Cellular Responses to Stress and Toxic Insults

Cellular Responses to Stress and Toxic Insults
Lisa Stevens, D.O.

Introduction Pathology Study (logos) of disease (pathos)
Structural, biochemical, and functional changes Cells, tissues, and organs that underlie disease

Introduction Four aspects of a disease process Cause (etiology)
Mechanisms of its development (pathogenesis) Biochemical and structural alterations (molecular and morphologic changes) Functional consequences of these changes (clinical manifestations)

Etiology Two major classes Genetic Acquired Inherited mutations
Disease-associated gene variants Acquired Infectious Nutritional Chemical Physical

Pathogenesis Sequence of events in the response of cells or tissues to the etiologic agent From the initial stimulus to the ultimate expression of the disease One of the main domains of pathology

Molecular and Morphologic Changes
Structural alterations in cells or tissues Characteristic of a disease Diagnostic of an etiologic process

Functional Derangements and Clinical Manifestations
Functional abnormalities End results of genetic, biochemical, and structural changes in cells and tissues Lead to the clinical manifestations (symptoms and signs) Lead to the progression of disease (clinical course and outcome)

Functional Derangements and Clinical Manifestations
Disease Starts with molecular or structural alterations in cells Concept first put forth by Rudolf Virchow (19th century) Father of modern pathology Injury to cells and to extracellular matrix Tissue and organ injury Determine the morphologic and clinical patterns of disease

Cellular Responses to Stress and Noxious Stimuli
Normal cell Confined to a narrow range of function and structure State of metabolism, differentiation, and specialization Constraints of neighboring cells Availability of metabolic substrates Maintains homeostasis (steady state)

Adaptations Reversible functional and structural responses Usually due to physiologic stresses and pathologic stimuli Hypertrophy (increase in the size of cells) Hyperplasia (increase in the number of cells) Atrophy (decrease in the size and metabolic activity of cells) Metaplasia (change in the phenotype of cells)

Cell injury Exposure to injurious agents or stress Deprivation of essential nutrients Compromised by mutations that affect essential cellular constituents Reversible Up to a certain point Irreversible injury and cell death Stimulus persists

Cell death End result of progressive cell injury One of the most crucial events in the evolution of disease Results from diverse causes Ischemia (reduced blood flow) Infection Toxins

Cell death Normal and essential process Embryogenesis Maintenance of homeostasis Two principal pathways of cell death Necrosis and apoptosis

Figure 1-2 The relationship between normal, adapted, reversibly injured, and dead myocardial cells. The cellular adaptation is myocardial hypertrophy (lower left), caused by increased blood flow requiring greater mechanical effort by myocardial cells. This adaptation leads to thickening of the left ventricular wall to over 2 cm (normal, cm). In reversibly injured myocardium (illustrated schematically, right) there are generally only functional effects, without any readily apparent gross or even microscopic changes. In the specimen showing necrosis, a form of cell death (lower right), the light area in the posterolateral left ventricle represents an acute myocardial infarction caused by reduced blood flow (ischemia). All three transverse sections of the heart have been stained with triphenyltetrazolium chloride, an enzyme substrate that colors viable myocardium magenta. Failure to stain is due to enzyme loss following cell death.

Adaptations of Cellular Growth and Differentiation
Hypertrophy Increase in the size of cells Results in an increase in the size of the organ No new cells, just larger cells Due to synthesis of structural components of the cells Cellular proteins

Hypertrophy Physiologic or pathologic Cause Increased functional demand Stimulation by hormones and growth factors

Hypertrophy Example: Striated muscle cells (heart and skeletal muscle) Limited capacity for division Respond to increased metabolic demands Most common stimulus Increased workload Example: Bodybuilders "pumping iron" Increase in size of the individual muscle fibers

Hypertrophy Mechanisms Two main biochemical pathways
Induced by linked actions Mechanical sensors Growth factors Vasoactive agents Two main biochemical pathways Phosphoinositide 3-kinase/Akt pathway Signaling downstream of G protein-coupled receptors

Hypertrophy Usually refers to increase in size of cells or tissues
HOWEVER, a subcellular organelle may undergo selective hypertrophy Example: Individuals treated with drugs (barbiturates) Hypertrophy of the smooth endoplamic reticulum (SER) in hepatocytes Adaptive response Increases the amount of enzymes (cytochrome P-450 mixed function oxidases) available to detoxify the drugs Eventually, patients respond less to the drug May result in an increased capacity to metabolize other drugs

Hyperplasia Increase in the number of cells in an organ or tissue
Results in increased mass of the organ or tissue May occur in the setting of hypertrophy Physiologic and pathologic

Hyperplasia Increase in the number of cells in an organ or tissue
Physiologic hyperplasia Hormonal hyperplasia Increases the functional capacity of a tissue when needed Compensatory hyperplasia Increases tissue mass after damage or partial resection

Hyperplasia Physiologic hyperplasia Hormonal hyperplasia
Proliferation of the glandular epithelium of the female breast Puberty Pregnancy Compensatory hyperplasia Myth of Prometheus Ancient Greeks recognized the capacity of the liver to regenerate Liver transplantation (donor)

Figure 1-3 Physiologic hypertrophy of the uterus during pregnancy
Figure 1-3 Physiologic hypertrophy of the uterus during pregnancy. A, Gross appearance of a normal uterus (right) and a gravid uterus (removed for postpartum bleeding) (left). B, Small spindle-shaped uterine smooth muscle cells from a normal uterus, compared with C, large plump cells from the gravid uterus, at the same magnification.

Hyperplasia Pathologic Hyperplasia
Caused by excesses of hormones or growth factors acting on target cells Endometrial hyperplasia Abnormal hormone-induced hyperplasia Common cause of abnormal menstrual bleeding

Hyperplasia Pathologic Hyperplasia Benign prostatic hyperplasia
Induced by responses to androgens Constitutes a fertile soil in which cancerous proliferation may eventually arise

Atrophy Reduced size of an organ or tissue
Results from a decrease in cell size and number Physiologic atrophy Common during normal development Embryonic structures Notochord Thyroglossal duct Uterus Decreased size shortly after parturition

Atrophy Pathologic atrophy Common causes of atrophy
Depends on the underlying cause Local or generalized Common causes of atrophy Decreased workload (atrophy of disuse) Muscle atrophy secondary to immobilization/bedrest Loss of innervation (denervation atrophy) Diminished blood supply

Atrophy Common causes of atrophy Inadequate nutrition
Profound protein-calorie malnutrition (marasmus) Use of skeletal muscle as a source of energy after other reserves (adipose stores) have been depleted Loss of endocrine stimulation Hormone-responsive tissues (breast and reproductive organs) Pressure Tissue compression for any length of time

Atrophy Mechanisms Results from decreased protein synthesis
Reduced metabolic activity Results from increased protein degradation in cells Ubiquitin-proteasome pathway Responsible for the accelerated proteolysis Catabolic conditions (cancer cachexia)

Atrophy Accompanied by increased autophagy Autophagy ("self eating")
Increases in the number of autophagic vacuoles Autophagy ("self eating") Process in which the starved cell eats its own components to survive

Atrophy Autophagic vacuoles
Membrane-bound vacuoles that contain fragments of cell components Vacuoles ultimately fuse with lysosomes Contents are digested by lysosomal enzymes Some cell debris (in the autophagic vacuoles) resist digestion Persist as membrane-bound residual bodies Lipofuscin granules (brown atrophy)

Figure 1-5 Atrophy. A, Normal brain of a young adult
Figure 1-5 Atrophy. A, Normal brain of a young adult. B, Atrophy of the brain in an 82-year-old male with atherosclerotic cerebrovascular disease, resulting in reduced blood supply. Note that loss of brain substance narrows the gyri and widens the sulci. The meninges have been stripped from the right half of each specimen to reveal the surface of the brain.

