4-22 Cell Injury Flashcards
What are 2 reasonable answers to any question in PBD?
Sarcoidosis
Amyloidosis
Difference between necrosis and apoptosis?
Necrosis is always abnormal
Whereas necrosis is always a pathologic process, apoptosis serves many normal functions and is not necessarily associated with cell injury
What are adaptations in regards to cell growth and development?
Adaptations are reversible changes in the size, number, phenotype, metabolic activity, or functions of cells in response to changes in their environment
What is hypertrophy? How is it achieved?
Hypertrophy refers to an increase in the size of cells, that results in an increase in the size of the affected organ
Hypertrophy is achieved by increasing the synthesis of cellular proteins.
What are some causes for hypertrophy?
- Mechanical stretch - major
- Agonists - pathologic state
- Growth factors - pathologic state
What is hyperplasia?
Hyperplasia is defined as an increase in the number of cells in an organ or tissue in response to a stimulus
What is physiologic hyperplasia?
Physiologic hyperplasia due to the action of hormones or growth factors occurs in several circumstances: when there is a need to increase functional capacity of hormone sensitive organs; when there is need for compensatory increase after damage or resection
For example: BPH
What is atrophy?
Atrophy is defined as a reduction in the size of an organ or tissue due to a decrease in cell size and number
What are 7 causes of pathologic atrophy?
Decreased workload (atrophy of disuse)
Loss of innervation (denervation atrophy)
Diminished blood supply
Inadequate nutrition
This results in marked muscle wasting (cachexia)
Loss of endocrine stimulation
Pressure
What is metaplasia?
Metaplasia is a reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type
Columnar epithelium can frequently metastasize to what?
Squamous cell type
What is the sequence of events for morphologic alterations in cells after irreversible injury?
Biochemical alterations
Ultrastructural changes
Light microscopic changes
Gross morphological changes
What 2 features of reversible cell damage can be recognized under light microscopy?
cellular swelling
fatty change
What is the biochemical mechanism for myocardial hypertrophy?
Increased mechanical stretch
Possible input by agonists and growth factors - ANG, IGF-1
Signal transduction pathways are activated
Trx factors made
Induction of embryonic/fetal genes - i.e. ANF
Increased synthesis of contractile proteins
Increased production of growth factors, which continues the process
What causes cell injury?
If limits of the cell’s adaptive responses are exceeded or if cell are exposed to injurious agents or stress, deprived of essential nutrients, or become compromised by mutations that affect essential cellular constituents, a sequence of events follows that is termed cell injury.
What is physiologic hypertrophy?
Some cells have a limited ability to divide - i.e. striated muscle in heart or skeletal muscles. Increased functional or metabolic demands, or stimulation by growth factors or hormones will frequently cause these cells to hypertrophy.
What is the physical stimulus for myocardiocyte hypertrophy?
Increased chronic hemodynamic overload, from HTN or faulty valves
What is a common cause for pathological hyperplasia?
Often caused by excessive or inappropriate actions of hormones or growth factors acting on target mature cells.
Hyperplasia can also result if new tissue grows from stem cells. (Robbins is unclear if this process is necessarily pathologic - example is growth of new liver tissue aft transplant or liver infection.)
What are some examples of pathologic hyperplasia that were discussed in class? How are these different from cancer?
Endometrial hyperplasia - failure of the endometrium to regress due to high levels of estrogen
Benign Prostatic Hyperplasia - growth of the prostate gland under the continued influence of testosterone
Both of these processes will involute if hormone is removed. In cancer, the drive towards growth is unchecked.
Hyperplasia is distinct from cancer, but pathologic hyperplasias are fertile ground for eventual cancerous proliferations.
What is atrophy?
Atrophy is defined as a reduction in the size of an organ or tissue due to a decrease in cell size and number
What are 6 causes of pathologic atrophy?
Decreased workload (atrophy of disuse)
Loss of innervation (denervation atrophy)
Diminished blood supply
Inadequate nutrition
This results in marked muscle wasting (cachexia)
Loss of endocrine stimulation
Pressure
What can result from decreased workload/atrophy of disuse?
Initial decrease in myocyte size is reversed when activity is resumed
With prolonged disuse, skeletal mm fibers decrease in size and number
Bone resorption is increased, osteoporosis of disuse can occur
What happens during denervation atrophy?
Normal metabolism and function of mm cells is dependent on nerve supply, damage to nerve results in atrophy of affected mm.
What happens during atrophy from diminished blood supply?
