Exam I: Pathology II Flashcards
Causes of Cell Injury
Oxygen deprivation Physical agents Chemical agents and drugs Infectious agents Immunologic reactions Genetic derangements Nutritional imbalances
O2 Deprivation
Hypoxia- deficiency of oxygen, and reduces aerobic oxidative respiration
Causes: reduced blood flow (ischemia), inadequate oxygenation of the blood leading to cardiorespiratory failure, 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
Physical Agents
Mechanical trauma
Extremes of temperature (burns and deep cold)
Sudden changes in atmospheric pressure
Radiation- UV or chemoradiation
Electric shock- thermal
Atmospheric pressure- scuba diving ascend too rapidly or climbing a mountain
Chemical Agents and Drugs
Chemicals (too many to list) Glucose or salt- hypertonic concentrations Oxygen- high concentrations Trace amounts of poisons Environmental and air pollutants Insecticides, herbicides Industrial and occupational hazards- CO and asbestos Recreational drugs (alcohol) Therapeutic drugs
Infectious Agents
Submicroscopic viruses to the large tapeworms Rickettsiae Bacteria Fungi Higher forms of parasites
Immunologic Reactions
Injurious reactions to endogenous self-antigens- several autoimmune diseases
Immune reactions to external agents like microbes and environmental substances; hypersensitivity reactions
Genetic Derangements
Severe 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 which influence the susceptibility of cells by chemicals and other environmental insults
Nutritional Imbalances
Protein-calorie deficiencies in underprivileged populations
Deficiencies of specific vitamins (scurvy/vitamin C)
Self-imposed problems like anorexia nervosa
Nutritional excesses: cholesterol and obesity
Effects of Duration of Injury
The first thing that happens during injury is biochemical alterations, then you see ultrastructural changes (electron microscopy), and then you notice bigger changes under a light microscope, and then you will gross changes
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, and DNA damage
Reversible Injury
Two features of reversible cell injury
- Cellular swelling: result of failure of energy-dependent ion pumps in the plasma membrane; Na+ in, which pulls H2O in, K+ out; Ca2+ in as well
- Fatty change: hypoxic injury (mostly liver and heart), various forms of toxic or metabolic injury; manifested by the appearance of lipid vacuoles in the cytoplasm (bubble like)
Morphology of Reversible Injury
Cellular swelling: difficult to appreciate with the light microscope, but 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) aka hydropic change or vacuolar degeneration
Cells may show increased eosinophilic staining
Reversible Injury: Ultrastructural Changes
Plasma membrane alterations: blebbing, blunting, loss of microvilli
Mitochondrial changes: swelling and small amorphous densities
Dilation of the ER: detachment of polysomes and intracytoplasmic myelin figures
Nuclear alterations: disaggregation of granular and fibrillar elements
Irreversible Cell Injury
Continuous damage: the cell injury becomes irreversible and the cell cannot recover and it dies
Two principal types of cell death: apoptosis and necrosis
Apoptotic bodies are attractive to the phagocyte because they are tagged with phosphatidylserine
See this only in electron microscopy; contents of the cell do not leak out
Necrosis: always a pathologic process; severe membrane damage; lysosomal enzymes enter the cytoplasm and digest the cell and cellular contents leak out
Renal Cell Changes: Reversible vs. Irreversible
Reversible injury; cells are more pink/eosinophilic, but see that each cell has a nucleus but not as well maintained
Irreversible: cells are missing, nuclei gone, irreversible injury especially due to nuclei loss (breakdown)
Necrosis
Morphologic appearance: result of denaturation of intracellular proteins and enzymatic digestion of lethally injured cell
May take hours to develop- if not = sudden cardiac death
Necrotic cells: unable to maintain membrane integrity, so contents leak, which elicits inflammation in the surrounding tissue
Characteristics of Necrosis
Necrotic cells
Increased eosinophilia in hematoxylin and eosin (H&E) stain due to loss of cytoplasmic RNA (binds the blue dye, hematoxylin) and denatured cytoplasmic proteins (binds the red dye, eosin)
Glassy homogeneous appearance- loss of glycogen particles
Digestion of cytoplasmic organelles- vacuolated cytoplasm (moth-eaten)
Dead cells are replaced by large, whorled phospholipid masses (myelin figures) derived from damaged cell membranes
Phospholipid precipitates are phagocytosed by other cells and further degraded into fatty acids
Nuclear Changes of Necrosis
Due to nonspecific breakdown of DNA:
1. Karyolysis: fading of the basophilia of the chromatin