Metaplasia Reversible change
One differentiated cell type replaced by another cell type Adaptive substitution of cells (sensitive to stress) Cell types better able to withstand adverse environments

Metaplasia Most common epithelial metaplasia
Columnar to squamous Occurs in the respiratory tract Chronic irritation Cigarette smoker Normal PCCE replaced by stratified squamous epithelial cells Lack of mucociliary elevator If persistent, may initiate malignant transformation in metaplastic epithelium

Metaplasia Metaplasia from squamous to columnar type
Barrett esophagus Esophageal squamous epithelium is replaced by intestinal-like columnar cells Influence of refluxed gastric acid Connective tissue metaplasia Formation of cartilage, bone, or adipose tissue (mesenchymal tissues) in tissues that do not contain these elements Bone formation in muscle (myositis ossificans) Can occur following an intramuscular hemorrhage

Metaplasia Mechanisms
Does not result from a change in the phenotype of an already differentiated cell type Result of reprogramming Stem cells (known to exist in normal tissues) Undifferentiated mesenchymal cells present in connective tissue Precursor cells differentiate along a new pathway

Figure 1-6 Metaplasia of columnar to squamous epithelium
Figure 1-6 Metaplasia of columnar to squamous epithelium. A, Schematic diagram. B, Metaplasia of columnar epithelium (left) to squamous epithelium (right) in a bronchus.

Practice Question A 43-year-old man has complained of mild burning substernal pain following meals for the past 3 years. Upper GI endoscopy is performed and biopsies are taken of an erythematous area of the lower esophageal mucosa 3 cm above the gastroesophageal junction. There is no mass lesion, no ulceration, and no hemorrhage noted. The biopsies show the presence of columnar epithelium with goblet cells. Which of the following mucosal alterations is most likely represented by these findings? A. Dysplasia B. Metaplasia C. Hypertrophy D. Hyperplasia E. Ischemia

Practice Question A 19-year-old woman gives birth to her first child. She begins breast feeding the infant. She continues breast feeding for almost a year with no difficulties and no complications. Which of the following cellular processes that began in the breast during pregnancy allowed her to nurse the infant for this period of time? A. Lobular hyperplasia B. Stromal hypertrophy C. Epithelial dysplasia D. Steatocyte atrophy E. Ductal epithelial metaplasia

Practice Question A study is performed involving the microscopic analysis of tissues obtained from surgical procedures. Some of these tissues have the microscopic appearance of an increased cell size of multiple cells within the tissue, due to an increase in the amount of cytoplasm, with nuclei remaining uniform in size. Which of the following conditions is most likely to have resulted in this finding? A. Uterine myometrium in pregnancy B. Female breast at puberty C. Liver following partial resection D. Ovary following menopause E. Cervix with chronic inflammation

Practice Question A 38-year-old man incurs a traumatic blow to his upper left arm. He continues to have pain and tenderness even after 3 months have passed. A plain film radiograph reveals a 4 cm circumscribed mass in the soft tissue adjacent to the humerus. The mass contains areas of brightness on the x-ray. Over the next year this process gradually resolves. Which of the following terms best describes this process? A. Dysplasia B. Hyperplasia C. Hypertrophy D. Metaplasia E. Neoplasia

Practice Question A 21-year-old woman has a routine Pap smear performed for a health screening examination. The pathology report indicates that some cells are found cytologically to have larger, more irregular nuclei. A follow-up cervical biopsy microscopically demonstrates disordered maturation of the squamous epithelium, with hyperchromatic and pleomorphic nuclei extending nearly the full thickness of the epithelial surface. No inflammatory cells are present. Which of the following descriptive terms is best applied to these Pap smear and biopsy findings? A. Dysplasia B. Metaplasia C. Anaplasia D. Hyperplasia E. Aplasia

Practice Question A 3-year-old child has been diagnosed with ornithine transcarbamylase deficiency and has developed hepatic failure. The left lobe of an adult donor liver is used as an orthotopic transplant. A year later, the size of each liver in donor and recipient is greater than at the time of transplantation. Which of the following cellular alterations is most likely to explain this phenomenon? A. Metaplasia B. Dysplasia C. Hyperplasia D. Anaplasia E. Neoplasia

Cellular adaptations Lecture #2
Lisa Stevens, D.O.

Causes of Cell Injury Oxygen deprivation Physical agents
Chemical agents and drugs Infectious agents Immunologic reactions Genetic derangements Nutritional imbalances

Injurious Stimuli Oxygen Deprivation Hypoxia Deficiency of oxygen
Reduces aerobic oxidative respiration Causes Reduced blood flow (ischemia) Inadequate oxygenation of the blood Cardiorespiratory failure

Injurious Stimuli Oxygen Deprivation Hypoxia Causes, continued
Decreased oxygen-carrying capacity of the blood Anemia Carbon monoxide poisoning Severe blood loss Depending on the severity Cells may adapt, undergo injury, or die

Injurious Stimuli Physical Agents Mechanical trauma
Extremes of temperature (burns and deep cold) Sudden changes in atmospheric pressure Radiation Electric shock

Injurious Stimuli Chemical Agents and Drugs
Chemicals (too many to list) Glucose or salt in hypertonic concentrations Oxygen at high concentrations Trace amounts of poisons Environmental and air pollutants Insecticides, herbicides Industrial and occupational hazards Recreational drugs (alcohol) Therapeutic drugs

Injurious Stimuli Infectious Agents
Submicroscopic viruses to the large tapeworms Rickettsiae Bacteria Fungi Higher forms of parasites

Injurious Stimuli Immunologic Reactions
Injurious reactions to endogenous self-antigens Several autoimmune diseases Immune reactions to external agents Microbes Environmental substances

Injurious Stimuli Genetic Derangements Severe defects Subtle defects
Congenital malformations associated with Down syndrome Chromosomal anomaly Subtle defects Decreased life span of red blood cells Single amino acid substitution in hemoglobin in sickle cell anemia Variations in the genetic makeup Influence the susceptibility of cells by chemicals and other environmental insults