Blood supply can gradually decrease due to arterial occlusive diseases
- brain undergoing atrophy due to atherosclerosis, called senile atrophy
- can see widened sulci and narrowed gyri on gross brain, globally
What happens in atrophy due to inadequate nutrition?
Marasmus (profound protein-aclorie malnutrition) causes utilization of skeletal mm protein as a source of energy after adipose stores have been depleted.
Muscle wasting that results is called cachexia.
Also seen in chronic inflammatory disease and cancers.
What happens in atrophy due to loss of endocrine stimulation?
Hormone sensitive tissue is dependent on endocrine stimulation for normal metabolism and function.
What happens with pressure atrophy?
Tissue compressing for any length of time can cause atrophy.
Can happen due to tissues adjacent to an enlarging benign tumor getting compressed.
What is the idea behind atrophy? Is it the same for all types of atrophy?
Mechanism is the same for all types of atrophy
Decrease in cell size and organelles, resulting in decreased metabolic demands. Metabolism will be in sync with blood and nutrition supply. Early atrophic cells have diminished function, but cell death is minimal.
Gradual loss of blood supply can result in apoptosis.
What is the cellular mechanism of atrophy?
Atrophy results from decreased protein synthesis and increased protein degradation in cells.
Degradation of proteins occurs mostly though ubiquitin-proteosome pathway.
- nutrient deficiency and disuse activates ubiquitin ligases
- U(ubiquitin) ligases attach U’s to cellular proteins and target them to proteasome for degradation
Often accompanied by autophagy, with autophagic vacuoles and resulting residual bodies.
- lipofuscin granules can result, staining tissues brown and creating brown atrophy
What is metaplasia?
Metaplasia is a reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type
What is a common reason for metaplasia to occur? What is the result?
Metaplasia is often an adaptive response where one cell type that is sensitive to a stress is replaced by another that can better withstand the environment.
Commonly see columnar → squamous epithelium change
- seen in respiratory tract of smokers
- excretory ducts of salivary glands, pancreas, or bile ducts with stones
Can also see squamous → columnar
- Barrett’s esophagus
Can also result due to injury, not as an adaptive response
-i.e bone formation in muscle after a hemorrhage
If metaplasia is an adaptive response, why is it concerning?
Can result in loss of protective mechanisms of original tissue
- i.e. loss of ciliated respiratory epithelium to ward off infection and crud
Influences that predispose to metaplasia, if persistent, can initiate malignant transformation in metaplastic epithelium.
What is the mechanism of metaplasia?
Metaplasia doesn’t result from a change in the phenotype of an already differentiated cell type, instead is the result of a reprogramming of stem cells that known to exist in normal tissues, or of undifferentiated mesenchymal cells present in connective tissue.
Precursor cells differentiate along a new pathway, brought about by signals generated by cytokines, growth factors, and extracellular matrix components. All promote gene expression to a certain pathway.
Dysregulation of trx factors results in metaplasia - i.e. retinoic acid, vitamin A.
What are 7 causes of cell injury?
Oxygen Deprivation
Chemical Agents and Drugs
Immunologic Reactions
Nutritional Imbalances
Genetic Derangements
Infectious Agents
Physical Agents
What is hypoxia? What are 3 causes for it? Is it always fatal for cells?
Hypoxia is deficiency of O2, with resulting cell injury due to reduced aerobic oxidative respiration
Causes include:
reduced blood flow (ischemia)
inadequate oxygenation of blood due to cardioresp failure
decreased O2 carrying capacity of blood (anemia, CO poisoning, severe blood loss)
Cells can potentially adapt or atrophy if hypoxia is gradual, but sudden hypoxia will result in injury and death
What 4 cellular changes happen with cellular injury? What do these changes cause?
Swelling of cell and organelles
blebbing of plasma membrane
detachment of ribosomes from plasma ER
clumping of nuclear chromatin
All cause:
decreased generation of ATP
loss of cell membrane integrity
defects in protein synthesis
cytoskeletal damage
DNA damage
What happens with cell death?
Same sequence that happens with injury, but with continued noxious stimulus or new stress
What changes of reversible cell injury can be seen under light microscope?
Cellular swelling - very common, due to breakdown of ATP-dependent ion pumps
Fatty change - happens in cells dependent on fat metabolism - heart and liver
What 4 ultrastructural cell changes occur as a result of reversible cell injury?
- Plasma membrane alterations
- blebbing, blunting, loss of microvilli - Mitochondrial changes
- swelling and appearance of small amorphous densities - Dilation of ER
- detachment of polysomes, intracytoplasmic myelin figures may appear - Nuclear alterations
- disaggregation of granular and fibillar elements
Why does necrosis happen?
