Exam I: Pathology II Flashcards

Question

Mechanisms of Cell Injury

Answer 1

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

Answer 2

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

Answer 3

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

Answer 4

``` 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 ```

Answer 5

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

Answer 6

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

Answer 7

Damaged by: increases of cytosolic Ca2+, reactive oxygen species, and oxygen deprivation Mutations in mitochondrial genes cause of some inherited diseases

Answer 8

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

Answer 9

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

Answer 10

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

Answer 11

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

Answer 12

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

Answer 13

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

Answer 14

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

Answer 15

1. Reduction-oxidation reactions occur during normal metabolic processes 2. Absorption of radiant energy: UV, x-rays, ionizing radiation, which hydrolyze water into •OH and hydrogen free radicals 3. Rapid bursts of ROS are produced during inflammation via activated leukocytes 4. Enzymatic metabolism of exogenous chemicals or drugs 5. Transition metals (iron and copper) donate or accept free electrons during intracellular reactions 6. NO: important chemical mediator that acts as a free radical generated by endothelial cells, macrophages, neurons, and others

Answer 16

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

Answer 17

1. 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 2. 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 3. 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

Answer 18

``` Biochemical mechanisms that cause membrane damage: Reactive oxygen species Decreased phospholipid synthesis Increased phospholipid breakdown Cytoskeletal abnormalities ```

Answer 19

1. Mitochondrial membrane damage: ppening of the mitochondrial permeability transition pore leading to decreased ATP via release of proteins that trigger apoptotic death 2. 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 3. 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

Answer 20

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