Cell Injury and Death Flashcards
Cell Injury Tree Diagram
Sequence of Events in Cell Injury and Death
Hypoxia in Cell Injury
Hypoxia interferes with aerobic respiration and depletes ATP.
Hypoxia is different from ischemia, or loss of blood supply to a tissue, which compromises nutrient delivery and waste removal (making it more damaging than hypoxia). Ischemia is the most common cause of hypoxia, but oxygen deficiency can also result from inadequate oxygenation of the blood (pneumonia) or reduction in the O2 -carrying capacity of the blood (anemia or CO poisoning).
Chemical agents in cell injury
Chemical agents can injure either directly (e.g. HgCl2 binding to membrane -SH groups), or indirectly via their metabolites. Virtually any chemical can cause injury – even oxygen and water(!) are toxic if sufficiently concentrated. Drugs can also cause injury at high doses (every drug has a therapeutic index), or at therapeutic doses in sensitive patients.
Infectious Agents in Cell Injury
Each agent tends to have a defined spectrum of injury.
Viruses multiply intracellularly, appropriating host biosynthetic machinery, and cause cell lysis.
Bacteria can cause injury in the same way if intracellular; in addition, extracellular bacteria have toxic cell wall constituents (endotoxin), and can release exotoxins.
In addition to these direct mechanisms, infectious agents can also cause injury indirectly: immune-mediated injury may occur (innate immunity, killing of infected cells, septic shock), and some infectious agents can cause malignant transformation.
Immune Responses in Cell Injury
Although the immune system serves to defend the body against foreign materials, immune reactions – intended or incidental – can also result in cell and tissue injury. Examples include anaphylaxis and autoimmune disease.
Genetic Defects in cell injury
Inborn errors of metabolism due to congenital enzyme deficiencies are excellent examples of cell and tissue damage resulting from genetic mutations
Nutritional Imbalances in cell injury
Nutritional deficiencies (e.g. protein-calorie malnutrition) remain a major world-wide cause of cell injury, but specific vitamin deficiencies are common even in industrialized nations. Nutritional excesses also cause cell injury; obesity increases risk of diabetes mellitus, and diets rich in animal fat are associated with increased risk of atherosclerosis and other disorders (including cancer).
Physical Agents in cell injury
Trauma, extremes of temperatures, radiation, electric shock, and sudden changes in atmospheric pressure all have wide-ranging effects on cells.
Healing and Aging in cell injury
Healing of injured tissues does not always result in a perfect restoration of structure or function. Repeated trauma can also lead to tissue degeneration even in the absence of outright cell death. Moreover, intrinsic cellular senescence (AKA: aging) leads to alterations in replicative and repair abilities of individual cells and tissues. All of these changes result in a diminished ability to respond to exogenous stimuli and injury, and eventually to the death of the organism.
Molecular mechanisms of cell injury
Cell membrane damage
Ischemia
Loss of calcium homeostasis
Calpains
Activated by increased cytoplasmic calcium. Intracellular cysteine proteases which break down cytoskeletal proteins, damage ion channels, and alter the activity of cell adhesion molecules and cell surface receptors.
Necrosis
Apoptosis
Mitochondrial permeability transition
Mitochondrial integrity is required for oxidative metabolism and, therefore, cell survival. Increases in cytosolic calcium, intracellular oxidative stress, and lipid breakdown products all culminate in formation of non-selective pores in the inner mitochondrial membrane, which dissipate the proton gradient across the mitochondrial membrane and prevent ATP generation. Cytochrome C also leaks into the cytosol and activates apoptosis.
_____ is the most common cause of cell injury in clinical medicine
Ischemia is the most common cause of cell injury in clinical medicine, typically occurring due to diminished blood flow in a particular tissue vascular bed.
Ischemia results in compromised nutrient delivery and waste removal in addition to hypoxia, making it categorically worse than hypoxia. In contrast to hypoxia, where glycolytic energy generation can continue, glycolysis will also cease in ischemic tissues after potential substrates are exhausted or glycolysis is inhibited by accumulation of metabolites that would normally be removed by blood flow.
Mechanisms in ischemic injury
ATP depletion causes reduced activity of the plasma membrane Na/K ATPase, with accumulation of intracellular sodium and diffusion of potassium out of the cell. The net gain of sodium causes osmotic gain of water, producing acute cellular swelling.
Anaerobic glycolysis increases. Activation of this pathway generates some ATP, but leads to rapid depletion of glycogen stores and causes accumulation of lactic acid and inorganic phosphates from hydrolysis of phosphate esters, lowering the intracellular pH.
Dropping pH and ATP levels cause ribosomes to detach from the rough endoplasmic reticulum (RER), with a resultant reduction in protein synthesis.
If hypoxia/ischemia is not relieved, worsening mitochondrial function and increasing membrane permeability cause further morphologic deterioration.
Ischemia/reperfusion injury
Under certain circumstances, restoration of blood flow to ischemic but otherwise viable tissues results in paradoxically exacerbated and accelerated injury.
