Pathology Module 2 PDF

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Summary

Cell Adaptation, Injury and Death - Key TermsAfter completing this module you will be able to understand the various ways in which the cell can respond to damaging stimuli and more specifically be able to: List several causes or agents of cell injury. Causes of Cell InjuryRudolf Virchow disease ari...

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Module 2: Cell Adaptation, Injury and Death

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Cell Adaptation, Injury and Death - Key Terms After completing this module you will be able to understand the various ways in which the cell can respond to damaging stimuli and more specifically be able to: 1. List several causes or agents of cell injury. Causes of Cell Injury Rudolf Virchow disease arises, not in organs or tissues, but in individual cells. Cells must react and adapt to changing internal and external environments in order to survive. When the environmental changes exceed the capacity of the cell to maintain homeostasis we recognize cell injury. A number of agents can cause injury or present a damaging stimulus to the cell, including: 

physical agents (trauma, radiation, excessive temperatures, changes in pressure)

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chemical agents (air pollutants, CO, pesticides, poisons, toxins, drugs)

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biological agents (microorganisms, e.g. viral or bacterial infections; biological toxins)

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nutritional or metabolic alterations (nutrient deficiencies or excesses, ischemia or lack of adequate blood supply; hypoxia or oxygen deficiency)

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immune reactions (allergens, autoimmune disease)

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genetic defects (single mutations such as hemoglobin mutation in sickle cell disease; chromosomal abnormalities such as trisomy 21 or Down syndrome)

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cellular aging (loss of intrinsic repair mechanisms; repeated healing & repair following external injuries).

2. Define and give appropriate physiological and pathological examples of cellular adaptation, i.e. atrophy, hypertrophy, hyperplasia, and metaplasia. Reaction of the cell to a stress or damaging stimulus can range from a mild, completely reversible response to a long-term adaptive change in cell growth or to irreversible damage and cell death. The moment when reversible injury becomes irreversible injury, or the 'point of no return', cannot be well defined. The cell's response depends to a large extent on the    

severity of the stimulus, the time frame over which it is exposed to the stressor (acute or chronic) the individual cell type and its characteristics (rate of division, presence of protective mechanisms (e.g. free radical scavenging systems) its nutritional or metabolic state, its blood supply).

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Four cell components are particularly vulnerable. These are 

cell membranes critical for ionic and osmotic homeostasis;

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mitochondria and the generation of energy via ATP;

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protein synthetic machinery; and

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cellular DNA.

Cellular Adaptation Long term or chronic stimuli result in different adaptive responses in cells. The response to persistent sublethal injury (chemical or physical) makes the cell change to a new steady state and preserve cell viability.  

Adaptive responses may include regulation of cell receptors or changes in cell protein synthesis and turnover (increases or decreases). These adaptations include changes in size (atrophy or hypertrophy), number (hyperplasia) or organization (metaplasia, dysplasia) of cells.

Atrophy: defined as a decrease in mass due to the shrinkage in cell size.    

Reduced demand leads to atrophy of organs (if you don't use it, you lose it!). Due to diminished blood supply (e.g. ischemia) or diminished nutritional or trophic (i.e. growth or hormonal) factors a new steady state is reached in which a smaller cell is able to survive. The degradation/breakdown of cellular proteins and decreased protein synthesis plays a key role in atrophy. Sometimes accompanied by autophagy (“self-eating”); the process in which the starved cell eats its own components in an attempt to survive

Atrophy can be physiological or pathological.  

physiological atrophy occurs in normal aging (e.g. shrinkage and loss of brain cells with age). pathological atrophy is 'disuse atrophy' of skeletal muscle in an immobilized limb or 'degeneration atrophy' following loss of nerve input to the muscle (e.g. following a spinal cord injury).

Hypertrophy: increase in the size of existing cells, due to the increase in synthesis of cellular protein and structural components and organelles responsible for producing them.  

Can be physiological or pathological in response to increasing functional demand or specific hormonal stimulation. The mechanisms driving cardiac hypertrophy involve at least two types of signals: mechanical triggers, such as stretch, and trophic triggers, which typically are soluble mediators that stimulate cell growth (ex: growth factors and adrenergic hormones)

Hyperplasia: Increase in number of cells caused by cell division. 