Result of denaturation of intracellular proteins and enzymatic digestion of lethally injured cell.
- lack of membrane integrity = contents of cell leaks out, causing inflammation
The enzymes that digest necrotic cells come from where?
Leaked lysosomes from dying cell
from leukocytes that are trying to clean up and incite inflammation
This process can take 2-12 hours to fully develop
What is a clinical correlation to the timeframe of necrosis?
After an MI, necrosis will take hours to manifest gross changes to the heart
Cardiac troponin and other cardiac enzymes will be leaking into bloodstream as early as ~2 hours after MI. Levels can be checked to determine if injury to cardiac tissue has happened.
Why are necrotic cells eosinophilic?
Loss of cytoplasmic RNA that would normally bind blue dye
Increase in proteins in cytoplasm, which binds pink eosin dye
Necrotic cells will appear chaotic in tissue organization, with mottled pink appearance and many cells lacking defining characteristics or nuclei
What 6 mechanisms of necrosis did we learn about?
- Coagulative necrosis
- Liquifaction necrosis
- Gangrenous necrosis
- Caseous necrosis
- Fibrinoid necrosis
- Fat necrosis
What causes coagulative necrosis? What is it associated with?
Necrosis due to sudden loss of blood supply
- small local area is called an infarct
- happens in kidney, heart
Often, ultrastructure of tissue/organ is left behind for a few days, and affected tissue has a firm texture. Proteolysis is blocked and dead cells may remain for weeks.
What is liquifactive necrosis? What is it associated with?
Necrosis with digestion of cells, resulting in tissue turning into liquid
- necrotic material is yellow, called pus
Hypoxic death of cells in CNS results in liquifactive necrosis
What is gangrenous necrosis?
Typically applies to limb that has lost blood supply and is undergoing (coagulative) necrosis in several tissue planes
With addition of a bacterial infection, it turns into liquifactive necrosis due to the degradative enzymes in bacteria = wet necrosis
What is caseous necrosis? What is it associated with?
Center of necrotic cells with granulomatous/inflammatory border
- this type of structure often called a granuloma
This IS tuberculosis (TB).
What is fat necrosis?
Refers to focal areas of fat destruction
- frequently a result of acute pancreatitis - pancreatic enzymes leak from acinar cells into abdomen and cause saponification of fat cells, and form chalky white blebs with Ca++ on the mesentary
What is fibrinoid necrosis? What is it associated with?
Necrosis in blood vessels that occurs after complexes of antigens and antibodies are deposited in vessel walls
Fibrin leaks out of vessels
Stains bright pink, results in immunologically-mediated vasculitis syndromes
What does the cellular response to injurious stimuli depend on?
Nature of the injury
Duration
Severity
What do the consequences of cell injury depend on?
Type, state and adaptability of injured cell
Depends on nutritional, hormonal, and metabolic status of cell
is cell vulnerable to insult?
genetic polymorphisms
What sites in a cell are damaged as a result of cell injury? What happens?
Mitochondria
- decreased ATP
- increased ROS
Entry of Ca++
- increased mitochondrial permeability
- activation of multiple cellular enzymes
Membrane damage
- plasma membrane - loss of cellular components
- lysosomal membrane - enzymatic digestion of cellular components
Protein misfolding and DNA damage
- activation of pro-apoptotic proteins
What is the fundamental cause of necrotic cell death? What are the major reasons why this occurs?
Fundamental cause is depletion of ATP/decreased ATP synthesis
Causes:
reduced supply of O2 and nutrients
mitochondrial damage
actions of some toxins - i.e. CN
Ischemia has happened. What is the sequence of events that follows?
Activity of plasma membrane energy-dependent sodium pump is reduced
- net gain of Na+, loss of K+
- cell swelling, blebbing, loss of microvilli follows
Cellular energy metabolism is reduced
- decrease in ox phos
- decrease in ATP levels
- increased anaerobic glycolysis, loss of glycogen stores
- increased lactate
- decreased pH → clumping of nuclear chromatin
Influx of Ca++ due to failure of Ca++ pump
Detachment of ribosomes from rough ER
- reduction in protein synthesis
No O2 or glucose results in misfolded proteins
- misfolded proteins clump in ER and trigger misfolding response
What are the 3 major consequences of mitochondrial damage?
- Formation of high conductance channel in mitochondrial membrane
- called mitochondrial permeability transition pore
- leads to loss of membrane potential
- loss of ox phos and ATP
- targeted by cyclophilin drugs to prevent graft rejection - Abnormal ox phos leads to formation of ROS’s
- Leakage of cytochome c from membranes
- activates caspases and starts apoptosis
What are 3 major consequences of Ca++ influx and loss of Ca++ homeostasis?
