Tissue Injury Lecture Oct 1 Flashcards
WHat is etiology?
Pathogenesis?
Clinical manifestations?
etiology is the causation
pathogenesis is the mechanism of disease development
Clinical manifestations are the end result of the changes resulting in functional abnormalities
What are the four main adaptations in response to cell injury?
hypertrophy
hyperplasia
autrotrophy
metaplasia
What is hypertrophy?
give an exmaple.
Hypertrophy is the increase in cell size, resulting in an increase in the organ size.
This results from increased production of cellualr proteins in response to increased demand or stimulation (can be physiologic or pathologic)
Selective hypertrophy can occur at the level of the subcellular organelle even (SER)
Examples include myocardial hypertrophy - thickening of ventricle wall - caused by an increased blood flow requiring greater mechanical effort by myocardial cells
Another example is the physiologic hypertrophy of the uterus during pregnancy
What is hyperplasia?
Give an example.
Hyperplasia is the increase in the number of cells, resulting in an increase in the size of the organ.
This will only occur if the cells of the organ are capable of dividing - the brain cant for example
This can be physiologica (hormonal or compensatory) or pathologic (excess hormones or growth factors)
An example is nodular prostatic hyperplasia - older men tend to have an increased sensitivity to testosterone, resulting in cell proliferation around the prostate gland
What is atrophy?
GIve an example
Decrease in cell size and number resulting in reduced size of the tissue or organ
this can be physiologic or pathologic
uptimately results from a decreased protein synthesis and increased protein degradation within the cells (increased autophagy may be involved)
WHat is metaplasia
GIve an example.
Reversible chain in which one differentiated type of cell is replaced by antoher cell type.
This results from the reprogramming of stem cells present in normal tissue or reprogramming of undifferentiated mesenchymal cells
External stimuli promote expression of genes that lead to a specific differentiation pathway
Barrett esophagus converts squamous to columnar in response to the high acid.
Connective tissue metaplasia - formation of bone instead
columnar to squamous (in the lungs)
What are the possible causes of cell injury?
osygen deprivation (hypoxia through ischemia, inadequat blood oxygenation, or decreased O2 carrying capacity – anemia, CO2, blood loss, etc)
Physical agents (trauma, temps, pressure, radiation, shock)
Chemicals and drugs
infectious agents
genetic derangements
nutritional imablance
What happens in necrosis?
If the injury is not reversible, the ER and mitochondria will beging to swell and myelin figures will develop.
the plasma membrane breaks down
organelles and nucleus break down
contents leak out of the cell
Extracellular cell contents trigger immune response
the hydrolytic enzymes that were withint the cell start to digest the cell parts and nearby tissue
NECROSIS
What are some morphological signatures of reversible cell injury?
in liver…
Cellular swelling (due to failure of ion pumps)
fatty change (buildup of cytoplasmic lipid vacuoles)
plasma membrane alterations
mitochondrial changes (swelling, condensation)
dilation of ER
Nuclear alterations
What is the morphology of necrosis (irreverislbe cell damage)?
increased cytoplasmic eosinophilia in tissue stains (DNA/RNA break down so it’s less blue and more pink)
myelin figures (dead cell replaced by mass of damaged cell membranes)
nuclear changes of karyolysis (nucleus faces away), pyknosis (srhunken nucleus) and karyorrhexis (fragmentation of the nucleus)
What are the 6 forms of necrosis?
coagulative
liquifactive
gangrenous
caseous
fat
fibrinoid
what happens in coagulative necrosis?
the architecture of the dead tissue is preserved (as is the case in an infarct)
WHat happens in liquefactive necrosis?
Digestion of the dead tissue results in liquid viscous mass
this is typically seen in focal bacterial or fungal infections because the microbes stimulate the accumulation of neutrophils which die and liberate enzymes that will break down the area into a liquid mass
What is gangrenous necrosis?
it’s a clinical term applied to necrosis of a limb undergoing coagulative ischemic necrosis (dry gengrene) or liquifactive necrosis (wet gangrene)
Describe caseous necrosis
cheeselike necrosis associated with necrotizing granulomas seen with TB and fungal infections
Describe fat necrosis
this refers to focal areas of fat destruction that result from the release of pancreatic enzymes into the nearby fat layers during pancreatitis
on the picture…the areas of white chalky deposits represent foci of fat necrosis with salcium soap formation (saponification) at sites of lipid breakdown in the mesentary
This can sometimes be associated with fibrosis and dystrophic calcification
What is fibrinoid necrosis?
a pattern of necrosis seen in immune reactions involving vessels
What are the 6 mechanisms of cell injury?
depletion of ATP
mitochondrial damage
influx of calcium/loss of Ca homeostais
accumulation of ROS
defects in membrane permeability
damage to DNA and proteins
How does depletion of ATP result in cell injury?
what are some causes of ATP depletion?