- Restoration of blood flow bathes cells in high concentrations of calcium. Increased intracellular calcium activates pathways causing loss of cellular integrity
- Restoration of blood flow into an area that is already irreversibly injured results in local augmentation of inflammatory cell recruitment. These cells release high levels of ROS that promote additional membrane damage as well as the mitochondrial permeability transition.
- Damaged mitochondria produce increased free radicals. In addition, ischemically-injured cells have compromised anti-oxidant defense mechanisms
Free radical-induced injury
Vulnerable targets:
Double bonds in membrane lipids
Thymidine in DNA
Thiols in proteins (produce non-physiological disulfide bridging and sulfur oxidation)
Cellular free-radical defusion mechanisms
Superoxide dismutases (2O2 •+ 2H+ —> H2O2 + O2)
Glutathione + glutathione peroxidase
Catalase
Endogenous or exogenous antioxidants
Metal storage and/or transport proteins (sequester ionized iron and copper, minimizing their potential for damage)
Atrophy
Shrinkage in the size of a cell or organ by loss of cell substance. Atrophic cells are not dead, although they do have diminished function. Cell loss can also lead to organ atrophy.
Causes of atrophy include decreased workload (e.g. immobilization or disuse of a limb), denervation, ischemia, inadequate nutrition, loss of hormone stimulation, and aging.
Atrophy represents a reduction in the structural components of the cell
Adaptive responses of cells
Hypertrophy, hyperplasia, metaplasia, and atrophy.
Lysosomal Catabolism
May be modified in subcellular adaptation to injury.
Lysosomes break down ingested materials in one of two ways: heterophagy (for extrinsic molecules) and autophagy (for intracellular materials). The enzymes in the lysosomes can completely catabolize most proteins and carbohydrates.
Induction of smooth ER
May be modified in subcellular response to injury.
The enzymes that metabolize most drugs are found in hepatocyte smooth endoplasmic reticulum. Certain toxins and drugs (including barbiturates) stimulate (induce) the synthesis of more SER, and therefore, more catabolic enzymes. In this manner, the cell adapts to be more effective at drug modification.
Heat Shock Proteins
May be modified in subcellular response to injury.
When induced after cell injury, they assist in refolding denatured proteins to restore their function. If re-folding is not successful, irretrievably denatured proteins are tagged by binding of the HSP ubiquitin, which targets them for catabolism by proteasomes
Conditions resulting in intracellular accumulation
A normal substance is produced at a normal or increased rate, but the metabolic rate is inadequate to remove it.
A normal or abnormal endogenous substance accumulates because of genetic or acquired defects in its metabolism, packaging, transport, or secretion.
An abnormal exogenous substance is deposited and accumulates because the cell lacks the enzymatic machinery to degrade it, and is unable to transport it to other sites.
Lipofuscin
A byproduct of “wear and tear” formed from crosslinked proteins and lipids. May accumulate with age. There is no metabolic mechanism to degrade it or method to transport it outside of the cell.
Cellular swelling
A pattern of morphologic changes correlating to reversible injury.
Cellular swelling is the first manifestation of most forms of injury to cells; it appears whenever cells are incapable of maintaining ionic and fluid homeostasis. When all cells in an organ are affected, there is pallor, increased turgor, and increased weight.
Microscopically, small, clear vacuoles may be seen within the cytoplasm; these represent distended and pinched-off segments of the endoplasmic reticulum. This pattern of reversible injury is sometimes called hydropic change or vacuolar degeneration.
Fatty change
A pattern of morphologic changes correlating to reversible injury.
Fatty change, occurring in hypoxic injury and various forms of toxic or metabolic injury, is manifested by the appearance of lipid vacuoles in the cytoplasm. It is principally seen in cells participating in fat metabolism, most often seen in the liver. Injury to hepatocytes interferes with their ability to package lipids into lipoproteins for export, resulting in fat accumulation within the cell.
Hepatic steatosis
“Fatty liver”
May be caused by toxins, malnutrition, diabetes mellitus, obesity, and hypoxia, but alcohol abuse is most common in the industrialized world.
If mild, it may have no effect on cellular function. More severe fatty change can transiently impair cellular function, but it is reversible unless some vital intracellular process is irreversibly impaired.
Definition of Irreversible Injury
- Inability to reverse mitochondrial dysfunction even after resolution of the original injury
- Cell membrane damage.
Cell membrane damage: Loss of membrane phospholipids
This can be caused by increased degradation due to activation of endogenous phospholipases by increases in cytosolic calcium. Progressive phospholipid loss can also occur secondary to decreased ATPdependent recycling or diminished de novo synthesis of phospholipids
Cell membrane damage: Cytoskeletal abnormalities
Activation of proteases by increased intracellular calcium may result in damage to the cytoskeleton. In the setting of cell swelling, such injury may cause detachment of the cell membrane from the cytoskeleton, rendering the membrane susceptible to stretching and rupture.