Hypertrophy and hyperplasia can occur as a normal response to various stimuli (e.g. hormonal stimulation, increased demand) and often occur together.

Module 2: Cell Adaptation, Injury and Death hyperplasia and hypertrophy of uterine smooth muscle occur in pregnancy in response to estrogen. o hypertrophy of skeletal muscle occurs as a normal physiological response in weight training. o compensatory hyperplasia occurs when a portion of tissue is removed (e.g. after partial liver resection mitotic activity in remaining cells begins within 12 hours and eventually l o hormonal hyperplasia: ex, increase of the glandular epithelium of the female breast at puberty and during pregnancy However, they may also be pathological responses. o Hypertrophy of cardiac muscle fibres occurs in response to increased workload as a result of systemic hypertension. o Excessive stimulation of the normal uterus by estrogen may result in endometrial hyperplasia. Metaplasia: If the long-term environment becomes unsuitable for certain types of cells, they may change into a different cell type, a process called metaplasia. o For example, cells in the bronchi of smokers change from ciliated columnar epithelial cells to squamous cells (they are more likely to survive) Dysplasia: refers to an alteration in the size, shape and organization of the cellular components of a tissue. o occurs most commonly in metaplastic squamous epithelium of the respiratory tract and cervix. o represents deranged cell growth it is potentially reversible after the irritating cause has been removed. o recognized as a preneoplastic lesion in a number of organs (e.g. cervix, prostate, bladder). o

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Summary atrophy - reduction in cell size hypertrophy - increase in cell size

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hyperplasia - increase in cell number metaplasia - change from one adult cell type to another dysplasia - disorganized or disorderly growth of cells ***Know a couple of examples of each adaptation and remember that in each case (except for dysplasia) these changes can occur physiologically (part of normal development or aging) or pathologically (an abnormal reaction)***

3. Provide examples of physiological (e.g., lipofuscin, melanin) and pathological intracellular accumulations (e.g., fatty change). Reversible Cell Injury - Intracellular Accumulations - Fatty Change  

Under normal circumstances cells store fats, glycogen, vitamins and minerals for use in general cell metabolism. Cells also store the products of turnover as endogenous pigments such as, o lipofuscin, degraded phospholipids as the golden-brown granules of the "wear-and-tear" pigment which increases with age particularly in heart, lung and brain o melanin, an insoluble brown-black pigment, found in the skin and in certain brain cells o hemosiderin, the iron brown pigment derived from the breakdown of red blood cells. o The most common exogenous pigment is carbon (from air pollution) which is inhaled and deposited in tracheobronchial lymph nodes and lung tissue. o Endogenous originated inside the organism o Exogenousoriginate outside the organism

Another form of reversible adaptation to cell stressors is fatty change or the abnormal accumulation of triglycerides within cells.  

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Fatty change (or steatosis) refers to any abnormal accumulations of triglycerides within cells. Fatty change is linked to the intracellular accumulation of fat either because of o an increased delivery of fat to the cell (e.g. in starvation, diabetes) o an impairment of fat metabolism within the cell (e.g. in liver cells in alcoholism) o a decreased synthesis of apolipoproteins for transport out of the cell (e.g. in protein malnutrition, CCl4 (carbon tetrachloride) toxicity). Small vacuoles of fat appear throughout the cytoplasm or may coalesce to form one large vacuole that displaces the nucleus.

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The liver, where most fats are stored and metabolized, is particularly susceptible to fatty change, but it may also occur in heart, kidney, muscle and other organs as a result of toxin exposure (e.g. alcohol, CCl4), protein malnutrition or starvation, diabetes, obesity and anoxia. o Fatty change is entirely reversible if the stimulus is removed.

Reversible Cell Injury - Hydropic Swelling 

Cells lose functional activity relatively quickly as a result of biochemical derangements, while the morphological changes of cell injury and death lag far behind. o Ex: heart cells lose the ability to contract after 1 to 2 minutes of ischemia, but do not die until 20 to 30 minutes of prolonged ischemia. Changes in cell ultrastructure may not be apparent until several hours later.

