2 - Cellular Response to Stress and Toxic Insults: Adaptation, Injury, and Death Flashcards
Is the ICF calcium level high or low relative to the ECF?
Very low (and this small amount is sequestered in the mitochondria and ER)
Why must intracellular calcium remain low?
Calcium activates phospholipases, proteases, ATPases, and endonucleases
How does the reperfusion of ischemic zones lead to ischemic-reperfusion injuries?
Oxygen- and calcium-rich ECF hits the ischemic zone and free radicals and calcium flood the damaged cells (thus leading to free radical damage and further calcium-induced damage)
Where do the toxic free radicals come from in reperfusion injury?
Polymorphonuclear leukocytes that infiltrate the ischemic site during reperfusion
What are the two main signs of reversible cell injury? What are some other signs?
Cellular swelling and fatty change;
decrease in ATP synthesis, decrease in pH, chromatin clumping, cellular swelling, ER dilation, loss of cytoskeletal structure
What leads to the swelling in damaged cells?
ATP deficiencies lead to a decrease in sodium-potassium ATPase activity
What is the main sign of irreversible cell damage?
Cell membrane damage
What are some of the causes of irreversible cell damage?
Decreased membrane phospholipids (excess phospholipase activity), lipid breakdown products; cytoskeletal abnormalities (excess protease activity), loss of intracellular amino acids; reactive oxygen species (reperfusion injury)
Why are free radicals so dangerous?
They can interact (and damage) all types of macronutrients; they can induce the formation of further free radicals
How can free radicals be formed within cells?
Radiation absorption, oxidative reactions, metabolism of exogenous chemicals / drugs
Normally, oxygen is reduced in the cell to form water. If a cell contains excess oxygen, what other products can be formed due to partial reductions?
Superoxide (O2 —> O2 -), hydrogen peroxide (O2 —> H2O2), and hydroxyl (O2 —> OH-) ions
How is superoxide produced naturally in the cell?
A variety of oxidative enzymes can turn O2 into O2-
How is hydrogen peroxide produced naturally in the cell?
Superoxide dismutase turns O2- into H2O2
How are hydroxyl ions produced naturally in the cell?
Ionizing radiation hydrolyzes water from H2O to OH-
Define pyknosis.
Clumping of nuclear chromatin, nuclear shrinkage, increased basophilia
Define karyolysis.
Fading basophilia of chromatin (increased DNAse activity destroys chromatin).
Define karyorrhexis.
Nuclear fragmentation.
What are the four main types of necrosis? What are two other types?
Coagulative, liquefactive, caseous, and fat necrosis; gangrenous, fibrinoid
What generally causes coagulative necrosis?
Hypoxia in all tissues except the CNS
What generally causes liquefactive necrosis?
Focal bacterial infections (due to WBC accumulation) or CNS hypoxia
What organism generally causes caseous necrosis (a type of coagulative necrosis)?
Mycobacterium tuberculosis
What generally causes fat necrosis?
Abnormal release of activated pancreatic lipases into pancreatic or peritoneal tissues
How are necrotic cells cleaned up?
Leukocytes and parenchymal cells phagocytose the remains
Do necrotic cells show eosinophilia or basophilia? Which is the natural state of the cell?
Eosinophilia; normally, the cell is basophilic due to RNA in the cytoplasm
What is the morphology of apoptosis?
Cell shrinkage, chromatin condensation, cytoplasmic surface blebs, apoptotic bodies
What is an apoptotic body?
Small fragments of the original cell containing tightly packed organelles (little phospholipid balls of cytoplasm and organelles)
Does apoptosis lead to inflammation like necrosis does?
No.
Does apoptosis usually happen in groups of cells?
No, it usually happens in single cells.
What are the main causes of necrosis versus apoptosis?
Hypoxia, toxins;
physiology (i.e. cell density regulation), pathology (i.e. a method of deleting abnormal and damaged cells)
Why would an inhibition in gene expression lead to apoptosis?
The apoptosis-suppressing proteins have a much shorter half-life than the apoptosis-inducing proteins.
So, if gene expression stops, the suppressing proteins are degraded before the inducing proteins and apoptosis occurs.
What type of calcification occurs in necrotic tissues and atheromas (in the absence of hypercalcemia)?
Dystrophic calcification
What type of calcification occurs principally in interstitial tissues of the blood vessels, lungs, kidneys, and gastric mucosa (in the presence of hypercalcemia)?
