Cellular Reaction to Injury Necrosis: Mechanisms and Morphologic Changes Flashcards
characteristics of reversible cell injury
- reduced energy production via oxidative process
- osmotic imbalance leading to water influx and cell swelling
irreversible cell injury
- results from persistent or excessive injury
- mitochondrial injury cannot be corrected
- disturbed irreparable membrane function
- cell cannot recover and dies (necrosis or apoptosis)
Types of Cell Injury
- physical
- oxygen deprivation
- chemical
- infectious
- immunologic
- genetic
- nutritional
define physical
direct physical trauma, thermal injury, radiation, electric shock
define oxygen deprivation
decreased oxygen state
define chemical
- wide range of agents
- environmental pollutants, drugs, aberrations in normal cell solutes leading to osmolar imbalances
define infectious
prions to parasites
define immunologic
immune reactions to external injury and autoimmune disease
define genetic
genetic aberrations, abnormal protein expression causing direct cell injury or increased susceptibility to deleterious agents
define nutritional
deficiencies and excess may lead to cell injury and disease
types of oxygen deprivation
- hypoxemia
- ischemia
- hemoglobin loss/dysfunction
define hypoxemia
- low partial pressure of oxygen in blood! ***
2. PaO2 < 60mmHg, SaO2 < 90%
causes of hypoxia
- high altitude with decreased atmospheric oxygen
- hypoventilation
- diffusion defect (pneumonia, interstitial lung disease)
- ventilation perfusion mismatch (right to left shunt)
describe the Right to Left Shunt (Tetralogy of Fallot)
- pulmonic stenosis
- right ventricular hypertrophy
- overriding of aorta
- ventricular septal defect
“PROVE”
what is ischemia
- hypo-perfusion of tissue with blood
2. both reduced supply of oxygen & substrates for glycolysis
causes of ischemia
- decreased arterial perfusion (atherosclerosis)
- decreased venous drainage (hepatic vein thrombosis)
- shock-generalized hypotension
Causes of Hb loss of dysregulation
- anemia (decreased RBC mass)
- carbon monoxide poisoning (CO binds HB instead of O2)
- methemoglobinemia
what is methemoglobinemia
- sulfate and nitrate drugs cause oxidant stress
- generates Fe3+, which cannot bind oxygen
- methylene blue can covert Fe3+ back to Fe2+
oxygen deprivation can lead to cell injury due to
reduced intracellular ATP production
mechanisms of injury/necrosis
ATP Depletion Mitochondrial Damage Loss of Calcium Homeostasis Oxidative Stress Membrane Permeability Defects DNA and Protein Damage
ATP is synthesized by
- ADP phosphorylation in mitochondria (aerobic)
- glycolysis (anaerobic)
causes of ATP depletion
decreased oxygen and nutrients, mitochondrial damage, toxins
all synthetic and degenerative processes require what
ATP, its depletion has widespread defects on many critical systems
example of membrane-bound pump malfunction
- Na/K-ATPase –> cell swelling/ER dilation
- CA++ pump –> influx of Ca+ = derangement of cellular process
- stimulation of glycolytic pathway –> decrease pH ER detachment of ribosomes –> decreased protein synthesis
- protein missfolding, mitochondrial, lysosomal, nuclear membrane damage = necrosis
what decreases ATP production
injury leads to formation of high-condunctance channel - the mitochondrial permeability transition pore –> decreased potential –> decreased ATP
activation of apoptosis occurs within
cytochrome c and caspases in the mitochondria
membrane injury and leakage of cytochrome c and caspases activates what pathway
apoptotic pathway
intracellular Ca 2+ levels
maintained at very low levels (~0.1 umol) in mitochondria and the ER
extracellular Ca 2+ levels
are high (1.3 mmil) therefore a loss of homeostasis can lead to massive Ca 2+ influx
massive Ca2+ influx leads to
- activation of the mitochondrial permeability transition pore (mPTP)
- activation of phospholipases, proteases, endonucleases
- increased mitochondrial permeability and activation of caspases and procaspases which directly induce apoptosis