ATP is required for virtually every process in the cell
ATP depletion can be caused by reduces supply of oxygen and nutrients, mitochondrial damage or exposure to certain toxins
Effects of ATP depletion:
failure of Na pump (alteration in ion concentrations - swelling)
altered energy metabolism - use anaerobic glycolysis (so increase in lactic acid)
calcium pump failure
disruption of ribosomes with rreduced protein synthesis (and misfolded proteins)
eventually irreversible damage and cell death
How does mitochondrial damage occur?
What is the impact of mitochondrial damage on the cell?
Mitochondria can be damaged by osygen deprivation, ROS, or increased cytosolic calcium
Mitochondria supply ATP to the cell through oxidative phosphorylation, so it can alo cause a depletion of ATP
mitochondrial membrane proteins will also excape out of the mitochondria which can activate apoptosis: cytochrome C
How does influx of calcium/loss of calcium homeostasis result in cell injury?
Cytosolic free calcium is normally very low, but if a cell is injuryed the calcium is released from intracellular stores and the cell membrane becomes more permeable to extracellular calcium
This results in mitochondrial membrane defect and failture of ATP generation
activation of lytic enzymes
this can activated casoases leading to apopotisis
How does ROS accumulation occur?
What is the effect of ROS on the cell?
ROS are types of osygen derived free radicals that are produced normally in the cell during mitochondrial respiration and energy production. THere are cellular defense mechanisms to remove ROS. However, if these e=mechanisms don’t work or if there is a sudden increase in ROS production, the cell runs into issues.
disruption of plasma membrane and organelles
loss of enzymatic activity and abnormal folding
DNA oxidation resulting in mutations and breaks
What are three “scavenger” mechanisms to remove ROS from the cell?
superoxide dismutates converts it to peroxide
glutathione peroxidase and catalase will convert the peroxide to water
antioxidants will also take care of ROS - like vitamin E, A, and C
WHat can cause membrane damage?
What will membrane damage cause in the cell?
Membrane damage can occur as a result of ROS species, decreased phospholipid synthesis, increased phospholipid breakdown, and cytoskeletal abnormalities (stretching)
Membrane damage will result in:
mitochondrial membrane damage - decreased ATP and necrosis
loss of osmotic balance and loss of cellular components
injury to lysosomal membranes with release of lytic enzymes with enzymatic digestion of proteins, RNA, DNA, glycogen, etc.
THe “point of no return” in cell injury is not fully understood, but what is irreverisbility typically characterized by?
inability to reverse mitochondrial dysfunction
profound distrubances in membrane function
WHat does ischemia refer to?
What does hypoxia refer to?
Which tends to be worse for the cell?
Hypoxia is reduced oxygen availability
ischemia refers to reduced blood flow, so oxygen AND nutrients are decreased
Ischemia tends to be works because anaerobic glycolysis can continue in hypoxia but not in ischemia
What is an ischemia-reperfusion injury?
Often times, restoration of blood flow can promote recovery of reverisbly damaged cells
However, in some instances injury can be exacerbated by reperfusion
THis is because reperfusion can increase ROS production, it can cause an influx of neutrophils, and can activate the complement system
Briefly describe chemical (toxic) injury.
Which organ is the primary target of this and why?
Injury will occur ether by the direct effect of the toxin or throuhg a toxic metabolite
they can damage membranes, create ROS, or disrupt enzymes
The liver is often the target because it metabolizes many drugs and toxins through first pass metabolism
Why does apoptosis limit collateral damage?
The membrane never lyses, so cell contents don’t enter the ECM and an immune response isn’t initiated
What are three examles of physiologic apopotisis?
cell loss in embryogenesis
loss of uterine epithelial cells in menstrual cycle
cell loss in normal proliferating cell populations (lymphocytes)
What are 4 causes of apoptosis initiation?
