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
2
Q
Transmembrane proteins
A
- Embedded in the phospholipid bilayer
- Essential for structural, transport, and enzymatic functions
- Transmembrane receptors often usurped by infectious microbes
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
4
Q
Cellular responses
A
- Homeostasis
- Adaptations
- Cellular injury
- Cell death
5
Q
Homeostasis
A
Normal cellular structure and functions are confined to a narrow range of physicochemical conditions
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
7
Q
Cellular injury
A
The alterations occurring in a cell that can no longer adapt to changes in its environment
8
Q
Cell death
A
A cell that is exposed to persistent or severe stimulus is irreversibly injured
9
Q
Causes of cell injury or death
A
- Hypoxia/anoxia
- Physical agents
- Infectious agents
- Immunologic reactions
- Genetic Derangements
- Nutritional imbalances
- Toxins
10
Q
Consequence of cell injury
A
Depend on the injury: type, duration, and severity
Depend on the cell: type, state, and adaptability
11
Q
Key mechanisms of cell injury or death
A
- Adenosine triphosphate (ATP) depletion
- Permeability of cell membranes
- Distribution of biochemical pathways, especially those of protein synthesis
- Damage to DNA and proteins
12
Q
- 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
13
Q
Ischemia
A
Decrease in oxidative phosphorylation –> decrease in ATP –> significant functional and morphologic consequences
14
Q
- Permeability of cell membranes
A
- Damage to mitochondrial membranes
- -Decreased ATP generation
- -Release of proteins that trigger apoptotic death
- -Oxidative stress - Damage to the plasma membrane results in loss of osmotic balance and influx of fluids and ions
- -Influx of calcium - 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
15
Q
- Disruption of biochemical pathways
A
- Damage to plasma membrane
- Disruption of ion transfer
- Damage to mechanisms
- Mitochondrial damage
- Influx of calcium
- etc.
16
Q
- 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
- 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 - Abnormal oxidative phosphorylation leads to the formation of ROS (leads to free radical damage)
- 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
- The reduction-oxidation reactions that occur during normal metabolic processes
- Absorption of radiation energy
- Rapid bursts of ROS are produced in activated leukocytes during inflammation
- Enzymatic metabolism of exogenous chemicals or drugs (ex: CCl4 can generate CCl3-)
- 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.
