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Pathology > Cellular Injury/Death I > Flashcards

Cellular Injury/Death I Flashcards

1
Q

Cell membrane

A
  • Phospholipid bilayer
  • Encloses organelles
  • Serves as a selective barrier
  • Serves as a structural base for the membrane-associated proteins that determine cell function
  • Fluidic because proteins and lipids travel through it in cytocavitary system
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2
Q

Transmembrane proteins

A
  • Embedded in the phospholipid bilayer
  • Essential for structural, transport, and enzymatic functions
  • Transmembrane receptors often usurped by infectious microbes
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3
Q

Cell injury

A
  • Begins at the cellular level
  • Important to correlate observable lesions with their biochemical bases
  • Functionality can be damaged with no apparent observable (morphologic) alterations
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4
Q

Cellular responses

A
  • Homeostasis
  • Adaptations
  • Cellular injury
  • Cell death
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5
Q

Homeostasis

A

Normal cellular structure and functions are confined to a narrow range of physicochemical conditions

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6
Q

Adaptations

A

Cells exposed to excessive physiologic stresses and some pathologic stimuli respond by a number of cellular adaptations which bring about a new and altered steady state

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7
Q

Cellular injury

A

The alterations occurring in a cell that can no longer adapt to changes in its environment

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8
Q

Cell death

A

A cell that is exposed to persistent or severe stimulus is irreversibly injured

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9
Q

Causes of cell injury or death

A
  • Hypoxia/anoxia
  • Physical agents
  • Infectious agents
  • Immunologic reactions
  • Genetic Derangements
  • Nutritional imbalances
  • Toxins
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10
Q

Consequence of cell injury

A

Depend on the injury: type, duration, and severity

Depend on the cell: type, state, and adaptability

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11
Q

Key mechanisms of cell injury or death

A
  1. Adenosine triphosphate (ATP) depletion
  2. Permeability of cell membranes
  3. Distribution of biochemical pathways, especially those of protein synthesis
  4. Damage to DNA and proteins
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12
Q
  1. ATP depletion
A
  • ATP is produced via:
  • -Oxidative phosphorylation: reduction of oxygen by the electron transfer system of mitochondria (requires oxygen)
  • -Glycolytic pathway: ATP synthesis by glucose derived either from body fluids or from the hydrolysis of glycogen (without oxygen)
  • Major causes of depletion include reduced supply of oxygen and mitochondrial damage
  • Increased influx of calcium
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13
Q

Ischemia

A

Decrease in oxidative phosphorylation –> decrease in ATP –> significant functional and morphologic consequences

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14
Q
  1. Permeability of cell membranes
A
  1. Damage to mitochondrial membranes
    - -Decreased ATP generation
    - -Release of proteins that trigger apoptotic death
    - -Oxidative stress
  2. Damage to the plasma membrane results in loss of osmotic balance and influx of fluids and ions
    - -Influx of calcium
  3. Damage to lysosomal membranes results in leakage of their enzymes into the cytoplasm and activation of the acid hydrolases in the acidic intracellular pH of the injured cell
    - -Activation of hydrolases leads to digestion of proteins, RNA, DNA, and glycogen
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15
Q
  1. Disruption of biochemical pathways
A
  • Damage to plasma membrane
  • Disruption of ion transfer
  • Damage to mechanisms
  • Mitochondrial damage
  • Influx of calcium
  • etc.
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16
Q
  1. Damage to DNA and proteins
A

Irreversible DNA damage or improperly folded proteins typically results in programmed cell death (apoptosis)

17
Q

Mitochondria

A
  • Supply life-sustaining energy by producing ATP
  • Have an important role in intermediary metabolism, and centrally involved in cell life-and-death decisions
  • Sensitive to virtually all types of injurious stimuli
18
Q

Consequences of mitochondrial damage

A
  1. Formation of the mitochondrial permeability transition pore which leads to a loss of mitochondrial membrane potential and progressive depletion of ATP
    - -Immunosuppressive drug, cyclosporine, attenuates a structural protein of the pore and prevents it from forming
  2. Abnormal oxidative phosphorylation leads to the formation of ROS (leads to free radical damage)
  3. Pro-apoptotic proteins are sequestered in the mitochondrial membrane. Increased permeability of this membrane may result in leakage of these proteins and death of the cell by apoptosis.
19
Q

