Cell Responses to Stress Flashcards
Regulation of a normal tissue state?
=Homeostasis
-means that an effective response to injury/infection etc will restore normal tissue functions
Regulation of a pathological tissue response?
-pathological tissue response results in tissue damage and/or tissue remodeling (scaring/altered function)
gross vs microscopic changes in tissue?
- both pathogenic and adaptation (muscle growth) of tissues can be seen both microscopically & grossly
- in entire tissue vs in individual cells
cell response to altered physiological stimulus or a nonlethal injury stimuli? (ex: decreased nutrients & stimulation; increased demand& stimulation)
- CELL ADAPTATIONS
ex: hyperplasia, hypertrophy, atrophy, metaplasia
cell response to reduced oxygen supply, chemical injury, microbial infection? ( acute & transient, progressive/severe including DNA damage)
- CELL INJURY
- acute reversible injury= cell swelling; fatty change
- irreversible injury= apoptosis & necrosis
when does cellular aging occur?
-when have a cumulative sublethal injury over long life span
what are cell adaptations?
-adaptations to stresses that push tissue one way or other; -are usually reversible if stressor removed
what is cell injury?
- can be pathological or physiological
- usually progressive; not all cells respond at same time to same thing
- can see ranges of when stress & death occur in same tissue
Hypertrophy
- ex of cell adaptation
- an increase in the size of cells w/o cell division
- see corresponding increase in organ size (ex: uterus)
- can be pathological or physiological stressors
- can be selective process
Hyperplasia
- ex of cell adaptations
- increase in the size of cells w/ cell division too
- can be pathological or physiological stressors
Hyperplastic
-an increase in cell number in response to pathological or physiological stressors
mechanism of cardiac hypertrophy?
- typically from increased workload or from increasing growth factors/vasoactive agents
- response: increased protein production, changes in gene expression
- can be SELECTIVE, the same organ can have 2 means of responding the same drug
- MANY DIFF MECHANISMS
What causes hyperplasia?
- result of cell division
- can be Physiologic or Pathologic
- same factors that effect hypertrophy can also affect hyperplasia
Physiologic Hyperplasia? (2 ways)
1) Hormonal: increased functional capacity when needed
2) compensatory: increases tissue mass after damage or tissue loss (ex liver regeneration after resection)
- always about returning to homeostasis
Pathologic Hyperplasia?
- most often caused by excess hormones/growth factors
- also by viral factors (HPV)
- distinct from cancer but can provide predisposing conditions
atrophy?
- a cell adaptation
- reduction of organ size due to decreased cell size & number
- physiological & pathological causes
physiological atrophy?
physiological: from malfunction in developmental processes
common causes of pathological atrophy?
1) decreased workload
2) loss of innervation
3) ischemia (loss blood supply)
4) malnutrition
5) loss of endocrine stimulation (menopause)
6) pressure; expanding. mass of benign tumor
Mechanisms of Atrophy?
- decreased protein synthesis, increased degradation
- autophagy
- early in process, cells may still be alive but cell death soon follows
autophagy
-cell cannibalizes its own components
Metaplasia
- a cell adaptation
- when one differentiated cell type is replaced by a different cell type in response to stress
Metaplasia in the respiratory track?
- in response to constant irritation
- change from Columnar to Squamous
- change provides a more resistant surface, but loose mucus secretion & ciliary clearance
Metaplasia in the esophogus?
- in response to reflux of gastric acid
- Squamous to Columnar
Connective Tissue Metaplasia
-formation of cartilage/bone in muscle in response to injury/hemorrage
Mechanism of Metaplasia
- reprogramming of stem cells to produce a different differentiated cell type
- is not transdifferentiation of existing cells from one differentiated cell phenotype into another phenotype
- in stem cells NOT differentiated cells*
why epithelial cells able to do metaplasia?
- because epithelial cells are alive, actively dynamic & constantly undergoing replacement from stem cells
- instead of correct replacement…do metaplasia & get diff cell type
What types of cells do stem cells produce?
-stem cells can produce any type of cell BUT once cell is made & mature…it is terminally differentiated can no longer change its function
cell injury & cell death causes (x7)
1) hypoxia (O2 defincency)
2) physical trauma
3) chemical agents & drugs
4) infectious agents
5) immunological rxts
6) genetic effects
7) nutritional imbalances
What is hypoxia? What is the result?