Injurious Stimuli Nutritional Imbalances Protein-calorie deficiencies
Underprivileged populations Deficiencies of specific vitamins Self-imposed problems Anorexia nervosa Nutritional excesses Excess of cholesterol Obesity

Morphologic Alterations
Sequential morphologic changes in cell injury Reversible injury Generalized swelling of the cell and its organelles Blebbing of the plasma membrane Detachment of ribosomes from the ER Clumping of nuclear chromatin Associations Decreased generation of ATP Loss of cell membrane integrity Defects in protein synthesis Cytoskeletal damage DNA damage

Reversible Injury Two features of reversible cell injury
Cellular swelling Cells are incapable of maintaining ionic and fluid homeostasis Result of failure of energy-dependent ion pumps in the plasma membrane Fatty change Hypoxic injury Various forms of toxic or metabolic injury Manifested by the appearance of lipid vacuoles in the cytoplasm Hepatocytes and myocardial cells

Reversible Injury Morphology Cellular swelling
First manifestation of almost all forms of injury to cells Difficult morphologic change to appreciate with the light microscope More apparent at the level of the whole organ Pallor, increased turgor, and increase in weight of the organ Microscopic examination Small clear cytoplasmic vacuoles (distended and pinched-off ER) Hydropic change or vacuolar degeneration

Figure 1-9 Morphologic changes in reversible cell injury and necrosis
Figure 1-9 Morphologic changes in reversible cell injury and necrosis. A, Normal kidney tubules with viable epithelial cells. B, Early (reversible) ischemic injury showing surface blebs, increased eosinophilia of cytoplasm, and swelling of occasional cells. C, Necrosis (irreversible injury) of epithelial cells, with loss of nuclei, fragmentation of cells, and leakage of contents. The ultrastructural features of these stages of cell injury are shown in Figure (Courtesy of Drs. Neal Pinckard and M.A. Venkatachalam, University of Texas Health Sciences Center, San

Reversible Injury Ultrastructural changes Plasma membrane alterations
Blebbing, blunting, and loss of microvilli Mitochondrial changes Swelling Appearance of small amorphous densities Dilation of the ER Detachment of polysomes Intracytoplasmic myelin figures may be present Nuclear alterations Disaggregation of granular and fibrillar elements

Irreversible Cell Injury and Cell Death
Continuous damage Cell injury becomes irreversible Cell cannot recover and it dies Two principal types of cell death Necrosis Severe membrane damage Lysosomal enzymes enter the cytoplasm and digest the cell, and cellular contents leak out Always a pathologic process Apoptosis Cell's DNA or proteins are damaged beyond repair Cell kills itself by nuclear dissolution, fragmentation of the cell without complete loss of membrane integrity, and rapid removal of the cellular debris Serves many normal functions Not necessarily associated with cell injury

Figure 1-7 Sequential development of biochemical and morphologic changes in cell injury. Cells may become rapidly nonfunctional after the onset of injury, although they are still viable, with potentially reversible damage; a longer duration of injury may eventually lead to irreversible injury and cell death. Note that irreversible biochemical alterations may cause cell death, and typically this precedes ultrastructural, light microscopic, and grossly visible morphologic changes.

Figure 1-8 Schematic illustration of the morphologic changes in cell injury culminating in necrosis or apoptosis.

Necrosis Morphologic appearance
Result of denaturation of intracellular proteins and enzymatic digestion of the lethally injured cell Necrotic cells Unable to maintain membrane integrity Contents leak Elicits inflammation in the surrounding tissue

Necrosis Necrotic cells
Increased eosinophilia in hematoxylin and eosin (H & E) stains Loss of cytoplasmic RNA (which binds the blue dye, hematoxylin) Denatured cytoplasmic proteins (which bind the red dye, eosin) Glassy homogeneous appearance Loss of glycogen particles Digestion of cytoplasmic organelles---vacuolated cytoplasm (moth-eaten) Dead cells Replaced by large, whorled phospholipid masses (myelin figures) Derived from damaged cell membranes Phospholipid precipitates Phagocytosed by other cells Further degraded into fatty acids

Necrosis Necrotic cells Nuclear changes
Due to nonspecific breakdown of DNA Karyolysis Fading of the basophilia of the chromatin A change that presumably reflects loss of DNA because of enzymatic degradation by endonucleases Pyknosis Nuclear shrinkage Increased basophilia Chromatin condenses into a solid, shrunken basophilic mass Karyorrhexis Pyknotic nucleus undergoes fragmentation Nucleus in the necrotic cell totally disappears (1 or 2 days)

Patterns of Tissue Necrosis
Coagulative necrosis Architecture of dead tissues is preserved for a span of a few days Tissue displays a firm texture Eosinophilic, anucleate cells persist for days or weeks Removed by phagocytosis of the cellular debris by infiltrating leukocytes Digestion of the dead cells by the action of lysosomal enzymes of the leukocytes Example: Ischemia caused by obstruction in a vessel may lead to coagulative necrosis of the supplied tissue Localized area Infarct

Figure 1-11 Coagulative necrosis
Figure 1-11 Coagulative necrosis. A, A wedge-shaped kidney infarct (yellow). B, Microscopic view of the edge of the infarct, with normal kidney (N) and necrotic cells in the infarct (I) showing preserved cellular outlines with loss of nuclei and an inflammatory infiltrate (which is difficult to discern at this magnification).

Liquefactive necrosis Characterized by digestion of the dead cells Resulting in transformation of the tissue into a liquid viscous mass Seen in focal bacterial infections Occasionally seen in fungal infections Creamy yellow Dead leukocytes Purulent matter (aka pus) Hypoxic death of cells in the CNS

Figure 1-12 Liquefactive necrosis
Figure 1-12 Liquefactive necrosis. An infarct in the brain, showing dissolution of the tissue.

Gangrenous necrosis Not a specific pattern of cell death Commonly used in clinical practice Applied to a limb (usually lower leg) Lost its blood supply and has undergone necrosis (typically coagulative necrosis) Involving multiple tissue planes Add in a bacterial infection More liquefactive necrosis Because of the actions of degradative enzymes in the bacteria and the attracted leukocytes Wet gangrene

Caseous necrosis Encountered most often in foci of tuberculous infection “Caseous" (cheeselike) Derived from the friable white appearance of the area of necrosis Microscopic examination Collection of fragmented or lysed cells Amorphous granular debris enclosed within a distinctive inflammatory border Characteristic of a focus of inflammation known as a granuloma

Figure 1-13 Caseous necrosis
Figure 1-13 Caseous necrosis. Tuberculosis of the lung, with a large area of caseous necrosis containing yellow-white and cheesy debris.