Influx of calcium

A
  • Normally, cytosolic free calcium is maintained at very low concentrations (~0.1 umol) compared with extracellular levels (1.3 mmol)
  • -Sequestered in mitochondria and the ER
  • Ischemia and toxins can cause an increase in cytosolic calcium
  • -Release of calcium from intracellular stores (mitochondrial and ER membranes)
  • -Decreased pH (anerobic glycolysis) causes build up of lactic acid, which causes release of calcium complexed to intracellular substances
  • -Increased influx of calcium across the plasma membrane - occurs late in cell injury
20
Q

Consequences of calcium influx

A
  • Increased cytosolic calcium activates
  • -Phospholipases (membrane damage)
  • -Proteases (breakdown membrane and cytoskeletal proteins)
  • -Endonucleases (DNA and chromatin fragmentation)
  • -ATPases (hasten ATP depletion)
  • Increased calcium induces apoptosis by direct activation of caspases
21
Q

Free radicals

A

=Chemicals that have a single unpaired electron in an outer orbit

  • -Extremely unstable and reactive chemicals
  • -Unpaired electrons are highly reactive and “attack” and modify adjacent molecules
  • -Autocatalytic: molecules that react with free radicals are themselves converted into free radicals
  • -Reactive Oxygen Species (ROS) are oxygen containing free radicals important in biological function
22
Q

Free radical examples

A

-Superoxide (O2-)
-Hydrogen peroxide (H2O2)
-Hydroxyl radial (OH)
-Lipid radicals-autocatalytic (in lipid bilayer)
-Nitric oxide (NO)
CCl3 and Cl- produced by breakdown of CCl4

23
Q

Oxidative stress

A
  • Cell injury induced by reactive oxygen species (ROS), is an important mechanism of cell damage
  • ROS: produced normally in cells during mitochondrial respiration and ATP synthesis, but they are degraded and removed by cellular defense systems
  • -Increased production or decreased scavenging of ROS may lead to an excess, called oxidative stress
24
Q

Generation of free radicals

A
  1. The reduction-oxidation reactions that occur during normal metabolic processes
  2. Absorption of radiation energy
  3. Rapid bursts of ROS are produced in activated leukocytes during inflammation
  4. Enzymatic metabolism of exogenous chemicals or drugs (ex: CCl4 can generate CCl3-)
  5. Nitric oxide is a chemical mediator generated by endothelial cells, neurons, and others, and can act as a free radical
25
Q

Removal of free radicals

A
  • Antioxidants either block free radical formation or inactivate free radicals
  • -Vitamin E and A, ascorbic acid, glutathione, riboflavin
  • A series of enzymes act as free radical-scavenging systems and are located near the sites of generation of the oxidants:
  • -Catalase
  • -Superoxide dismutase
  • -Glutathione peroxidase (requires selenium and riboflavin)
  • –The intracellular ratio of oxidized glutathione to reduced glutathione is a reflection of the oxidative state of the cell and is an important indicator of the cells ability to detoxify ROS
26
Q

Pathological effects of free radicals

A
  • Membrane damage
  • Breakdown, misfolding
  • Mutations
27
Q

Ischemia - Reperfusion injury

A
  • Restoration of blood flow to ischemic tissues can promote recovery of cells if they are reversibly injured, but can also paradoxically exacerbate injury and cause cell death
  • -Important in myocardial, myoskeletal, and cerebral infarction
  • -Often the cause of mortality in post-op colic cases in equine, displaced abomasum in cattle, or resolved GDV
  • New damaging processes are set in motion during reperfusion causing the death of cells that might have been recovered
28
Q

Possible mechanisms of reperfusion injury

A
  • Oxidative stress: incomplete reduction of O2 by damaged mitochondria; antioxidants may be compromised by ischemia
  • Intracellular calcium overload: exacerbated during reperfusion
  • Inflammation: neutrophil influx with reperfusion
  • -Experimental treatment with antibodies that block cytokines or adhesion molecules and thereby reduce neutrophil extravasation
  • Activation of the complement system: IgM antibodies are deposited in ischemic tissue. During reperfusion, complement proteins bind to antibodies and activate the cascade.

Pathology (6 decks)

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