- Accumulation of Ca++ in mitochondria opens mitochondrial permeability transition pore and failure of ATP generation
- Increased cytosolic Ca++ activates phospholipases, proteases, endonucleases, and ATPases
- all hasten cell breakdown - Increased intracellular Ca++ activates caspases and increases mitochondrial permeability
What is oxidative stress?
Accumulation of oxygen-derived free radicals
Cell injury, as a result of ROS damage, results from what pathological conditions?
Chemical and radiation injury
ischemia-reperfusion injury - restoration of blood flow in ischemic tissues
cellular aging
microbial killing by phagocytes
How does oxidative stress occur?
ROS are produced as a byproduct of normal respiration and energy production
- systems in place to scavenge them
Loss of ROS scavengers or overproduction of ROS leads to oxidative stress
What diseases is oxidative stress implicated in?
Cancer
aging
degenerative diseases like Alzheimer’s
How are free radicals generated?
Normal metabolic processes
- RedOx rxns
Absorption of radiant energy (ionizing radiation)
Inflammation
- made by leukocytes during inflammatory processes
Enzymatic metabolism of exogenous chemicals or drugs
Transition metals
NO, or ONOO-
How are free radicals removed?
Antioxidants
Binding of transition metals - Fe, Cu - to carrier proteins
Enzymes that scavenge free radicals
Lipid peroxidation in membranes
Oxidative modification of proteins
(oxidation of side chains, formation of disulfide bonds, oxidation of protein)
Lesions in DNA
What are the enzymes that scavenge free radicals/ROS?
SOD
Catalase
Glutathione peroxidase
(intracellular balance of reduced versus oxidized glutathione is an indicator of oxidative stress)
Are free radicals always pathologic? Do they cause cell injury and death by necrosis?
Not always pathologic, do not directly cause necrosis
- frequently a prelude to necrosis, not causative
- free radicals can trigger apoptosis
Signalling via superoxide triggers production of degradative enzymes
What are some mechanisms of membrane damage?
ROS - via lipid peroxidation
Decreased phospholipid synthesis
Increased phospholipid breakdown - due to Ca++ dependent phospholipases
Cytoskeletal abnormalities - loss of microfilaments that anchor membrane, making membrane susceptible to shearing and stretching
What are some consequences of membrane damage?
Mitochondrial membrane damage
Plasma membrane damage
Injury to lysosomal membranes
What 2 things characterize irreversible cell injury?
Inability to revere mitochondrial disfunction
Profound disturbances in membrane function
What is the most common type of cell injury in clinical medicine? What does it result from?
Ischemia
Results from hypoxia induced by reduced blood flow
- most commonly due to mechanical arterial obstruction
What happens with a reperfusion injury?
Restoration of blood flow to ischemic tissues can promote recovery of cells if they are reversibly injured
- but -
can also exacerbate the injury and cause cell death
How does reperfusion injury occur?
Oxidative stress
- reduced antioxidant systems, and increased ROS reduction by damaged mitochondria, or increased oxidase production by endothelials, leukocytes, or parenchymal cells
Intracellular Ca++ overload
Inflammation
Activation of complement system
-IgM Ab tend to deposit in ischemic tissues, and complement cascade occurs when perfusion resumes
What type of cell injury is a major limitation to drug therapy?
Chemical/toxic injury
- many drugs are metabolized in the liver, and the drugs themselves or their metabolites can wreak havoc
How is direct toxicity induced?
Injury via chemicals combining to critical molecular components
Injury is usually to cells that use, absorb, excrete, or concentrate the chemicals
What are some examples of chemicals that induce direct toxicity?
Mercuric chloride
- binds sulfhydryl groups of cell membrane proteins
- increased membrane permeability and inhibition of ion transport
Cyanide
- poisons mitochondrial cytochrome oxidases
- stops ox phos
Antineoplastic chemotherapeutics, antibiotics
- directly cytotoxic
How is indirect toxicity induced?
Via conversion to toxic metabolites
Chemicals have to converted to toxic metabolites before having their effect on targets
- conversion frequently mediated by cytochrome p450, in liver and other organs
- damage frequently caused by conversion to a free radical
What are some examples of chemicals that are indirectly toxic?
CCl4
- converted by cytocrhome p450 to highly reactive CCl3-
- causes lipid peroxidation and damages many cellular structures
Acetaminophen
- creates many toxic metabolite when broken down by liver