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Injury caused by a variety of agents (e.g. chemical or biological toxins, viral or bacterial infections, ischemia or hypoxia, excessive heat or cold) produces a characteristic cellular or hydropic swelling when seen under the microscope. Hydropic swelling or hydropic change is an increase in cell volume characterized by a large, pale and vacuolated cytoplasm and a normally located nucleus. This cellular swelling results from impairment of the process that controls ionic (sodium) concentrations in the cytoplasm. Agents can impair the sodium-potassium (Na-K ATPase) pump leading to an accumulation of sodium in the cell. o leads to an increase in water in the cell to maintain isosmotic conditions and the cell swells. o Mitochondria may also swell, the cisternae of the endoplasmic reticulum also become dilated, and blebs may form on the plasma membrane. o Classic case is due to short periods of hypoxia (reduced oxygen in blood) or ischemia (reduced blood supply and hence oxygen and other nutrients).

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4. Define and contrast reversible versus irreversible cell injury. a. Describe the cellular changes seen in reversible cell injury (e.g. cellular swelling / hydropic degeneration; fatty change). b. Describe the cellular changes seen in irreversible cell injury leading to necrosis (e.g. within the nucleus - pyknosis, karyorrhexis, karyolysis; within the cytoplasm eosinophilia).

Irreversible Cell Injury and Cell Death - Necrosis 

At early stages or in mild forms of injury the functional and morphological changes are entirely reversible if the stimulus is removed. At this stage the injury has not progressed to severe membrane or nuclear damage. With continuing damage, cell injury becomes irreversible; the cell cannot recover and dies.

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There are two types of cell death - necrosis and apoptosis - which differ in their morphology, mechanisms, and cause (whether physiological or pathological). o If overwhelming injury occurs or occurs at a rate at which the cell cannot adapt, irreversible cell injury leads to necrosis or cell death. Necrosis is characterized by certain structural changes; these include intense eosinophilia (pinkness) of the cytoplasm and pyknosis (shrinkage), karyorrhexis (the pyknotic nucleus fragments or breaks up) and karyolysis (dissolution) of the nucleus.

c. Describe coagulative, liquefactive, fat, caseous, and gangrenous necrosis and be able to give an example of each. Several types of necrosis are seen. These are associated with different types of cell damage. 

Coagulative: The most common form of necrosis - microscopically all of the changes described above are seen (eosinophilia, pyknosis, karyorrhexis and karyolysis). Cells appear like "ghosts" of themselves in which the basic structural outline of the coagulated cell persists for a number of days. o

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Liquefactive: Rapid loss of tissue architecture and digestion of the dead cells. o

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Most often seen in CNS. Typical of bacterial damage.

Fat: Specific to fat (adipose) tissue. Released enzymes digest fat that complexes with calcium to form chalky-white deposits o

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Typical of ischemia, e.g. in heart (myocardial) cells.

e.g. pancreatitis, damage to breast tissue.

Caseous: Soft, friable, "cheesy" material. Characteristic of tuberculosis. Note: the term "gangrenous necrosis" or "wet gangrene" is used to refer to coagulative necrosis (most frequently of a limb) when there is superimposed infection with a liquefactive component.

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If the necrotic tissue dries out (with no infectious component) it becomes dark black and mummified and is called "dry gangrene"

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5. Define and contrast apoptosis and necrosis. Describe the morphological changes that characterize each. Programmed Cell Death - Apoptosis  

Apoptosis is the morphologic manifestation of programmed cell death and is distinct from necrosis, an uncontrolled process of cell death in response to overwhelming injury. Apoptosis is an energy-dependent process specifically designed to switch off unneeded or damaged cells and eliminate them.

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Apoptosis can occur under either physiological (e.g. during embryogenesis in shaping of fingers and toes; the physiological involution of the thymus during development or the endometrium during the menstrual cycle; removal of an infected or damaged cell) or pathological (e.g. following radiation injury, in some cancers) conditions.

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Apoptotic cells initiate their own death by the activation of proteases known as caspases and endogenous endonucleases that breakdown the cell nucleus and cytoskeleton. o

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The cell nucleus collapses, the cell shrinks and is cleaved into membrane-bound clumps enclosing organelles (apoptotic bodies). The membrane bound material is recognized and engulfed by phagocytic cells

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In apoptosis the initial changes consist of nuclear chromatin condensation and fragmentation, followed by cytoplasmic budding and phagocytosis of the extruded apoptotic bodies. o In contrast, signs of necrosis include chromatin clumping, organelle swelling and membrane damage.