- reduced oxygen availability
- energy production has to go through anaerobic glycolysis
What is ischemia?
-reduced blood flow reduced O2, reduced supply of nutrients
what happens during cell injury?
- decreased ATP generation
- cell cytoskeleton & membrane degeneration
- mitochondrial swelling
- is potentially reversible if caught in time*
protective response to hypoxia/ischemia? Treatment?
1) anaerobic glycolysis
2) production of HIF-1
-transient protection of tissue by induction of hypothermia (92degrees) for brain & spinal cord injuries
HIF-1
- Hypoxia-indicble factor
- trxn factor that promotes blood vessel formation
- regulates erythropoietin production
How HIF-1 regulated?
1) HIF-1 is always produced (but never on) so don’t have to waste time w/ trxn&trans when need it
2) HIF-1 constantly being ubiquitnated so is degraded
3) when PHD enzyme senses hypoxia ; halts ubiquitnation causes hydroxylation & activation of HIF-1
4) HIF-1 can make new blood vessels and repair hypoxic damage
HIF-1 & tumor angiogenesis?
- angiogeniss= when tumors build blood vessels to feed their growth
- if inhibit HIF-1; then no blood vessels made
HIF-1 inhibited? vs uninhibited?
- inhibited(no hypoxia)=ubiquinated= no blood vessel formation
- activated (in hypoxic situations)= hydroxylate day PHD= blood vessel formation
Potential treatment of anemia?
- blocking HIF-1 degradation
- so are building more blood vessels and organs are receiving more nutrients it needs
what is ischemia-reperfusion injury?
–when hypoxia/ischema is revered but repercussion causes worse damage
How reperfusion cause damage (x3)?
1) increased reduced oxygen species (ROS)
2) induction of inflammatory processes
3) activation of complement from IgM deposition in tissue, adding to the activation of inflammatory processes
How does reperfusion cause increases reduced oxygen species (ROS)?
- repercussion causes mitochondrial damage& and reduced capacity to reduce oxygen, leading to free radical accumulation
How does reperfusion cause inflammatory processes?
- reperfusion causes an incerased production of cytokines & expression of adhesion molecules on endothelium
- helps recruitment & activation of neutrophils, & macrophages from blood leading to tissue damage
What are gross tissue changes?
1) changes in tissue integrity ( intact, cheesy, gooey, liquid/slimy)
2) changes in tissue color (hemorrhage, pallor, fibrous scars)
gives clues to microscopic damages
What are microscopic/histological changes?
changes in:
1) tissue organization
2) cell size & shape
3) cell nuclei (color, size, shape)
4) cytoplasm color
5) infiltrations by inflammatory cells
gives clues to tissue damage
what are inflammatory cells?
macrophages & neutrophils
Apoptosis: (cell size?) (nucleus?) (PM & cell contents?) (inflammation?) (physiological/pathologoical?)
1) reduced (shrinkage)
2) DNA fragmentation into 200bp
3) intact PM & cell contents
3) no inflammation
4) usually physiological; removing unwanted cells in development; CAN be pathological after DNA damage
Necrosis: (cell size?) (nucleus?) (PM & cell contents?) (inflammation?) (physiological/pathologoical?)
1) cell swelling (enlarged)
2) randomly fragmented
3) disrupted; enzymatic digestion may leak out o cell
4) inflammation
5) irresverisbly pathologic
Why is loss of PM & cellular contents bad?
-occurs in necrosis
-because activates inflammatory response
(macrophages & neutrophils)
Coagulative Necrosis
- morophological change due to cell injury
- integrity of connective tissue is preserved, but loss of nuclei during necrosis
- inflamamtory cells enter & destroy nuclei, but maintain other structures
Liquefactive necrosis
- morophological change due to cell injury
- digestion of dead cells, with change to liquid viscous mass
- due to bacteria/fungal infection
- recuritment of inflammatory cells & enzymatic digestion of tissue (pus)
- Hypoxic death in CNS often manifests this way
Gangrenous necrosis
- morophological change due to cell injury
- due to lost blood supply
- can be coagulative or liquefactive necrosis
Caseous necrosis
- morophological change due to cell injury
- seen in TB infections
- charcateristic of granulomatous inflammation
Fat necrosis?
