What is adaptation?
Changes in a cell due to adverse environmental factors (alternative to death)
What is the most common cause of significant cell injury?
Hypoxia (low oxygen)
What's the difference between eschemia and hypoxia?
Eschemia is lack of blood supply, hypoxia is lack of oxygen. Eschemia will cause hypoxia.
What's the most common cause of insignificant cell injury?
What are four major ways to damage a cell?
Mess up the energy system (ATP), damage the membrane (plasma membrane, organelle membranse), destroy everything inside the cell (toxic levels of intracellular Ca), or cause the cell to commit suicide (Free radicals aka reactive oxygen species --> protein/DNA breakdown)
What happens when mitochondria are damaged?
Channels are formed in the membrane which REDUCE ATP PRODUCTION and allows leakage of CYTOCHROME C which activates APOPTOSIS
What is one of the most common reasons for ATP Depletition?
Hypoxia (low oxygen)
Most forms of injury result in damage of what component of the cell?
What are the biochemical/cellular results of ischemia or hypoxia (as it relates to mitochondria)?
Limited oxygen = decreased oxidative phosphorylation = decreased ATP = increased anaerobic glycolysis = decreased glycogen and pH = clumping of nuclear chromatin. Also decreased protein synthesis and decreased Na Pump [activity??] --> influx of Ca, H2O, Na --> cellular swelling
What decreases as a result of hypoxia (as it relates to mitochondria)?
Oxydative phosphorylation, ATP, Glycogen, pH, protein synthesis, Na Pump
What increases as a result of hypoxia (as it relates to mitochondria)?
Anaerobic glycolysis, influx of Ca; H2O; Na, eflux of K
What are the sources of cytosolic calcium after injury?
Initially extracellular influx and release from mitochondria and ER. Sustained increase due to increased membrane permeability
What does increase cytosolic calcium result in?
Enzyme activation: ATPase, Phospholipases, Proteases, Endonucleases.
What are the four main reactive oxygen species associated with injury?
Superoxide, Hydrogen Peroxide, Hydroxyl Radical, Nitric Oxide
Which of the following is not technically a free radical? Superoxide, Hydrogen Peroxide, Hydroxyl Radical, Nitric Oxide
T/F: Free radicals are dangerous things that you don't want running around your system
False: Free radicals are normal and helpful for killing bugs
How are reactive oxygen species created?
Stepwise reduction of molecular oxygen due to chemical, physical, and radiation injury; cellular aging; or inflammation
How long do free radicals exist for?
What are the effects of free radicals on your cells?
membrane lipid peroxidation (chemical); protein cross linking and fragmentation (result of "little bombs"); DNA fragmentation,mutation, and chromosome breakage (cancer)
What are the effects of low levels of reactive oxygen species?
What are the effects of intermediate levels of reactive oxygen species?
What are the effects of high levels of reactive oxygen species
How do we neutralize free radicals?
Neutralize with enzymes that we make, or using electron-trapping molecules (what you read about in magazines)
What is reperfusion?
Restoration of blood flow following ischemia
After reperfusion, should you except a cease or increase of cell death?
You should expect further cell death following reperfusion (the reversal of ischemia) for the next few days
What can you expect to happen after reperfusion?
Increase ROS, endothelial damage, inflammation, mitochondrial dysfunction. All of this leads to hypotension, apoptosis, organ dysfunction, and cerebral edema.
Do bacterial toxins cause direct or secondary membrane damage?
Does activation of degradative enzymes cause direct or secondary membrane damage?
Does ROS generation cause direct or secondary membrane damage?
Does complement cause direct or secondary membrane damage?
What are two ways that a chemical can cause cell damage?
Maybe be converted to a reactive free radical (CCl4 --> CCl3, fatty liver poisoning), or it may combine with a critical molecule or organelle (mercury to membrane protein)
What are the four forms of cell adaptation?
Atrophy, hypertrophy, hyperplasia, metaplasia
Decreased cell MASS
Increased cell MASS
Increased cell NUMBER
Change from one mature cell type to another
Abnormal development or growth
Defective development or complete absence of an organ due to failure of development of embryonic tissues
Reversion of a cell to a less differentiated form
Why should a cancer patient be concered about aplasia?