Change that reflects loss of DNA because of enzymatic degradation by endonucleases; nuclear fading due to action of RNAases and DNAases
- Pyknosis: nuclear shrinkage, increased basophilia, and chromatin condenses into solid, shrunken basophilic mass; nuclear shrinkage
- Karyorrhexis; pyknotic nucleus undergoes fragmentation, and nucleus in the necrotic cell totally disappears (1 or 2 days); nuclear fragmentation
All three end up going through anuclear dissolution and then anuclear necrosis
Coagulative Necrosis
Architecture of dead tissues preserved for a span of a few days
Tissue displays a firm texture
Eosinophilic, anucleate cells persist for days or weeks, but then removed by phagocytosis of the cellular debris by infiltrating leukocytes, and 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
Liquefactive Necrosis
Characterized by digestion of the dead cells where transformation of the tissue into a liquid viscous mass
Seen in focal bacterial infections, and occasionally seen in fungal infections
Creamy yellow color from dead leukocytes and purulent matter
Hypoxic death of cells in the CNS/brain
Digestion of cells with no structures left
Gangrenous Necrosis
Not a specific pattern of cell death
Commonly used in clinical practice
Applied to a limb (usually lower leg) that 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 causing wet gangrene
Infection + blocked blood supply = coagulative + liquefactive necrosis
Caseous Necrosis
Encountered most often in foci of tuberculous infection
“Caseous” (cheeselike)
Derived from the friable (crumbly like blue cheese) white appearance of the area of necrosis
Microscopic examination: collection of fragmented or lysed cells, and amorphous granular debris enclosed within a distinctive inflammatory border= granuloma
Fat Necrosis
Term that is well fixed in medical parlance, and 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 (due to pancreatitis)
Microscopic examination: foci of shadowy outlines of necrotic fat cells, basophilic calcium deposits, and inflammatory reaction
An area that there is destruction of fat cells
Can live with it and not even know it.. can also die from it
Fibrinoid Necrosis
Special form of necrosis
Seen in immune reactions involving blood vessels (autoimmune disease and phenomena)
Complexes of antigens and antibodies deposited in the walls of arteries
Microscopic examination: deposits of these “immune complexes” and fibrin with a bright pink and amorphous appearance (“fibrinoid”)
Mechanisms of Cell Injury
Cell injury results from different biochemical mechanisms that can act on several essential cellular components such as the mitochondria, cell membranes, DNA in nuclei
Any injurious stimulus may simultaneously trigger multiple interconnected mechanisms
Cannot blame one single or even dominant biochemical derangement
Consequences of Cell Injury
Depend on type, state, and adaptability of injured cell
Nutritional, hormonal status and metabolic needs of a cell
Important in its response to injury
Example: Striated muscle cell in the leg = deprived of its blood supply, it can be placed at rest and preserved; not so much in the striated muscle of the heart
Cellular Response to Injury
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 or slow, irreversible injury leading in time to cell death
Two Ways of ATP Production
Major pathway (mammalian cells): oxidative phosphorylation of adenosine diphosphate, which results in reduction of oxygen; aka electron transfer system of mitochondria (ETC) Second pathway: glycolytic pathway, which generates ATP in the absence of oxygen; uses glucose and derived from body fluids or hydrolysis of glycogen
Depletion of ATP
ATP depletion and decreased ATP synthesis
Associated with both hypoxic and chemical (toxic) injury
Major causes include reduced supply of oxygen and nutrients, mitochondrial damage, actions of toxins (i.e. cyanide)
High-energy phosphate in the form of ATP= CRITICAL
Required for virtually all synthetic and degradative processes within the cell
Depletion of ATP to 5% to 10% of normal levels causes widespread effects on many critical cellular systems
Depleted ATP: Celluluar & ER Swelling
Effects on critical cellular systems
Reduced activity of the plasma membrane energy-dependent sodium pump leading to failure
Na+ to enter and accumulate inside cells, and K+ diffuses out with a net gain of solute accompanied by isosmotic gain of water
Ca2+ in as well= failure of the Ca2+ pump leads to influx of Ca2+ therefore damaging intracellular organelles
Cell swelling and dilation of the ER
Oxygen or glucose deprivation cause proteins to be misfolded triggering a cellular reaction (unfolded protein response) leading to cell injury and even death
Irreversible damage to mitochondrial and lysosomal membranes= necrosis
Mitochondria Injury
