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1

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

2

What are the three causes of cell death?

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

3

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

4

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

5

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.

6

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

7

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

• cellular swelling
• fatty change

8

What causes cellular swelling?

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

9

What causes fatty change?

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

10

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

11

What is the mechanistic cause of necrosis?

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

12

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.

13

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

14

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)

15

What are the six types of necrosis?

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

16

What are the features of Coagulative necrosis?

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

17

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

• the brain
• Why?

18

What degrades the coagulative necrosis?

• note: may persist for weeks
• degraded by leukocytes

19

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

20

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

21

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)

22

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

23

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

24

Term: dystrophic calcification come back later

Term: dystrophic calcification come back later

25

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

26

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

27

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

28

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

29

What are the sources of ↑intracellular Ca?

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

30

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