Cell membrane damage: Toxic oxygen radicals
Partially reduced oxygen species are highly toxic and cause injury to cell membranes and other cell constituents. Such oxygen radicals are increased in ischemic tissues, particularly after restoration of blood flow.
Cell membrane damage: Lipid breakdown products
These catabolic products accumulate in ischemic cells as a result of phospholipid degradation and have a detergent effect on membranes.
____ is a likely mediator of the final cell death knell.
Calcium is a likely mediator of the final cell death knell.
The gross and histologic correlate of cell death occurring in the setting of irreversible exogenous injury
Necrosis
Characterized by cell swelling, denaturation of cytoplasmic proteins, and breakdown of cell organelles.
Cytoplasmic morphologic features of necrosis
Eosinophilia (attributable in part to denatured intracytoplasmic proteins, and in part to loss of the basophilia from cytoplasmic mRNA)
Vacuolated cytoplasm
Degraded organelles
Dystrophic calcification
Dystrophic calcification
If necrotic cells and cellular debris are also not promptly eliminated, they tend to attract calcium and other minerals
Pyknosis
The nucleus condenses into a solid shrunken mass via degradation of nuclear matrix, histones, and nucleic acids
Karyorrhexis
Pattern seen after the pyknotic nucleus fragments into smaller, but discernable pieces.
Karyolysis
In 1 to 2 days, the nucleus in a dead cell completely disappears, presumably due to DNAse degradative activity
Coagulative necrosis
When denaturation is the primary pattern, coagulative necrosis develops. Coagulative necrosis implies preservation of the structural outline of the cell or tissue.
Coagulative necrosis, with preservation of the general tissue architecture, is characteristic of hypoxic death of cells in all tissues except the brain.
Liquefactive necrosis
Observed in the instance of dominant enzyme digestion. Liquefactive necrosis is characteristic of microbial (bacterial or sometimes fungal) infections, since these provide powerful stimuli for the accumulation of white cells. For unclear reasons, hypoxic death of cells within the central nervous system also results in liquefactive necrosis. Liquefaction completely digests the dead cells.
Gangrenous necrosis
Not actually a distinctive pattern of cell death, but refers to ischemic coagulative necrosis of an extremity. The term is still commonly used in surgical practice.
When there is superimposed infection with a liquefactive component, the lesion is called “wet gangrene.“
Caseous necrosis
Caseous necrosis is a distinctive form of necrosis encountered most often in foci of tuberculosis infection. The term “caseous” is derived from the cheesy, white gross appearance of the central necrotic area.
Microscopically, the necrotic focus is composed of amorphous granular debris enclosed within a distinctive ring of granulomatous inflammation. Unlike coagulative necrosis, the tissue architecture is completely effaced (unrecognizable).
Fat necrosis
Describes focal areas of fat destruction resulting from pathologic release of activated lipases
This occurs, for example, in the disastrous abdominal emergency known as acute pancreatitis; activated pancreatic lipases escape from acinar cells and ducts, liquefying fat cell membranes and hydrolyzing the triglycerides contained within them. The released fatty acids combine with calcium to produce visible chalky white areas (fat saponification).
Cardiac Creatine Phosphokinase
Heart-muscle-specific intracellular protein
Leakage of intracellular proteins across the degraded cell membrane into the peripheral circulation can provide a means of detecting tissue-specific cellular injury and death in blood serum samples.
In this case, cardiac creatine phosphokinase in peripheral circulation would be evidence of heart injury.
Apoptosis
single cells, or clusters of cells, that appear as round or oval masses with intensely eosinophilic cytoplasm
The nuclear chromatin is condensed and aggregates peripherally, under the nuclear membrane, into well-defined aggregates of various shapes and sizes. Ultimately, DNA is chopped into nucleosome-sized pieces, presumably through the activation of endonucleases. The cells shrink, form cytoplasmic buds, and fragment into apoptotic bodies composed of membrane-bound vesicles of cytosol and organelles which are phagocytosed or degraded.
Hormone-dependent physiologic involution
ex, shedding of the endometrium during the menstrual cycle.
Regulated by hormone-dependent apoptosis.
Failure of cells to undergo apoptosis may result ____.
Failure of cells to undergo apoptosis may result in aberrant development, unimpeded tumor proliferation, or autoimmune disease.
Necrosis vs Apoptosis Table
Additionally, necrosis usually involves regions while apoptosis usually involves individual cells.
Molecular features of apoptosis
Bcl-2 family
Proteins that negatively regulate mitochondrial permeability (i.e., protect against apoptosis).
Suppress apoptosis by preventing increased mitochondrial permeability, and by stabilizing proteins to prevent caspase activation.
Bax and Bad
Promote apoptosis by inhibiting Bcl-2
Caspases
So-called because they have an active site cysteine, and cleave after aspartic acid residues
Apoptotic DNA laddering
DNA breakdown into 180-200 base pair segments (the length of DNA within a nucleosome) occurs through the action of endonucleases. This may be visualized on agarose gel electrophoresis.
This pattern is different from the random DNA fragmentation (forming a “smear” on agarose gels) typically seen in necrotic cells.