Damaged by: increases of cytosolic Ca2+, reactive oxygen species, and oxygen deprivation
Mutations in mitochondrial genes cause of some inherited diseases
Mitochondria: Necrosis
Formation of a high-conductance channel in the mitochondrial membrane= permeability transition pore
Opening of this conductance channel leads to the loss of mitochondrial membrane potential and results in failure of oxidative phosphorylation and progressive depletion of ATP = necrosis
Mitochondria: Apoptosis
Sequester proteins between their outer and inner membranes, which are capable of activating apoptotic pathways
Cytochrome c and caspases (indirectly activate apoptosis-inducing enzymes)
Increased permeability of the outer mitochondrial membrane causes leakage of these proteins into the cytosol = death by apoptosis
ATP Depletion: Clumping of Nuclear Chromatin
Reduced cellular metabolism causing:
1. Reduced supply of oxygen to cells (i.e. ischemia)
2. Oxidative phosphorylation ceases resulting in a decrease in cellular ATP, increase in AMP, and glycogen stores are rapidly depleted
Increase in anaerobic glycolysis because lack of O2 leading to depletion of glycogen stores, increase in lactic acid, which decreases the pH = clumping of chromatin
ATP Depletion: Lipid Deposition
Prolonged or worsening depletion of ATP causes structural disruption of the protein synthetic apparatus including detachment of ribosomes from the rough ER and dissociation of polysomes due to a consequent reduction in protein synthesis leading to lipid deposition
Calcium Homeostasis
Calcium ions are important mediators of cell injury
Cytosolic free calcium is maintained at very low concentrations (∼0.1 μmol) aka sequestered in mitochondria and the ER
Increased cytosolic Ca2+ activates a number of enzymes causing deleterious cellular effects
ex. phospholipases (membrane damage), proteases (break down both membrane and cytoskeletal proteins), endonucleases (responsible for DNA and chromatin fragmentation), and ATPases (hastening ATP depletion)
Increased intracellular Ca2+ levels causes the induction of apoptosis, direct activation of caspases, and increasing mitochondrial permeability
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, and nucleic acids
Reactive O2 species are innate to our bodies, but they are damaging
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 like neutrophils and macrophages
Generation of Free Radicals
- Reduction-oxidation reactions occur during normal metabolic processes
- Absorption of radiant energy: UV, x-rays, ionizing radiation, which hydrolyze water into •OH and hydrogen free radicals
- Rapid bursts of ROS are produced during inflammation via activated leukocytes
- Enzymatic metabolism of exogenous chemicals or drugs
- Transition metals (iron and copper) donate or accept free electrons during intracellular reactions
- NO: important chemical mediator that acts as a free radical generated by endothelial cells, macrophages, neurons, and others
Removal of Free Radicals
Free radicals: inherently unstable, and generally decay spontaneously
Multiple nonenzymatic and enzymatic mechanisms in cells remove free radicals to minimize injury
Iron and copper can catalyze the formation of ROS, but minimize levels by binding ions to storage and transport proteins like transferrin, ferritin, lactoferrin, and ceruloplasmin
Enzymes acts as free radical-scavenging systems
Pathologic Effects of Free Radicals (3)
- Lipid peroxidation in membranes: in the presence of O2= oxidative damage of membranes
Initiated when double bonds in unsaturated fatty acids of membrane lipids are attacked by O2-derived free radicals - Oxidation modification of proteins which lead to misfoldings of the proteins
Oxidation of amino acid side chains
Formation of protein-protein cross-linkages (e.g., disulfide bonds)
Oxidation of the protein backbone - Lesions in the DNA: so cross linking of DNA strands causing the formation of adducts
Oxidative DNA damage
Implicated in cell aging and malignant transformation
Membrane Damage
Biochemical mechanisms that cause membrane damage: Reactive oxygen species Decreased phospholipid synthesis Increased phospholipid breakdown Cytoskeletal abnormalities
Consequences of Membrane Damage
- Mitochondrial membrane damage: ppening of the mitochondrial permeability transition pore leading to decreased ATP via release of proteins that trigger apoptotic death
- Plasma membrane damage: due to loss of osmotic balance and influx of fluids and ions, loss of cellular contents
Cells may also leak metabolites, which are 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 leading to enzymatic digestion, then cells die by necrosis
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
Rapid removal of the cellular debris
Serves many normal functions, not necessarily associated with cell injury