Fat necrosis Term that is well fixed in medical parlance Does not denote a specific pattern of necrosis Focal areas of fat destruction Release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity Microscopic examination Foci of shadowy outlines of necrotic fat cells Basophilic calcium deposits Inflammatory reaction

Figure 1-14 Fat necrosis. The areas of white chalky deposits represent foci of fat necrosis with calcium soap formation (saponification) at sites of lipid breakdown in the mesentery.

Fibrinoid necrosis Special form of necrosis Seen in immune reactions involving blood vessels Complexes of antigens and antibodies Deposited in the walls of arteries Microscopic examination Deposits of these "immune complexes" and fibrin Bright pink and amorphous appearance (“fibrinoid”)

Figure 1-15 Fibrinoid necrosis in an artery
Figure 1-15 Fibrinoid necrosis in an artery. The wall of the artery shows a circumferential bright pink area of necrosis with inflammation (neutrophils with dark nuclei).

Mechanisms of Cell Injury
Principles that are relevant to most forms of cell injury Cellular response to injurious stimuli Depends on the nature of the injury, its duration, and its severity Small doses of a chemical toxin or brief periods of ischemia may induce reversible injury Large doses of the same toxin or more prolonged ischemia Instantaneous cell death Slow, irreversible injury leading in time to cell death Consequences of cell injury depend on the type, state, and adaptability of the injured cell

Mechanisms of Cell Injury
Principles that are relevant to most forms of cell injury Cell injury results from different biochemical mechanisms acting on several essential cellular components Mitochondria Cell membranes DNA in nuclei Any injurious stimulus may simultaneously trigger multiple interconnected mechanisms that damage cells Difficult to ascribe cell injury in a particular situation to a single or even dominant biochemical derangement

ATP ATP is produced in two ways Major pathway (mammalian cells)
Oxidative phosphorylation of adenosine diphosphate Reaction that results in reduction of oxygen by the electron transfer system of mitochondria Second pathway Glycolytic pathway Generates ATP in the absence of oxygen Uses glucose derived either from body fluids or from the hydrolysis of glycogen

Depletion of ATP ATP depletion and decreased ATP synthesis
Associated with both hypoxic and chemical (toxic) injury Major causes Reduced supply of oxygen and nutrients Mitochondrial damage Actions of toxins (e.g., cyanide)

ATP High-energy phosphate in the form of ATP
Required for virtually all synthetic and degradative processes within the cell Depletion of ATP to 5% to 10% of normal levels Widespread effects on many critical cellular systems

Depletion of ATP Effects on critical cellular systems
Activity of the plasma membrane energy-dependent sodium pump is reduced Failure of this active transport system causes sodium to enter and accumulate inside cells and potassium to diffuse out The net gain of solute is accompanied by isosmotic gain of water, causing cell swelling, and dilation of the ER Cellular energy metabolism is altered Reduced supply of oxygen to cells (i.e. ischemia) Oxidative phosphorylation ceases Decrease in cellular ATP Increase in adenosine monophosphate Glycogen stores are rapidly depleted

Failure of the Ca2+ pump leads to influx of Ca2+ Damages intracellular organelles Prolonged or worsening depletion of ATP Structural disruption of the protein synthetic apparatus occurs Manifested as detachment of ribosomes from the rough ER Dissociation of polysomes Consequent reduction in protein synthesis

Oxygen or glucose deprivation Proteins may become misfolded Trigger a cellular reaction (unfolded protein response) Cell injury and even death Irreversible damage to mitochondrial and lysosomal membranes Cell necrosis

Figure 1-17 Functional and morphologic consequences of decreased intracellular ATP during cell injury. The morphologic changes shown here are indicative of reversible cell injury. Further depletion of ATP results in cell death, typically by necrosis. ER, endoplasmic reticulum.

Mitochondrial Damage Mitochondria
Cell's suppliers of life-sustaining energy in the form of ATP Critical players in cell injury and death Damaged by: Increases of cytosolic Ca2+ Reactive oxygen species Oxygen deprivation Mutations in mitochondrial genes are the cause of some inherited diseases

Mitochondrial Damage Formation of a high-conductance channel in the mitochondrial membrane Mitochondrial permeability transition pore Opening of this conductance channel leads to the loss of mitochondrial membrane potential Resulting in failure of oxidative phosphorylation and progressive depletion of ATP Necrosis of the cell

Mitochondrial Damage Mitochondria
Sequester proteins between their outer and inner membranes Capable of activating apoptotic pathways Cytochrome c and caspases (indirectly activate apoptosis-inducing enzymes) Increased permeability of the outer mitochondrial membrane Leakage of these proteins into the cytosol Death by apoptosis

Figure 1-18 Consequences of mitochondrial dysfunction, culminating in cell death by necrosis or apoptosis.

Calcium Homeostasis Calcium ions are important mediators of cell injury Cytosolic free calcium Normally maintained at very low concentrations (∼0.1 μmol) Intracellular calcium is sequestered in mitochondria and the ER Increased cytosolic Ca2+ activates a number of enzymes Deleterious cellular effects Phospholipases (membrane damage)

Calcium Homeostasis Increased cytosolic Ca2+ activates a number of enzymes Proteases (break down both membrane and cytoskeletal proteins) Endonucleases (responsible for DNA and chromatin fragmentation) ATPases (hastening ATP depletion) Increased intracellular Ca2+ levels Induction of apoptosis Direct activation of caspases and by increasing mitochondrial permeability

Figure 1-19 The role of increased cytosolic calcium in cell injury
Figure 1-19 The role of increased cytosolic calcium in cell injury. ER, endoplasmic reticulum

Free Radicals Free radicals
Chemical species that have a single unpaired electron in an outer orbit Energy created by this unstable configuration is released through reactions with adjacent molecules Inorganic or organic chemicals-proteins, lipids, carbohydrates, nucleic acids Reactive oxygen species (ROS) Type of oxygen-derived free radical Produced normally in cells during mitochondrial respiration and energy generation Degraded and removed by cellular defense systems Produced in large amounts by leukocytes, particularly neutrophils and macrophages

Generation of Free Radicals
The reduction-oxidation reactions that occur during normal metabolic processes Absorption of radiant energy (ultraviolet light, x-rays) Ionizing radiation can hydrolyze water into •OH and hydrogen (H) free radicals Rapid bursts of ROS Produced in activated leukocytes during inflammation Enzymatic metabolism of exogenous chemicals or drugs

Generation of Free Radicals
Transition metals such as iron and copper donate or accept free electrons during intracellular reactions (Fenton reaction (H2O2 + Fe2+ → Fe3+ + OH + OH Nitric oxide Important chemical mediator that can act as a free radical Generated by endothelial cells, macrophages, neurons, and other cell types

Removal of Free Radicals
Free radicals are inherently unstable and generally decay spontaneously Cells have developed multiple nonenzymatic and enzymatic mechanisms to remove free radicals Minimize injury Iron and copper can catalyze the formation of ROS Levels of these reactive metals are minimized by binding of the ions to storage and transport proteins (e.g., transferrin, ferritin, lactoferrin, and ceruloplasmin), thereby minimizing the formation of ROS Enzymes acts as free radical-scavenging systems