The less differentiated the cancerous cell is, the worse off the patient is
Is atrophy normal or abnormal during embryologic development?
What are the two types of atrophy?
Physiologic and pathologic atrophy
What is atrophy during development called?
Normal physiologic atrophy
Gives some examples of a normal form of atrophy in development?
Notochord, thryoglossal duct
T/F: Simple pressure can cause atrophy
True: e.g. bed sores
Why would a woman in menopause possibly have an increased rate of atrophy?
Because of loss of endocrine stimulation
What is the main event in atrophy?
What are the two systems for protein degredation?
Lysosomes and Ubiquitin-proteasome pathways
T/F: Atrophy is associated with aging
True: "shrunken brain syndrome" given as example
When comparing a normal muscle tissue biopsy with one that has undergone atrophy, what can you look for besides shrunken cells?
White lipid droplets
T/F: Hypertrophy can be described as cell swelling
False: it's an actual increase in size
What are two common forms of physiologic hypertrophy?
Uterine hypertrophy (also an example of when hypertrophy and hyperplasia happen at the same time), and muscle hypertrophy in weight lifters
What is an example of pathologic hypertrophy?
Cardiac hypertrophy in hypertension caused by increased workload (increases function up to a point)
Define compensatory hyperplasia and where it occurs.
Regeneration of even large portions of the liver after removal
When a hotshot med student is talking about an elderly patient with "prostatic hypertrophy" what is he probably refering to?
Prostatic hyperplasia (increased cell number, not size)
Graves disease involves what kind of cell adaptation?
Hyperplasia (increased cell number)
Warts are a form of hyperplasia that rely on an increase in expression of what?
Increased expression of transciption factors
T/F: Drugs can cause hyperplasia
True, e.g. gingival hyperplasia
What are the three categories of pathologic hyperplasia?
Hormonal (thyroid), Growth Factors (warts), Drugs (Gingival hyperplasia)
What is gingival hyperplasia treated with?
Cyclosporine and nifedipine
T/F: metaplasia is irreversible
What's the most common type of epithelial metaplasia?
Columnar to squamous epithelium is the most common -- one example is via chronic irritation from smoking
Gastric reflux can cause what type of metaplasia?
Gastric reflux can cause stratified squamous to gastric-type columnar epithelial metaplasia
What is a major concern with metaplasia?
Predisposition for malignancy
What is a name for stratified squamous to columnar epithelia metaplasia?
If a patient is diagnosed with barret esophagus, what is his chance of developing esophageal cancer?
What is the mitochondrial response to hypertrophy?
To increase in number (more mass requires more mitochondria)
What is the mitochondrial response to atrophy?
To decrease in number (less mass requires less mitochondria)
Describe phagocytosis of exogenous matter. What is another term for this?
Heterophagy: matter is taken up via phago/endocytosis, fusion with primary lysosome to form phagolysosome (secondary lysosome), matter is broken down and residual body exocytoses
Vacuole buds off ER, fusion with lysosome to form autophagic vacuole, residual body formed and exocytosed.
How does a cell get rid of damaged organelles?
Autophagy (most common in atrophic cells)
Intracellular accumulation of triglycerides (steatosis) is usually an indicator of what?
Irreversible damage. Alcohol abuse in the liver.
What are foam cells?
Macrophages that accumulate cholesterol
Foam cells are often seen in what cardiovascular disease?
What's an example of a pathological intracellular accumulation of protein
Mallory bodies in hepatocytes in alcholic liver disease
What disease is associated with intracellular accumulation of glycogen?
Poorly controlled diabetes mellitus, glycogen storage disease
What is the most common source of intracellular accumulation of exogenous pigments?
Carbon, from breathing the air
What is lipofuscin?
A brown pigment found in aging cells of the heart, liver, and brain. Considered normal but also seen in atrophy.
Lipofuscin is a side effect of what process?
Free radical peroxidation of subcellular membranes (ROS attacks)
What are the two categories of calcification?
Dystrophic (due to necrosis from injury) and metastatic (due to hypercalcemia)
T/F: A patient with dystrophic calcification due to atherosclerosis has a high blood Ca level
False, dystrophic calcification is due to injury. Hypercalcemia is involved in metastatic calcification
What are the three types of changes that can happen to the nucleus an irreversibly injured cell?
