteases that dam- age the cytoskeleton and membrane proteins, ATPases that break down ATP and hasten its depletion, and endo- nucleases that fragment chromatin. Although it is known that injured cells accumulate calcium, it is unknown whether this is the ultimate cause of irreversible cell injury.