Pathologic Effects of Free Radicals
Three reactions Lipid peroxidation in membranes Presence of O2, free radicals may cause peroxidation of lipids within plasma and organellar membranes Oxidative damage is initiated when the double bonds in unsaturated fatty acids of membrane lipids are attacked by O2-derived free radicals Oxidative modification of proteins Free radicals promote: Oxidation of amino acid side chains Formation of protein-protein cross-linkages (e.g., disulfide bonds) Oxidation of the protein backbone Lesions in DNA Single- and double-strand breaks in DNA Cross-linking of DNA strands Formation of adducts

Figure 1-20 The role of reactive oxygen species (ROS) in cell injury
Figure 1-20 The role of reactive oxygen species (ROS) in cell injury. O2 is converted to superoxide () by oxidative enzymes in the endoplasmic reticulum (ER), mitochondria, plasma membrane, peroxisomes, and cytosol. is converted to H2O2 by dismutation and thence to •OH by the Cu2+/Fe2+-catalyzed Fenton reaction. H2O2 is also derived directly from oxidases in peroxisomes (not shown). Resultant free radical damage to lipids (by peroxidation), proteins, and DNA leads to injury to numerous cellular components. The major antioxidant enzymes are superoxide dismutase (SOD), glutathione peroxidase, and catalase.

Membrane Damage Several biochemical mechanisms may contribute to membrane damage Reactive oxygen species Decreased phospholipid synthesis Increased phospholipid breakdown Cytoskeletal abnormalities

Membrane Damage Consequences
The most important sites of membrane damage during cell injury Mitochondrial membrane damage Opening of the mitochondrial permeability transition pore leading to decreased ATP Release of proteins that trigger apoptotic death Plasma membrane damage Loss of osmotic balance and influx of fluids and ions Loss of cellular contents Cells may also leak metabolites Vital for the reconstitution of ATP, thus further depleting energy stores Injury to lysosomal membranes Leakage of their enzymes into the cytoplasm Activation of the acid hydrolases in the acidic intracellular pH of the injured cell Activation of these enzymes leads to enzymatic digestion Cells die by necrosis

Figure 1-21 Mechanisms of membrane damage in cell injury
Figure 1-21 Mechanisms of membrane damage in cell injury. Decreased O2 and increased cytosolic Ca2+ are typically seen in ischemia but may accompany other forms of cell injury. Reactive oxygen species, which are often produced on reperfusion of ischemic tissues, also cause membrane damage (not shown).

Cellular Responses Part Three
Lisa Stevens, D.O.

Ischemic and Hypoxic Injury
Most common type of cell injury in clinical medicine Studied extensively Humans Experimental animals Culture systems Hypoxia Reduced oxygen availability Occurs in a variety of clinical settings

Ischemia Supply of oxygen and nutrients is decreased Because of reduced blood flow Consequence of a mechanical obstruction in the arterial system/reduced venous drainage Compromises the delivery of substrates for glycolysis

Ischemic tissues Aerobic metabolism compromised Anaerobic energy generation stopped Glycolytic substrates are exhausted Glycolysis is inhibited Accumulation of metabolites Ischemia tends to cause more rapid and severe cell and tissue injury than does hypoxia in the absence of ischemia

Mechanisms of Ischemic Cell Injury
Sequence of events (post-hypoxia or ischemia) Oxygen tension within the cell decreases Loss of oxidative phosphorylation Decreased generation of ATP Failure of the sodium pump Loss of potassium Influx of sodium and water Cell swelling Influx of Ca2+ Progressive loss of glycogen Decreased protein synthesis Functional consequences may be severe at this stage

Example: Heart muscle ceases to contract within 60 seconds of coronary occlusion Loss of contractility does not mean cell death Continued hypoxia Worsening ATP depletion Further deterioration Cytoskeleton disperses Loss of ultrastructural features (microvilli and the formation of blebs) Myelin figures (degenerating cellular membranes) Seen within the cytoplasm (in autophagic vacuoles) or extracellularly

Example: Continued hypoxia (continued from previous slide) Cytoskeleton disperses Mitochondria—swollen Due to loss of volume control in these organelles ER remains dilated Entire cell is markedly swollen Increased concentrations of water, sodium, and chloride Decreased concentration of potassium If oxygen is restored, all of these disturbances are reversible!!!!

If ischemia persists, irreversible injury and necrosis ensue!!!! Irreversible injury Severe swelling of mitochondria Extensive damage to plasma membranes (giving rise to myelin figures) Swelling of lysosomes Large, flocculent, amorphous densities develop in the mitochondrial matrix

Example: Myocardium Irreversible injury can be seen as early as 30 to 40 minutes after ischemia Massive influx of calcium into the cell (ischemic zone) Death is mainly by necrosis, but apoptosis also contributes Apoptotic pathway is activated by release of pro-apoptotic molecules from leaky mitochondria Cell's components are progressively degraded Widespread leakage of cellular enzymes into the extracellular space Dead cells replaced by large masses (myelin figures) Either phagocytosed by leukocytes Degraded further into fatty acids Calcification of fatty acid residues

Despite many investigations No reliable therapeutic approaches for reducing the injurious consequences of ischemia in clinical situations Most useful strategy in ischemic (and traumatic) brain and spinal cord injury Transient induction of hypothermia (core body temperature to 92°F) Reduces the metabolic demands of the stressed cells Decreases cell swelling Suppresses the formation of free radicals Inhibits the host inflammatory response

Ischemia-Reperfusion Injury
Restoration of blood flow to ischemic tissues Promotes recovery of cells (reversibly injured) Certain circumstances Blood flow is restored to cells that have been ischemic but have not died Paradoxical injury is exacerbated Proceeds at an accelerated pace Reperfused tissues may sustain loss of cells in addition to the cells that are irreversibly damaged at the end of ischemia Ischemia-reperfusion injury Clinically important Contributes to tissue damage during myocardial and cerebral infarction and following therapies to restore blood

Reperfusion injury occur New damaging processes are set in motion during reperfusion Causes the death of cells that might have recovered otherwise Several proposed mechanisms Damage may be initiated during reoxygenation Increased generation of reactive oxygen and nitrogen species Produced in reperfused tissue as a result of mitochondrial damage Cellular antioxidant defense mechanisms may be compromised by ischemia Accumulation of free radicals Mediators of cell injury (calcium) may also enter reperfused cells Damages various organelles Increasing the production of free radicals

Ischemic injury Associated with inflammation Result of the production of cytokines Causes additional tissue injury Activation of the complement system May contribute to ischemia-reperfusion injury Involved in host defense Important mechanism of immune injury