Pyknosis (nuclear shrinkage), karyolysis (nuclear fading), or karyorrhexis (nuclear fragmentation)
What's more common: necrosis or apoptosis?
Is necrosis ever physiologic?
No, it is always pathologic
You just saw a youtube video of a cell shrinking and the nucleus fragmenting. What process does that describe?
Apoptosis with karyorrhexis
A histological slide is filled with a number of swollen cells. A higher magnification shows organelle breakdown, and you are told there is protein denaturation. What are you observing?
T/F: Apoptosis often causes tissue disruption
False, apoptosis affects individual cells so there's no loss of function in most circumstances
Necrosis is always accompanied by what physiologic response?
What are the four types of necrosis, and which is most common?
Coagulative (most common), liquefactive, caseous, fat. Osteonecrosis is difficult to categorize.
What are the two processes of necrosis?
Enzymatic digestion of the cell and dentaturation of proteins
Which form of necrosis is due to hypoxia?
Coagulative, which makes sense since it's the most common, and hypoxia is the most common form of injury
T/F: Cells that have undergone coagulative necrosis may persist for weeks
True: and they do so without a nucleus
Tissue that has undergone necrosis due to vascular blockage (ischemia)
A histological slide of myocardium looks relatively normal except for an extremely high number of PMNs. What is the pathology?
Coagulative necrosis (neutrophils brought in to carry away debris)
Liquefactive necrosis is associated with what kind of infection?
Bacterial or fungal infection (usually bacterial)
A brain infarct due to hypoxia will undergo what type of necrosis?
Liquefactive (you would think coagulative since it's an infarct from hypoxia, but this is an exception)
Describe the process of liquefactive necrosis
A bacterial or fungal infection attracts leukocytes which clear the infection and produce enzymes to digest dead cells. These enzymes liquify as they digest.
T/F: Liquefactive necrosis can be superimposed on top of coagulative necrosis
True: an area undergoing coagulative necrosis due to hypoxia can become infected and get liquefactive necrosis
What are the causes of Osteonecrosis?
Ischemia, trauma, infection, radiation, bisphosphonates
Caseous necrosis is associated with what kind of infection?
What kind of necrosis is associated with tuberculosis
What is fat necrosis associated with?
Describe the process of fat necrosis
Acute pancreatitis causes a release of pancreatic enzymes which then causes a release of FA and phospholipids which combine with calcium and get deposited as white chunky fat/calcium (fat saponification)
What is fat saponification?
Deposition of calcium/fat associated with fat necrosis.
Which category of necrosis is a misnomer?
Fat necrosis -- not really a necrosis, just a deposition of fat/calcium (fat saponification)
T/F: Apoptosis can initiate an inflammatory response
False: there is no inflammatory response with apoptosis
What is the death cascade?
The signalling process that leads to apoptosis via effector caspases and other enzymes. Involves TNF, Fas-Fas binding, and intracellular death domains
What does FADD bind with and what does TRADD bind with?
FADD binds to the death domain of FAS and TRADD binds to the death domain of TNF-R1 (Receptor 1)
Death signals are transmitted by what category of proteins?
What regulates mitochondrial permeability?
BCL-2 family of proteins
Where do BCL-2 proteins come from, and what do they do specifically?
They are mitochondrial proteins and they suppress apoptosis. Prevents leakage, inhibits caspase activation.
What is the most powerful suppressor of apoptosis?
BCL-XI, BAX, and BAD are all members of what protein family?
How do BCL-XI, BAX, and BAD function?
They all regulate BCL-2. BCL-XI upregulates to inhibit apoptosis, BAX and BAD downregulate to promote apoptosis.
What BCL-2 family protein inhibits apoptosis?
What BCL-2 family proteins promote apoptosis?
BAX and BAD
Why are caspases named thusly?
Because they have a cysteine in the active site and they cleave proteins after aspartic acid
In apoptosis, endonuclease is activated by what?
How are apoptotic bodies formed?
Transglutaminase causes protein crosslinking which causes the cytoskeleton to essentially pinch off part of the cell which then buds off.