DNA damage (radiation, cytotosic drugs, ypoxia)
accumulation of misfolded proteins
cell death in infections (particularly viral)
pathologic atrophy of organs associated with duct obstruction
What are hte morphological features of apoptotic cells?
cell shrinkage
condensation of nuclear chromatin
formation of blebs and fragments (apoptotic bodies)
Phagocytosis (usually by macrophages)
WHy will DNA damage lead to apoptosis?
Damaged DNA activates the p53 tumor suppressor gene which can induce apoptosis by expression of Bax and inhibition of Bcl2 in the intrinsic pathway
How can protein misfolding trigger apoptosis?
Unfolded or misfolded proteins can accumulate in the ER
This accumulation will induce an unfolded protein response which results in apoptosis
THe TNF receptor family including Fas and FasL are important for the regulation of lymphocyte apoptosis.
What happens if this is mutated?
You don’t get appropriate apopotsis of the lymphocytes, resulting in lymphomas
How do cytotoxic T cells mediate apoptosis?
They will recognize antigens present on the surface of infected cells
they will bind infected cells and secrete perforin which pokes holes in the cell’s membrane
it then secretes granzymes through the holes which will activate caspases inside the cell and induce apoptosis
What is autophagy?
How does it occur?
When does it occur?
a process of cell death in which the cell eats its own contents
under times of stress the cell forms an autophagic vacuole which then fuses with a lysosome to form an autophagolysosomes
cellular components are brought into these autophagolysosomes and digested by the lysosomal enzymes
this may play a role in degenerative diseases of the nervous system and muscle
What are the four main types of intracellular accumulations?
- abnormal metabolism (as in lipid accumulation in the liver)
- Defect in protein folding and transport resulting in the accumulation of abnormal proteins
- Lack of an enzyme so you don’t break down a complex substrate to a soluble product and lysosomal storage diasease results: accumulation of the complex substrate
- Ingestion of indigestable materials , resulting in the accumulation of exogenous products
What are some of the ways proteins can accumulate?
- reabsorption droplets in proximal renal tubues in renal diseases
- excessive protein production (Russell bodies in plasma cells)
3, Defective secretion of proteins (alpha-1-antitrypsin def.)
- Addumulation of cytoskeletal proteins (Mallory bodies in liver)
- Aggregation of abrnomal proteins - amyloidosis
- Hyaline change
What are some endogenous pigments that can accumulate in cells?
lipofuschin - it’s a brown lipid that results from free radical injury and membrane breakdwon - it’s seen in liver and heart as normal aging, also in malnutrition and cancer
melanin
hemosiderin granules - these are aggregates of ferritin - a protein iron complex. THe common bruise is an example of localized hemosiderosis. can also be systematic if there is an overload of iron
Lipofuschin and hemosiderin addumulation will look similar on an H&E stain, so what do you need to use to distinguish the two?
a prussian blue stain which is specific for iron and will stain blue in hemosiderin
What does pathological calcification refer to?
the abrnomal tissue accumulation of calcium
Under what two situations does calcification occur?
- dystrophic calcification - occurs in areas of necrosis with deposition of crystalline calcium phosphate, which can result in heterotopic bone formation (often seen with atherosclerosis, valve disease, fat necrosis, or TB)
- Metastatic calcification - due to hypercalcemia secondary to disordered calcium metabolism - elevated serum Ca. THis will result in serum calcium phosphate being depositied in normal tissues (lungs, kidneys, gastric, arteris, pulmonary beigns, heterotopic bone formation
What are the 4 principal causes of hypercalcemia in the serum?
- increased parathyroid hormone production
- destruction of bone tissue
- renal fialure
- Vitamin D related disorders
Which cellular changes contribute to cellular aging?
Decreased cellular replication (after a fixed # of divisions all somatic cells become arrested in senescence). telomere shortening likely involved.
Accumulation of metabolic and genetic damage over time
WHat do laboratory tests for cellular injury rely on
THey rely on cellular constituents that will be in the blood after a cell is lysed through necrosis
What tests will establish the presence of hepatocellular damage?
AST and ALT will be eleveted
NOTE: AST is not specific for liver because its also found in heart, skeletal muscle, brain and kidneys
ALT is only located in the liver, so ALT is a more specific indicator of hepatocyte injury
Which tests will etablish the presence of bile duct damage?
Alkaline phosphatase (ALP) will increase usually due to bone or liver disease
A second test, gamma-glutamyl transferase (GGT) will only be elevated in biliary damage, so it will assist in determining if an ALP is elevated due to bone or liver disease
What elevated enzyme suggests damage to cardiac muscle?
troponin 1