Chemical (Toxic) Injury
Chemical injury remains a frequent problem in clinical medicine Major limitation to drug therapy Many drugs are metabolized in the liver Frequent target of drug toxicity Toxic liver injury Most frequent reason for terminating the therapeutic use or development of a drug

Chemical (Toxic) Injury
Chemicals induce cell injury Direct injury Combining with critical molecular components Example: Mercuric chloride poisoning Mercury binds to the sulfhydryl groups of cell membrane proteins Causes increased membrane permeability and inhibition of ion transport Damage is usually to the cells that use, absorb, excrete, or concentrate the chemicals Cells of the gastrointestinal tract and kidney

Apoptosis Pathway of cell death
Induced by a tightly regulated suicide program Cells destined to die activate enzymes that degrade the cells' own nuclear DNA and nuclear and cytoplasmic proteins Cells break up into fragments (apoptotic bodies) Contain portions of the cytoplasm and nucleus Plasma membrane of the apoptotic cell and bodies remains intact Structure is altered Tasty targets for phagocytes Dead cell and its fragments are rapidly devoured Before the contents have leaked out Cell death by this pathway does not elicit an inflammatory reaction in the host

Apoptosis Death by apoptosis Causes of Apoptosis
Normal phenomenon that serves to eliminate cells that are no longer needed Maintains a steady number of various cell populations in tissues Causes of Apoptosis Involution of hormone-dependent tissues upon hormone withdrawal Endometrial cell breakdown during the menstrual cycle Ovarian follicular atresia in menopause Regression of the lactating breast after weaning Prostatic atrophy after castration

Apoptosis Causes of Apoptosis, continued
Cell loss in proliferating cell populations to maintain a constant number (homeostasis) Immature lymphocytes in the bone marrow Thymus that fails to express useful antigen receptors B lymphocytes in germinal centers Epithelial cells in intestinal crypts

Apoptosis Causes of Apoptosis, continued
Elimination of potentially harmful self-reactive lymphocytes Before or after they have completed their maturation Prevent reactions against one's own tissues Death of host cells that have served their useful purpose Neutrophils in an acute inflammatory response Lymphocytes at the end of an immune response

Apoptosis in Pathologic Conditions
Apoptosis eliminates cells that are injured beyond repair without eliciting a host reaction Thus limiting collateral tissue damage Death by apoptosis is responsible for loss of cells in a variety of pathologic states DNA damage Radiation, cytotoxic anticancer drugs, and hypoxia Production of free radicals

Death by apoptosis is responsible for loss of cells in a variety of pathologic states Accumulation of misfolded proteins Improperly folded proteins Mutations in the genes encoding these proteins Damage caused by free radicals Accumulation of these proteins in the ER ER stress

Death by apoptosis is responsible for loss of cells in a variety of pathologic states Cell death in certain infections Viral infections Apoptosis is induced by the virus (as in adenovirus and HIV infections) or by the host immune response (as in viral hepatitis) Pathologic atrophy in parenchymal organs after duct obstruction Pancreas, parotid gland, and kidney

Morphology of Apoptosis
Cell shrinkage Smaller in size Cytoplasm is dense Organelles are more tightly packed Recall that in other forms of cell injury, an early feature is cell swelling, not shrinkage Chromatin condensation Most characteristic feature of apoptosis Chromatin aggregates peripherally, under the nuclear membrane, into dense masses of various shapes and sizes Nucleus itself may break up, producing two or more fragments

Morphology of Apoptosis
Formation of cytoplasmic blebs and apoptotic bodies Extensive surface blebbing Fragmentation into membrane-bound apoptotic bodies Phagocytosis of apoptotic cells or cell bodies Macrophages

Figure 1-22 Morphologic features of apoptosis
Figure 1-22 Morphologic features of apoptosis. A, Apoptosis of an epidermal cell in an immune reaction. The cell is reduced in size and contains brightly eosinophilic cytoplasm and a condensed nucleus. B, This electron micrograph of cultured cells undergoing apoptosis shows some nuclei with peripheral crescents of compacted chromatin, and others that are uniformly dense or fragmented. C, These images of cultured cells undergoing apoptosis show blebbing and formation of apoptotic bodies (left panel, phase contrast micrograph), a stain for DNA showing nuclear fragmentation (middle panel), and activation of caspase-3 (right panel, immunofluorescence stain with an antibody specific for the active form of caspase-3, revealed as red color). (B, From Kerr JFR, Harmon BV: Definition and incidence of apoptosis: a historical perspective. In Tomei LD, Cope FO (eds): Apoptosis: The Molecular Basis of Cell Death. Cold Spring Harbor, NY, Cold Spring Harbor Laboratory Press, 1991, pp 5-29; C, Courtesy of Dr. Zheng Dong, Medical College of Georgia, Augusta, GA.)

Biochemical Features of Apoptosis
A specific feature of apoptosis is the activation of several members of a family of cysteine proteases Caspases Two properties of this family of enzymes The “c" refers to a cysteine protease The "aspase" refers to the unique ability of these enzymes to cleave after aspartic acid residues

Biochemical Features of Apoptosis
The caspase family Divided functionally into two groups Initiator Caspase-8 and caspase-9 Executioner Caspase-3 and caspase-6 Exist as inactive pro-enzymes, or zymogens, and must undergo an enzymatic cleavage to become active The presence of cleaved, active caspases is a marker for cells undergoing apoptosis

Mechanisms of Apoptosis
Process of apoptosis Divided Initiation phase Caspases become catalytically active Execution phase Caspases trigger the degradation of critical cellular components Two pathways Intrinsic (mitochondrial) Extrinsic (death-receptor initiated)

The Intrinsic (Mitochondrial) Pathway of Apoptosis Major mechanism of apoptosis in all mammalian cells Result of increased mitochondrial permeability Result of release of pro-apoptotic molecules (death inducers) into the cytoplasm leads to activation of the initiator caspase-9

Figure 1-25 The intrinsic (mitochondrial) pathway of apoptosis
Figure 1-25 The intrinsic (mitochondrial) pathway of apoptosis. A, Cell viability is maintained by the induction of anti-apoptotic proteins such as Bcl-2 by survival signals. These proteins maintain the integrity of mitochondrial membranes and prevent leakage of mitochondrial proteins. B, Loss of survival signals, DNA damage, and other insults activate sensors that antagonize the anti-apoptotic proteins and activate the pro-apoptotic proteins Bax and Bak, which form channels in the mitochondrial membrane. The subsequent leakage of cytochrome c (and other proteins, not shown) leads to caspase activation and apoptosis.