O2 derived free radicals are
species with an unstable single election on its outer orbit which easily reacts with many key components of the cell
free radicals initiate
autocatalytic reactions, converting molecules that they react with into free radicals, propagating the cellular damage
define physiologic generations
ROS are produced normally in cells but they are degraded and removed by cellular defense systems
loss of steady state (where ROS are transient and in low concentrations) results in
oxidative stress
during normal respiration, O2 is reduced to
2H2O2 by transfer of 4 electrons to )2
oxidative enzymes in the cell catalyze this rxn and produce
partially reduced intermediates (ROS) during the process (see slide 26)
radiation can break down water into
OH and H free radical
inflammation leads to bursts of ROS which activate what
leukocytes which generate ROS via a redox rxn lead by NADPH oxidase in PM
enzymatic drug metabolism CCL4 is converted to
toxic CCL3 in liver
nitric oxide (NO) generated by many cells can react with
O2 and be converted to highly reactive peroxynitrite anion (ONOO-), NO2 and NO3-
during reoxygenation of blood flow to ischemic viable tissue, what can occur
- ROS generated (from damaged mitochondria, inflammatory cells, endothelial cells, parenchymal cells)
- influx of plasma proteins and leukocytes
- activation of complement system
- cellular antioxidant defense mechanisms not normal
spontaneous decay
Superoxide (O2.-) –> O2 and H2O2 in the presence of water
what are the active mechanisms of cellular removal of ROS
- antioxidants
2. transferring, ferritin, lactoferrin and ceruloplasmin
what are antioxidants
block initiation of free radical formation or inactive free radicals
examples of antioxidants
Lipid-soluble vitamins E and A , ascorbic acid and glutathione in the cytosol
what are transferrin, ferritin, lactoferrin and ceruloplasmin
-are transport and storage proteins that chelate iron and copper which can catalyze the formation of ROS
what enzymes remove ROS cellularly
- catalase
- superoxide dismutases
- glutathione peroxidase
(see rxns on slide 34)
name 4 membrane disruptions
- ROS
- Decreased phospholipid synthesis
- increased phospholipid breakdown
- protease activation
ROS can cause
injury to cell membrane via lipid peroxidation
decreased phospholipid synthesis
low ATP leads to decreased production of phospholipids affecting all cellular membranes
increased phospholipid breakdown
- Cell injury leads to activation of endogenous phospholipases and membrane breakdown
- Lipid breakdown products have a detergent effect on membranes resulting in changes in permeability
protease activation
increased intracellular calcium proteases that damage cytoskeleton
what are the effects of membrane disruption
- mitochondrial membrane damage
- plasma membrane damage
- injury to lysosomal membranes
mitochondrial membrane damage
- Mt permeability transition pore
- decreased ATP, release of apoptotic proteins
plasma membrane damage
loss of osmotic balance and influx of fluids and ions –>further decrease in ATP
injury to lysosomal membrane
- leakage of hydrolases into cytoplasm (RNases, DNases, proteases, phosphatases, glucosidases) and degradation of targets
- Low intracellular pH allows for activation of hydrolases
DNA damage can be caused by
toxic drugs, radiation, oxidative stress
normal DNA repair mechanisms do what
correct damage and maintain the steady state
If DNA damage is too extensive for repair and misfolded proteins accumulate, what happens to the cell
the cell initiates a self destructive program called apoptosis
What are the mechanisms of Cell injury
ATP Depletion Mitochondrial Damage Loss of Calcium Homeostasis Oxidative Stress Membrane Permeability Defects DNA and Protein Damage
what are reversible morphologic changes of cell injury
cellular swelling
cellular swelling is the first response to
injury
-loss of energy disables ATP-dependent ion pumps and leads to loss of osmotic homeostasis
