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Distinguish reversible from permanent and lethal cell injury.

• Reversible injury leads to altered cell composition such that if and when the offensive stimulus is removed, the cell will restore its original function
• Hallmarks include: reduced oxidative phosphorylation with resultant depletion of energy stores in the form of ATP, cell swelling due to ion concentrations, alterations in cytoskeletal structures, organelles, and mitochondria
o Examples of reversible ischemic injury include
• Mitochondrial swelling
• Membrane blebs
• Increased cell volume
• Cytoskeletal disorganization
• Influx of Ca, Na, H2O
• Efflux of K
• Decrease in protein synthesis and increase in lipid deposition
• Irreversible injury leads to either a permanently altered cell or cell death
o Ex: Mitochondria
• become porous and enter a low energy state.
• Lose enzymatic systems and cannot recover normal function.
• Swell and Ca precipitate forms (pathologic calcification)
• Apoptosis cascade may begin


What are the three causes of cell death?

• apoptosis
• necrosis
• (also autophagy during nutrient deprivation)


What is necrosis?

• When damage to membranes is severe, lysosomal enzymes enter the cytoplasm and digest the cell, and cellular contents leak out
• This is always a pathologic process


What is Apoptosis?

• a form of cell death that is characterized by nuclear dissolution, fragmentation of the cell without complete loss of membrane integrity, and rapid removal of the cellular debris
• This is sometimes a pathologic process and sometimes a normal cell function


Details: apoptosis and necrosis sometimes have similar causes. Apoptosis can sometimes lead to necrosis. Autophagy can sometimes be similar to apoptosis.

Details: apoptosis and necrosis sometimes have similar causes. Apoptosis can sometimes lead to necrosis. Autophagy can sometimes be similar to apoptosis.


What are the causes of cell injury?

• O2 deprivation aka hypoxia
• Physical agents (temperature, pressure, radiation, electric shoc)
• Chemical agents
• Infectious agents (microbiology to large tapeworms)
• Immune reactions
• Genetic derangements (ex: decreased life span of RBCs)
• Nutritional imbalances


What are two features of reversible cell injury that can be recognized under the light microscope?

• cellular swelling
• fatty change


What causes cellular swelling?

• lack of ATP causes ion pumps to not function and osmotic imbalance occurs


What causes fatty change?

• found usually in cells that depend on fat metabolism: heart, liver, and others
• Several mechanism (check back later)


What are the ultracellular changes of reversible cell injury?

• plasma membrane: blebbing, blunting, loss of microvilli
• mitochondria: swell and have small amorphous densities
• dilation of the ER and detachment of ribosomes
• nuclear alterations: desegregation of granular and fibrillar elements
• may include increased eosinophillic staining


What is the mechanistic cause of necrosis?

• denaturation of intracellular proteins and enzymatic digestion of the lethally injured cell


See Table 1-2 page 13 robbins for differences between necrosis and apoptosis.

See Table 1-2 page 13 robbins for differences between necrosis and apoptosis.


What digests the contents of necrotic cells?

• lysosomes from the necrotic cells
• lysosomes from inflammatory leukocyte
• Note: this takes hours, so may not occur in sudden infarct. Instead, cellular components from the heart are released into the blood stream


What are the ultrastructural changes in general necrosis?

• increased esosinophilia due to the loss of cytoplasmic RNA (blue) and increased denatured proteins
• glassy homogenous: loss of glycogen
• dead cells may be replaced by myelin figures (from damaged cell membranes)
• calcification
• discontinuous cell and organelle membranes
• very large mitochondria
• Nuclear changes (3)
o Karyolysis (fade of basophilia)
o Pyknosis (nuclear shrinkage)
o Karyorrhexis (nuclear fragmentation)


What are the six types of necrosis?

• Coagulative necrosis
• Liquefactive necrosis
• Gangrenous necrosis
• Caseous necrosis (cheese-like)
• Fat necrosis
• Fibrinoid necrosis


What are the features of Coagulative necrosis?

• denaturation of proteolytic enzymes, so much of the structure of the cells remain intact.
• Eosinophilic, anucleate cells


Ischemia can lead to coagulative necrosis in all organs except? Why?

• the brain
• Why?


What degrades the coagulative necrosis?

• note: may persist for weeks
• degraded by leukocytes


What are the characteristics of liquefactive necrosis?

• digestion of dead cells, resulting in a viscous mass
• seen in focal bacterial or fungal infections because microbes stimulate the accumulation of leukocytes, which then digest the necrotic cells
• Pus
• Infarction of the brain produces liquifactive necrosis


What are the characteristics of Gangrenous necrosis?

• a type of liquifactive necrosis
• usually on a limb that lacks circulation
• bacteria invade and attract leukocytes, which digest the tissue


What are the characteristics of Caseous necrosis?

• classically in tuberculosis infections with granuloma
• caseous = cheese-like
• white, appears like it can be broken into pieces like cheese
• collection of fragmented or lysed cells and amorphous granular debris within a distinctive inflammatory border (granuloma)


What are the characteristics of fat necrosis?

• focal areas of fat destruction from the release of pancreatic lipases in the pancrease or peritoneal cavity
• occurs during acute pancreatitis
• lipases split fat esters ==> fat combines with Ca to form chalky white areas of saponification
• see Robbins page 17, figure 1-14


What is fibrinoid necrosis?

• antigen-antibody complexes deposit in blood vessels
• Immune complexes leak out of the vessels bound to fibrin
• Result in bright pink and amorphous H&E stain, called “fibrinoids”
• Seen in vasculitis


Term: dystrophic calcification come back later

Term: dystrophic calcification come back later


What are the basic principles of Cell Injury?

• cellular response depends on the nature of the injury, duration, and severity
• consequences of cell injury depend on the type, state, and adaptability of the injured cell
• cell injury results from different biochemical mechanisms action on cell components


What are the different biochemical mechanisms action on cell components that cause cell injury?

• ↓ATP
• Mitochondrial damage
• ↑ Ca
• ↑ ROS
• Membrane damage
• Protein misfolding and DNA damage


What are the causes and effects of ↓ATP?

• cause: reduced O2 or nutrients, mitochondrial damage
• effects:
o Na/K pump (ouabain sensitive) effects ion balance
o Cellular energy metabolism altered (glycolysis, etc..)
o Ca pump ==> increased intracellular Ca
o Reduction in protein synthesis and increase in protein misfolding


What are the causes and effects of mitochondrial damage?

• Causes: ↑ Ca, ↑ ROS, hypoxia
• Effects:
o Mitochondrial membrane ==> loses H gradient
o Cytochrome C release ==> caspase cascade


What are the sources of ↑intracellular Ca?

• cell injury lets in extracellular Ca
• mitochondrial Ca
• Smooth ER


What are the effects of ↑ Ca?

• ↑ mitochondrial permeability
• May induce apoptosis via direct activation of caspases
• activation of many cellular processes
o phospholipase
o protease
o endo-nuclease
o ATPase