-focal areas of fat destruction
-from release of lipases into pancreas & peritoneum
-Fatty acids combine w/ calcium to produce calcium soaps
(saponification)
saponification
-fatty acids combine with calcium to produce calcium soaps
Fibrinoid necrosis
-vascular lesions in vasculitis from immune complex deposition in arterial wall
Mechanisms of Cell Injury? (x6)
1) ATP depletion
2) mitochondrial damage
3) Ca+ influx
4) oxidative stress (ROS)
5) membrane permeability
6) DNA/protein damage
Depletion of ATP & cell injury ?
- associated w/ hypoxic chemical injury
- affects many systems since loosing cell’s energy source
- can lead to necrosis due to mitochondrial damage
Mitochondrial Damage & cell injury?
2 consequences
1) mito. permeability increase, loose membrane potential, depletion of ATP–> necrosis
2) leakage of apoptosis-inducing proteins; activation of caspases & initation of apoptosis
Calcium Influx & cell injury?
- intracellular Ca2+ (normal=low) is then increased. Causes:
1) mito. permeability increased, loss of ATP production, necrosis
2) Ca dependent enzymes (phosphatases, ATPases, proteases) are activated w/ bad outcomes
3) activation of caspases & apoptosis
how do reactive oxygen species (ROS) cause cell injury?
1) peroxidation of membrane lipids
2) oxidation of protein amino acid side chains
3) DNA damage (strand breaks)
How does peroxidation of membrane lipids occur?
1) O2 converted to superoxide by oxidative enzymes in the ER& mito;
2) then converted to H202
3) results in peroxidation of lipids, protein & DNA
how does membrane permeability cause cell damage?
- cell membrane permeability occurs by ROS, toxins, phospholipase
- causes damage by effecting 3 targets
1) mito-loss of ATP/apoptosis induction
2) PM- loss of osmotic balance
3) lysosome- Leake of degradative enzymes leading to necrosis
What could intracellular accumulation be due to?
1) increased accumulation/production of normal cell products
2) defective metabolism due to increased accumulation of abnormal proteins/ genetic defect in degradative enzyme
3) ingestion & accumulation of abnormal exogenous substances (ex. silica)
what is Steatosis? where is it at? what causes it?
- triglyceride accumulation in the liver due to excessive entry of fatty food or defective metabolism caused by (ethanol)
what is Cholesterolosis? What called in wall of large blood vessel?
- accumulation of cholesterol-laden macrophages in the wall of the gall bladder
- if in the wall of large blood vessels is called: ATHEROSCLEROTIC PLAGUES
intracellular Protein Accumulations?
- intracellular accumulation of protein appears as eosinophilic material
- accumulation of cytoskeletal proteins can be normal (keratin in skin) or abnormal (Alzheimers disease)
Extracellular protein accumulations?
- protein accumulations can also happen extracellular
- ex: amyloid
Two types of pigment accumulation?
1) exogenous pigments
2) endogenous pigments
exogenous pigments example?
- coal dust accumulating in lung tissue
- tattoo pigments on skin
endogenous pigments examples?
1) lipofuscin
2) melanin
3) hemosiderin
lipofuscin
- polymers of lipids & phospholipids w/ protein
- sign of free radical injury & lipid peroxidation
- seen in cells undergoing slow regressive changes
melanin?
- brown-black pigment by tyrosinase in melanocytes
hemosiderin?
- golden yellow/brown granular pigment, derived from hemoglobin
- serves as iron storage from RBC breakdown
two types of calcification?
1) dystrophic:
2) metastatic
dystrophic calcification
- in areas of necrosis & in foci of enzymatic necrosis of fat
- seen in advanced atheromatous plaques & aging/damaged hart valves
- bone can form from them
metastatic calcification due to (x4)?
- can occur in normal tissue w/ hypercalcemia
1) increased secretion of parathyroid hormone (PTH) w/ bone resorption due to parathyroid tumor
2) destruction of bone tissue, due to bone marrow tumors
3) vitamin D disorders
4) renal failure, cause retention of phosphate & secondary hyperparathyroidism