The Extrinsic (Death Receptor-Initiated) Pathway of Apoptosis Initiated by engagement of plasma membrane death receptors on a variety of cells Death receptors are members of the TNF receptor family Contain a cytoplasmic domain involved in protein-protein interactions that is called the death domain Delivering apoptotic signals Leads to activation of the caspase-8 and -10

The Execution Phase of Apoptosis Two initiating pathways converge to a cascade of caspase activation Mediates the final phase of apoptosis Enzymatic death program is set in motion by rapid and sequential activation of the executioner caspases Caspase-3 and -6 Act on many cellular components

Figure 1-24 Mechanisms of apoptosis
Figure 1-24 Mechanisms of apoptosis. The two pathways of apoptosis differ in their induction and regulation, and both culminate in the activation of "executioner" caspases. The induction of apoptosis by the mitochondrial pathway involves the action of sensors and effectors of the Bcl-2 family, which induce leakage of mitochondrial proteins. Also shown are some of the anti-apoptotic proteins ("regulators") that inhibit mitochondrial leakiness and cytochrome c-dependent caspase activation in the mitochondrial pathway. In the death receptor pathway engagement of death receptors leads directly to caspase activation. The regulators of death receptor-mediated caspase activation are not shown. ER, endoplasmic reticulum; TNF, tumor necrosis factor.

Removal of Dead Cells Formation of apoptotic bodies breaks cells up into "bite-sized" Edible for phagocytes Healthy cells Phosphatidylserine is present on the inner leaflet of the plasma membrane Apoptotic cells Phospholipid "flips" out and is expressed on the outer layer of the membrane Recognized by several macrophage receptors Cells that are dying by apoptosis secrete soluble factors that recruit phagocytes

Clinico-pathologic Correlations
Examples of Apoptosis Growth Factor Deprivation Hormone-sensitive cells deprived of the relevant hormone Lymphocytes that are not stimulated by antigens and cytokines Neurons deprived of nerve growth factor die by apoptosis DNA Damage Exposure of cells to radiation or chemotherapeutic agents

Autophagy Process in which a cell eats its own contents
Survival mechanism in times of nutrient deprivation Starved cell lives by cannibalizing itself and recycling the digested contents Intracellular organelles and portions of cytosol are first sequestered from the cytoplasm in an autophagic vacuole Subsequently fuses with lysosomes to form an autophagolysosome Cellular components are digested by lysosomal enzymes

Figure 1-28 Autophagy. Cellular stresses, such as nutrient deprivation, activate autophagy genes that create vacuoles in which cellular organelles are sequestered and then degraded following fusion of the vesicles with lysosomes. The digested materials are recycled to provide nutrients for the cell.

Intracellular Accumulations
Manifestation of metabolic derangements in cells Intracellular accumulation of abnormal amounts of various substances Stockpiled substances fall into two categories Normal cellular constituent Water, lipids, proteins, and carbohydrates Accumulates in excess Abnormal substance Exogenous (mineral or products of infectious agents) Endogenous (product of abnormal synthesis or metabolism) May be harmless to the cells Occasionally they are severely toxic Located in either the cytoplasm (frequently within phagolysosomes) or the nucleus

Attributable to four types of abnormalities A normal endogenous substance is produced at a normal or increased rate, but the rate of metabolism is inadequate to remove it Fatty change in the liver and reabsorption protein droplets in the tubules of the kidneys An abnormal endogenous substance, accumulates because of defects in protein folding and transport and an inability to degrade the abnormal protein efficiently Accumulation of mutated α1-antitrypsin in liver cells Various mutated proteins in degenerative disorders of the central nervous system

Attributable to four types of abnormalities A normal endogenous substance accumulates because of defects, usually inherited, in enzymes that are required for the metabolism of the substance Storage diseases (genetic defects in enzymes involved in the metabolism of lipid and carbohydrates, resulting in intracellular deposition of these substances) An abnormal exogenous substance is deposited and accumulates because the cell has neither the enzymatic machinery to degrade the substance nor the ability to transport it to other sites Accumulations of carbon particles and nonmetabolizable chemicals (silica)

Figure 1-29 Mechanisms of intracellular accumulations discussed in the text.

Lipids All major classes of lipids can accumulate in cells
Triglycerides Cholesterol/cholesterol esters Phospholipids Components of the myelin figures found in necrotic cells

Lipids Steatosis (Fatty Change)
Abnormal accumulations of triglycerides within parenchymal cells Seen in the liver The major organ involved in fat metabolism Occurs in heart, muscle, and kidney

Lipids Steatosis (Fatty Change) Causes
Toxins, protein malnutrition, diabetes mellitus, obesity, and anoxia Most common causes of significant fatty change in the liver (developed countries) Alcohol abuse Nonalcoholic fatty liver disease Associated with diabetes and obesity

Lipids Mechanisms for triglyceride accumulation in the liver
Free fatty acids from adipose tissue or ingested food are normally transported into hepatocytes Esterified to triglycerides, converted into cholesterol or phospholipids, or oxidized to ketone bodies Excess accumulation of triglycerides within the liver may result from excessive entry or defective metabolism and export of lipids Such defects are induced by alcohol Hepatotoxin that alters mitochondrial and microsomal functions Leading to increased synthesis and reduced breakdown of lipids

Lipids Morphology Fatty change is most often seen in the liver and heart Appears as clear vacuoles within parenchymal cells Intracellular accumulations of water or polysaccharides (e.g., glycogen) may also produce clear vacuoles Identification of lipids requires the avoidance of fat solvents commonly used in tissue preparation Prepare frozen tissue sections of either fresh or aqueous formalin-fixed tissues Sections may then be stained with Sudan IV or Oil Red-O Orange-red color to the contained lipids

Lipids Gross examination--Liver Gross examination—Heart
Mild fatty change may not affect the gross appearance Progressive accumulation Organ enlarges and becomes increasingly yellow Extreme instances, the liver may weigh two to four times normal Bright yellow, soft, greasy organ Gross examination—Heart Grossly apparent bands of yellowed myocardium Alternating with bands of darker, red-brown, uninvolved myocardium (tigered effect)

Figure 1-30 Fatty liver. A, Schematic diagram of the possible mechanisms leading to accumulation of triglycerides in fatty liver. Defects in any of the steps of uptake, catabolism, or secretion can result in lipid accumulation. B, High-power detail of fatty change of the liver. In most cells the well-preserved nucleus is squeezed into the displaced rim of cytoplasm about the fat vacuole. (B, Courtesy of Dr. James Crawford, Department of Pathology, University of Florida School of Medicine, Gainesville, FL.)

