LEC 9 Cellular Adaptation to Injury Flashcards
(38 cards)
What are the 6 mechanisms of cell injury?
- Mitochondrial damage
- Cell membrane damage
- DNA damage
- Oxidative stress
- Disturbance in calcium homeostasis
- Endoplasmic reticulum (ER) stress
Slide 4
How does michochondrial damage occur?
- Damaged by increases of calcium, reactive oxygen species (ROS), and oxygen deprivation
- Leads to inadequate aerobic respiration
Slide 5
What are the consequences of mitochondrial damage?
- ATP depletion
- Formation of ROS
- Irreversible damage to mitochondrial and lysosomal membranes
Slide 5
How does cell membrane damage lead to cell injury?
Leads to increased permeability and damage to mitochondrial, plasma, and lysosomal membranes
Slide 6
Mitochondrial membrane damage results in the opening of what?
What does this cause?
Opening of the mitochondrial permeability transition pore (PTP)
Decreased ATP & release of proteins that trigger cell death
Slide 6
How can DNA damage lead to cell injury?
- Mutations that affect p53 (and thus interfere with its ability to arrest cell cycling or to induce apoptosis) are associated with cancer development
- p53 arrests cells in G1 or activates DNA repair mechanisms
- If these mechanisms fail, p53 triggers apoptosis via the mitochondrial pathway
Slide 7
How does oxidative stress lead to cell injury?
Accumulation of oxygen-derived free radicals (ROS) resulting in:
* Lipid peroxidation - membrane damage
* Protein modifications - breakdown, misfolding
* DNA Damage - mutations
Slide 8
What are the 3 most important free radicals?
- H2O2 (hydrogen peroxide)
- *OH (hydroxyl radical)
- O2*- (superoxide anion)
Slide 9
How does a disturbance in calcium homeostasis lead to cell injury?
- Cytosolic free Ca2+ is normally maintained at LOW concentrations (~0.1 μmol) compared with extracellular levels (~1.3mmol)
- Most intracellular Ca2+ is sequestered in mitochondria and the ER
- Results in mitochondrial damage (loss of ATP) and damage to plasma and nuclear membranes
Slide 11
How does ER stress lead to cell injury?
- Accumulation of misfolded proteins in the ER activates adaptive mechanisms that help the cell to survive
- UNFOLDED PROTEIN RESPONSE
- If the cellular repair capacity is exceeded, overload triggers apoptosis
Slide 12
What are the 3 examples of cell injury?
- Oxygen Deprivation (hypoxia & ischemia)
- Ischemia-Reperfusion
- Chemical (Toxic)
Slide 13
Differentiate b/w hypoxia and ischemia.
- Hypoxia: Decreased oxygen, though blood flow is maintained; energy production by anaerobic glycolysis can continue
- Ischemia: Results from hypoxia induced by reduced blood flow, most often due to a mechanical arterial obstruction; can also be due to decreased venous drainage. Stops aerobic and anaerobic metabolism.
Ischemia causes more rapid & severe cell & tissue injury
Slide 14
How does ischemic cell injury occur?
- Functional and morphologic consequences of decreased intracellular ATP due to mitochondrial damage
- Reversible
- Continued ATP depletion leads to cell death
Slide 14
How does Ischemic-Reperfusion injury occur?
- Restoration of blood flow to ischemic tissues can promote recovery of cells if they are reversibly injured
- However, it can also paradoxically exacerbate cell injury and cause cell death
- Consequently, reperfused tissues may sustain loss of viable cells in addition to those that are irreversibly damaged by the ischemia
- Caused by: Free Radical Production resulting in Apoptosis and Necrosis
Slide 15
What areas in the body are susceptible to hypoxia/ichemia?
- Brain: (ACA/MCA/PCA boundary areas; hippocampus & cerebellum). “watershed areas” - border zones, receive dual blood supply from most distal branches of 2 arteries but susceptible to ischemia in states of systemic hypoperfusion
- Heart: (LV subendocardium) - “watershed area”
- Kidney: (areas of medulla)
- Liver: (area around central vein - “zone 3”)
- Colon: (Splenic flexure, rectum - “watershed areas”)
Slide 16
What are the 2 ways that chemicals induce cell injury?
- Direct toxicity: the chemical combines with critical molecular components. Ex: mercuric chloride, cyanide
- Conversion to toxic metabolites: most toxic chemicals must be converted to reactive toxic metabolites in the liver, which then act on target molecules. Ex: acetaminophen, Carbon Tetrachloride
Slide 17
What are adaptations?
reversible functional and structural responses to changes in physiologic states and some pathologic stimuli
Slide 19
What are the 4 major types for cellular adaptive response?
- Atrophy
- Hypertrophy
- Hyperplasia
- Metaplasia
Slide 19
What is atrophy?
- Shrinkage in size of the cells by loss of cell substance
- Decreased weight and size of tissue or organ
- Cells may turn off non-essential functions, but they are still alive
Slide 20
What are some physiologic causes of atrophy?
- Thymus atrophy with age
- Uterus atrophy after parturition
Slide 20
What are some pathological causes of atrophy?
- Decreased workload - disuse atrophy
- Loss of innervation - denervation atrophy
- Diminished blood supply - chronic ischemia
- Inadequate nutrition
- Loss of endocrine strimulation
- Pressure (mass effect) -atrophy of normal tissue adjacent to large tumor
Slide 20
What are the biochemical mechanisms within the cell that cause atrophy to happen?
- Decreased protein synthesis
- Increased protein degradation (ubiquitin-proteasome pathway)
- Autophagy (cell eats itself from inside) - evolutionarily conserved survival mechanism; Lipofuscin granules–>brown atrophy
Slide 22
The image below shows an example of what?
Where the red arrow is specifically.
Brown Atrophy
caused by lipofuscin pigment
Slide 23
The image below shows an example of what?
Circled parts
Denervation Atrophy
Reduced size of the spinal muscle w/i the circles d/t denervation
