LEC 9 Cellular Adaptation to Injury Flashcards
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
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How does michochondrial damage occur?
- Damaged by increases of calcium, reactive oxygen species (ROS), and oxygen deprivation
- Leads to inadequate aerobic respiration
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What are the consequences of mitochondrial damage?
- ATP depletion
- Formation of ROS
- Irreversible damage to mitochondrial and lysosomal membranes
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How does cell membrane damage lead to cell injury?
Leads to increased permeability and damage to mitochondrial, plasma, and lysosomal membranes
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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
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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
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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
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What are the 3 most important free radicals?
- H2O2 (hydrogen peroxide)
- *OH (hydroxyl radical)
- O2*- (superoxide anion)
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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
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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
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What are the 3 examples of cell injury?
- Oxygen Deprivation (hypoxia & ischemia)
- Ischemia-Reperfusion
- Chemical (Toxic)
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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
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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
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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
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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”)
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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
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What are adaptations?
reversible functional and structural responses to changes in physiologic states and some pathologic stimuli
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What are the 4 major types for cellular adaptive response?
- Atrophy
- Hypertrophy
- Hyperplasia
- Metaplasia
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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
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What are some physiologic causes of atrophy?
- Thymus atrophy with age
- Uterus atrophy after parturition
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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
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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
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The image below shows an example of what?
Where the red arrow is specifically.
Brown Atrophy
caused by lipofuscin pigment
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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
What is hypertrophy?
- Increase in cell size (not number) resulting in increased organ or tissue size
- Occurs in organs where cells have a limited capacity to divide
(e.g. - cardiac and skeletal muscle; no new cells!)
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What is the mechanism for hypertrophy?
Increased synthesis of structural proteins
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What are some physiological causes of hypertrophy?
- Massive growth of the uterus during pregnancy (hormone-driven)
- Body builders (response to demand)
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What is the most common stimulus for hypertrophy of skeletal and cardiac muscle?
Increased workload
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What is an example of a pathological cause of hypertrophy?
Enlargement of heart in response to pressure overload, usually resulting from either hypertension or valvular disease
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What is the biochemical mechanism for hypertrophy?
- mechanical sensors detect stress
- sensors activate complex signaling pathways
- signaling pathways stimulate increased production of growth factors and vasoactive agents
- these in turn, activate transcription factors that increase the expression of genes that encode muscle proteins
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Which signaling pathway is associated with physiological (excercise induced) hypertrophy?
Phosphoinositide 3-Kinase (PI3K)/AKT pathway
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Which signaling pathway is associated with pathological hypertrophy?
G-protein coupled receptor initiated pathways
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What is hyperplasia?
Increase in the number of normal cells
Same type of cell as the original
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What is the biochemical mechanism of hyperplasia?
- Growth-factor driven proliferation of cells via mitosis and cell division
- Mature cells
- Increased output of new cells from tissue stem cells
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What are some causes of hyperplasia?
- Hormonal stimulation
- Chronic irritation
- Stimulating antibodies
- Viral infections
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How can pathologic hyperplasia lead to malignant cancer?
- Hyperplasia is normally controlled and can be regulated
- If this regulation is messed up, then it can lead to malignant change
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What is metaplasia?
- Replacement of one adult cell type by another adult cell type (reversible)
- Adaptive: New cell type is better able to withstand the adverse environmental change that initiated metaplasia
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What are the types of metaplasia?
- Glandular to squamous (MOST COMMON) - epithelial tissue
- Squamous to glandular - epithelial tissue
- Connective tissue - Mesenchymal tissue
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