Cholesterol and Cholesterol Esters
Most cells use cholesterol for the synthesis of cell membranes Without intracellular accumulation of cholesterol or cholesterol esters Accumulations manifested histologically by intracellular vacuoles are seen in several pathologic processes Atherosclerosis Atherosclerotic plaques Smooth muscle cells and macrophages within the intimal layer of the aorta and large arteries are filled with lipid vacuoles, most of which are made up of cholesterol and cholesterol esters Foamy appearance (foam cells), and aggregates of them in the intima produce the yellow cholesterol-laden atheromas

Cholesterol and Cholesterol Esters
Xanthomas Intracellular accumulation of cholesterol within macrophages (acquired and hereditary hyperlipidemic states) Clusters of foamy cells are found in the subepithelial connective tissue of the skin and in tendons Cholesterolosis Focal accumulations of cholesterol-laden macrophages in the lamina propria of the gallbladder Niemann-Pick disease, type C Lysosomal storage disease Caused by mutations affecting an enzyme involved in cholesterol trafficking Cholesterol accumulation in multiple organs

Figure 1-31 Cholesterolosis
Figure 1-31 Cholesterolosis. Cholesterol-laden macrophages (foam cells, arrow) in a focus of gallbladder cholesterolosis. (Courtesy of Dr. Matthew Yeh, Department of Pathology, University of Washington, Seattle, WA.)

Proteins Intracellular accumulations of proteins
Appear as rounded, eosinophilic droplets, vacuoles, or aggregates in the cytoplasm Reabsorption droplets in proximal renal tubules Seen in renal diseases associated with protein loss in the urine May be normal secreted proteins that are produced in excessive amounts Plasma cells engaged in active synthesis of immunoglobulins

Figure 1-32 Protein reabsorption droplets in the renal tubular epithelium. (Courtesy of Dr. Helmut Rennke, Department of Pathology, Brigham and Women's Hospital, Boston, MA.)

Proteins Defective intracellular transport and secretion of critical proteins α1-antitrypsin deficiency Emphysema Accumulation of cytoskeletal proteins Microtubules, thin actin filaments ,thick myosin filaments, and intermediate filaments Alcoholic hyaline is an eosinophilic cytoplasmic inclusion in liver cells and is composed predominantly of keratin intermediate filaments Neurofibrillary tangle found in the brain in Alzheimer disease contains neurofilaments and other proteins Aggregation of abnormal proteins Deposits can be intracellular, extracellular, or both Certain forms of amyloidosis

Hyaline Change Alteration within cells or in the extracellular space
Gives a homogeneous, glassy, pink appearance Widely used as a descriptive histologic term rather than a specific marker for cell injury Produced by a variety of alterations Does not represent a specific pattern of accumulation

Glycogen Readily available energy source stored in the cytoplasm of healthy cells Excessive intracellular deposits of glycogen Seen in patients with an abnormality in either glucose or glycogen metabolism Appear as clear vacuoles within the cytoplasm Dissolves in aqueous fixatives Tissues are best fixed in absolute alcohol Staining with Best carmine or the PAS reaction Rose-to-violet color to the glycogen

Pigments Pigments are colored substances, some of which are normal constituents of cells (melanin) Others are abnormal and accumulate in cells only under special circumstances Exogenous pigments (coming from outside the body) Carbon (coal dust) Ubiquitous air pollutant of urban life Accumulations of this pigment blacken the tissues of the lungs (anthracosis) and the involved lymph nodes Tattooing Localized, pigmentation of the skin Pigments inoculated are phagocytosed by dermal macrophages

Pigments Endogenous pigments (synthesized within the body itself)
Lipofuscin Insoluble pigment Also known as lipochrome or wear-and-tear pigment Composed of polymers of lipids and phospholipids in complex with protein Not injurious to the cell or its functions Telltale sign of free radical injury and lipid peroxidation Yellow-brown, finely granular cytoplasmic, often perinuclear, pigment in tissue sections Seen in cells undergoing slow, regressive changes Prominent in the liver and heart of aging patients or patients with severe malnutrition and cancer cachexia

Figure 1-33 Lipofuscin granules in a cardiac myocyte shown by (A) light microscopy (deposits indicated by arrows), and (B) electron microscopy (note the perinuclear, intralysosomal location).

Pigments Melanin Endogenous, non-hemoglobin-derived, brown-black pigment Formed when the enzyme tyrosinase catalyzes the oxidation of tyrosine to dihydroxyphenylalanine in melanocytes The only endogenous brown-black pigment

Pigments Hemosiderin Hemoglobin-derived, golden yellow-to-brown, granular or crystalline pigment Serves as one of the major storage forms of iron Represents aggregates of ferritin micelles Seen normally in mononuclear phagocytes of the bone marrow, spleen, and liver Actively engaged in red cell breakdown

Figure 1-34 Hemosiderin granules in liver cells
Figure 1-34 Hemosiderin granules in liver cells. A, H+E stain showing golden-brown, finely granular pigment. B, Prussian blue stain, specific for iron (seen as blue granules).

Pigments Iron pigment appears as a coarse, golden, granular pigment
Within the cell's cytoplasm Visualized in tissues by the Prussian blue histochemical reaction Underlying cause is the localized breakdown of red cells Hemosiderin is found initially in the phagocytes in the area Systemic hemosiderosis Mononuclear phagocytes of the liver, bone marrow, spleen, and lymph nodes and in scattered macrophages throughout other organs such as the skin, pancreas, and kidneys

Pigments Bilirubin Normal major pigment found in bile
Derived from hemoglobin Contains no iron

Pathologic Calcification
Abnormal tissue deposition of calcium salts, together with smaller amounts of iron, magnesium, and other mineral salts Two forms of pathologic calcification Dystrophic calcification Local deposition in dying tissues It occurs despite normal serum levels of calcium and in the absence of derangements in calcium metabolism Encountered in areas of necrosis Coagulative, caseous, or liquefactive type Metastatic calcification Deposition of calcium salts in otherwise normal tissues Hypercalcemia secondary to some disturbance in calcium metabolism

Figure 1-35 Dystrophic calcification of the aortic valve
Figure 1-35 Dystrophic calcification of the aortic valve. View looking down onto the unopened aortic valve in a heart with calcific aortic stenosis. It is markedly narrowed (stenosis). The semilunar cusps are thickened and fibrotic, and behind each cusp are irregular masses of piled-up dystrophic calcification.

Pathologic Calcification
Morphology Calcium salts Basophilic, amorphous granular, clumped appearance Intracellular or extracellular, or in both locations Over time, heterotopic bone may be formed in the focus of calcification Lamellations (psammoma bodies) Present in benign and malignant conditions

Cellular Aging Result of a progressive decline in cellular function and viability Caused by genetic abnormalities and the accumulation of cellular and molecular damage due to the effects of exposure to exogenous influences Aging is a regulated process that is influenced by a limited number of genes Aging is associated with definable mechanistic alterations

Cellular Aging The known changes that contribute to cellular aging
Decreased cellular replication Accumulation of metabolic and genetic damage Cellular life span Determined by a balance between damage resulting from metabolic events occurring within the cell and counteracting molecular responses that can repair the damage

Figure 1-36 Mechanisms of cellular aging
Figure 1-36 Mechanisms of cellular aging. Genetic factors and environmental insults combine to produce the cellular abnormalities characteristic of aging. How calorie restrictions prolong life span is net established. IGF, insulin-like growth factor.

Cellular Responses to Stress and Toxic Insults

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