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Comparison of Cell Death by Apoptosis versus Necrosis 

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The magnitude and type of injurious stimulus can determine whether a cell undergoes apoptosis or necrosis. Severe damaging stimuli tend to result in necrosis and lower-grade stimuli and immune-mediated damage tend to cause apoptosis. A critical factor is how much cellular ATP is available after cell damage where there is severe depletion of ATP the necrotic pathway is followed because apoptosis is energy dependent

6. Describe the mechanism of cell injury and/or cell death in response to decreased oxygen. Ischemic Cell Death   

The reduction or interruption of blood flow in ischemia is the most common type of cell injury and an important cause of coagulative necrosis. Ischemia can injure tissues faster than reduced levels of oxygen alone (hypoxia) since both oxygen and substrates for glycolysis and continued ATP generation disappear. Reduced levels of oxygen or the absence of oxygen (anoxia) during ischemia leads to a sequence of steps resulting in necrosis. o Decreased oxygen compromises respiration in mitochondria damaging the ability to produce ATP. o Decreased ATP impairs the ability of the cells to pump ions and water (via Na-K ATPase) with the subsequent accumulation of intracellular sodium and the diffusion of potassium out of the cell. o The net gain of sodium is accompanied by an isosmotic gain of water resulting in acute cellular swelling and in the swelling of cellular components with damage and rupture to the cell membranes.

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Decreased oxygen also results in increased anaerobic glycolysis and the depletion of glycogen stores resulting in a buildup of lactic acid in the cell (and hence a decrease in intracellular pH or a more acidic environment - acidosis). Decreased ATP and pH levels cause ribosomes to detach from rough endoplasmic reticulum (RER) with a reduction in protein synthesis.

If oxygen is restored all of the above disturbances are reversible. If ischemia or hypoxia is not relieved, worsening mitochondrial function and increasing membrane permeability cause further deterioration with irreversible cell injury and: o The acidic environment releases proteolytic enzymes from their normal compartments in the cell which induces widespread damage. o In addition, calcium increases in cells due to pump failure (Ca-ATPase). Increase in intracellular calcium activates many enzyme systems inappropriately, leading to further cell damage.  Some of the enzyme systems attack cellular skeletal proteins which cause cells to become abnormally fragile. Leakage of cell proteins across the degraded cell membrane into the peripheral circulation provides a means of detecting tissue-specific cell injury and death by measuring their levels in blood serum samples o e.g. heart muscle cells contain a specific isoform of the enzyme creatine kinase (CKMB) and of the contractile protein troponin which become elevated in blood following a 'heart attack' or myocardial infarction and death of cardiac cells

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Cell Adaptation, Injury and Death - Key Terms adaptation - cells attempt to maintain an internal steady-state, but when exposed to an adverse stimulus undergo various adaptations atrophy, hypertrophy, hyperplasia, metaplasia, or dysplasia) to establish a new 'steady-state'. If the stimulus is removed the cell reverts to normal. anoxia - absence or almost complete absence of oxygen from inspired gases, arterial blood or tissues. apoptosis - programmed cell death; characteristically seen during development (e.g. death of cells to shape fingers and toes); may also occur pathologically (e.g. after radiation). atrophy - a decrease in tissue mass due to shrinkage of cells irreversible cell injury - results from an overwhelming injury or one in which the cell has no time for an adaptive response; necrosis & apoptosis. reversible cell injury - results from an acute injury to the cell (morphologically: hydropic swelling) or low level, long term or chronic stimulus (atrophy, hypertrophy, hyperplasia) that can revert dysplasia - an alteration in the size, shape and/or organization of the cells in a tissue. fatty change - the accumulation of fat within a cell due to impaired fat metabolism, e.g. fatty change within liver cells in alcoholism. hemosiderin - an insoluble form of tissue storage iron, can be seen under the microscope with or without special stains. hydropic swelling - an increase in cell volume due to the impairment of normal ion regulating mechanisms that leads to an increase in cellular...