what are the morphological manifestations of cellular swelling
Plasma membrane blebbing or loss of microvilli
Mitochondrial swelling
ER swelling with detachment of ribosomes
Nuclear chromatin clumping (see chunks of nuclear material)
Cytoplasm may contain myelin figures (phospholipid masses from damaged cell membranes)
irreversible changes (necrosis)
- nuclear changes - breakdown of DNA
- severe mt damage - ATP depletion
- lysosome damage - autophagy
- cytoplasmic changes - increased eosinophilia, loss of glycogen particles, more prominent myelin figures
- membrane damage - leakage of cellular contents
necrosis often leads to what
inflammation/injury of surrounding cells
nuclear changes due to breakdown of DNA
- pyknosis
- karyorrhexis
- karyolysis
- loss of nuclei
define pyknosis
Shrinkage and increased basophilia (blue) due to chromatin condensation (often seen in apoptosis)
define karyorrhexis
Fragmentation of pyknotic nuclei
define karyolysis
Decreased nuclear basophilia due to DNA degradation by nucleases
loss of nuclei
With time necrotic nuclei disappear
what are cytoplasmic changes of necrosis
- cytoplasmic eosinophilia
- glassy cytoplasm
- myelin figures
cytoplasmic eosinophilia due to
decline in cytosolic mRNA, which is basophilic, and an increase in cytosolic concentration of denatured proteins
glassy cytoplasm result of
loss of glycogen particles
myelin figures formed by
broken cell membrane
irreversible cell injury is characterized by what 2 main events
- mitochondrial dysfunction (lack of oxidative phosphorylation and ATP generation) even after resolution of the original injury
- disturbances in membrane function
lysosomal injury results in
the enzymatic degradation of the cell that is characteristic of necrosis
leakage of intracellular proteins through the damaged cell membrane leads to
recruitment of inflammatory response also typical of necrosis
patterns of tissue necrosis
- coagulative necrosis
- Liquefactive Necrosis
- Gangrenous Necrosis
- Caseous Necrosis
- Fat Necrosis
- Fibrinoid Necrosis
what is coagulative necrosis
- Overall architecture is preserved, individual cells have a ghostly appearance
- Destruction of proteolytic enzymes hinders proteolysis of necrotic cell
- Necrotic cells remain until phagocytosis by infiltrating leukocytes occurs
(ex. ischemia –> infarction)
what is liquefactive necrosis
Digestion of dead cells which gives tissue a liquid appearance
liquefactive necrosis occurs in
- abscess
- brain infarction
define abscess
infectious process leads to recruitment of white cells which release proteolytic enzymes which digest the dead cells
define brain infarction
Microglial monocytic cells produce proteolytic enzymes and liquefy brain tissue
grossly, liquefactive necrosis often seen as
a circumscribed lesion filled with pus and cellular debris or as gelatinous tissue with cavity
define gangrenous necrosis
- More than a pattern of necrosis it is a clinical descriptor (often a combination of coagulative and liquefactive necrosis)
- often used to describe limb necrosis secondary to loss of blood supply (coagulative necrosis) with superimposed bacterial infection (liquefactive necrosis)–> wet-gangrene
caseous necrosis is commonly seen in
mycobacterial/fungal infections and refers to the cheese-like appearance of the necrotic tissue
what is a granulomatous reaction
- where there is an amorphous granular debris enclosed within an inflammatory border
- tissue architecture is completely obliterated, unlike coagulative necrosis
define fat necrosis
- not a real pattern of necrosis
- refers to fat necrosis of pancreas and peritoneal cavity as seen in pancreatitis
in acute pancreatitis, what happens to pancreatic enzymes
- pancreatic enzymes leak into the peritoneum and liquefy surrounding fat cells releasing fatty acids
- these fatty acids combine with calcium to form calcium salts (soap)
define fibrinoid necrosis
necrosis caused by deposition of immune-complexes and fibrin within walls of blood vessels