Metastatic calcification
Define hyaline change.
Homogenous, glassy, pink appearance (after H&E staining)
Why do cells die as they age?
Genetic mutation, telomeric shortening, accumulated free radical damage, accumulated non-enzymatic glycosylation, heat-shock protein alterations
What are the four aspects of pathology?
(1) Etiology, (2) pathogenesis, (3) morphological changes, (4) clinical significance
What are the two processes of tissue repair?
(1) Regeneration and (2) replacement by connective tissue (fibroplasia)
What is needed for the orderly regeneration of epithelial tissue?
An intact basement membrane (specialized ECM)
What are two methods by which cell number can increase?
Increased cell proliferation or decreased cell death
What are the most important factors in increasing cell growth?
Factors that recruit G0 cells into the cell cycle.
What is another name for stable cells?
Quiescent cells
For what is the underlying stroma (especially the basement membrane) in the parenchyma responsible following organ damage?
It serves as a scaffold for the replicating parenchymal cells
What are some of the principal connective tissue and mesenchymal cells?
Fibroblasts, endothelial cells, smooth muscle cells, chondrocytes, and osteocytes
In which part of the cell cycle are permanent cells?
They aren’t; they’ve left the cell cycle.
In which part of the cell cycle are stable cells?
G0
What main chemical substances affect cell growth?
Polypeptide growth factors
What are the two types of polypeptide growth factor?
Competence factors and progression factors
What do competence factors do?
Render cells in G0 and G1 ready to synthesize new DNA.
What do progression factors do?
Stimulate DNA synthesis in competent cells.
What are some of the genes that are involved in cell replication when activated?
c-fos, c-jun, c-myc (many injurious stimuli increase the expression of these genes and, thus, cell replication)
To what enzyme are most cellular growth factor receptors linked?
Tyrosine kinase
What are some examples of growth factors?
Insulin, insulin-like growth factor (1 and 2), platelet-derived growth factor, fibroblast growth factor, epidermal growth factor, erythropoietin, nerve growth factor, granulocyte-macrophage colony stimulating factor
What are some examples of growth-inhibiting factors?
Transforming growth factor-beta, tumor necrosis factor, and beta-interferon
What is a common method of hypertrophy?
Increased intracellular protein synthesis
What are some common causes of atrophy?
Decreased workload; loss of innervation, endocrine signaling, or blood supply; inadequate nutrition; mechanical pressure
What is a common method of atrophy?
Decreased intracellular protein synthesis and increased protein degradation
What is the most common form of metaplasia?
Columnar to squamous (reversed in Barrett’s esophagus)
What is a common method of metaplasia?
Reprogramming of stem cells (NOT the reprogramming of already differentiated cells)
What two free metals commonly form reactive oxygen species in the cell?
Iron and copper
What three enzymes help to break down free radicals?
Catalase, superoxide dismutase, and glutathione peroxidase
What is the mitochondrial apoptosis pathway?
The intrinsic pathway due to growth factor withdrawal; mitochondrial proteins –> initiator caspases in the cytosol –> executioner caspases
What is the death receptor apoptosis pathway?
The extrinsic pathway due to receptor binding; Fas receptor or TNF receptor –> adaptor proteins –> initiator caspases in the cytosol –> executioner caspases
What family of proteins regulates apoptosis?
The BCL2 family
Which of the BCL2 proteins are anti-apoptotic? (3)
BCL2, BCL-XL, MCL1
Which of the BCL2 proteins are pro-apoptotic? (2)
BAX, BAK
Which of the BCL2 proteins are sensors (responsible for sensing cell stress/damage and regulating the other BCL2 proteins)? (5)
BAD, BID, BIM, Puma, and Noxa
Growth factors stimulate the production of which BCL2 proteins?
The anti-apoptotic (BCL2, BCL-XL, MCL1)
What do executioner caspases do?
Activate DNAses and other enzymes to digest the nucleus
When does p53 accumulate in the cell to inhibit the cell cycle (and either allow time for DNA repair or trigger apoptosis)?
Following DNA damage
Define necroptosis.
It is a third form of cell death in which the cell shows signs typical of necrosis (cellular swelling, loss of ATP, rupture of the plasma membrane), but this death is programmed (a sort of caspase-independent programmed necrosis).
What form of cell death releases interleukin-1 and is a programmed inflammatory response to try and kill microbes?
Pyroptosis
What is it called when a cell digests its own contents (e.g. damaged organelles)?
Autophagy
