Mechanism of cell injury

Question 1

What is Cell Injury?

Answer 1

• When basic cell functions or viability are threatened
• Usually occurs due to situations where the ability of teh cell to respond or adapt are exceeded
• Can be reversible or irreversible

Question 2

What are general causes of cell injury?

Answer 2

• Changes in available nutrients
• Direct cell damage
  
  • microorganisms
  • Toxins
  • Physial forces

Question 3

What are the specific causes of Cell injury?

Answer 3

• Physical agents:
  
  • Trauma, temperature extremes
• Chemicals:
  
  • Xenobiotics (toxins, endogenous and exogenous substances
• Nutrients:
  
  • Too few, too many
• Infectious agents

Question 4

What determines a cells susceptibility to injury?

Answer 4

• Cells have widely variable resistance to detrimental stimuli
  
  • Neurons and cardiac myocytes are highly susceptible to hypoxia
  • Fibroblasts or squamous epithelium can survive in the absence of adequate oxygen
• Metabolic status will influence cell susceptibility

Question 5

What are the mechanisms for cell injury?

Answer 5

• Loss of membrane integrity
• Loss of ability to produce energy
• Genetic damage

Question 6

How does the loss of membrane integrity cause cell injury?

Answer 6

• Cell membranes breakdown and lose the ability to segregate reactions within the cell
• Damage to the plasma membrane removes the barrier to the extracellular environment and the gradients that it forms
• Damage to organelle membranes disrupts the segregation of reactions within a cell

Question 7

What are the mechanisms that cause loss of membrane integrity?

Answer 7

• Free radical-induced damage
• Phopholipase-induced damge
• Direct membrane damage

Question 8

What is Free Radical Injury?

Answer 8

• Free radicals are chemicals with unparied electron that readily react with surrounding molecules
• A chain reaction occurs as teh electon passes from molecule to molecule
• Free radicals can dmage membranes, and other cell components
• Free radicals are formed during metaboism and by normal ell reactions

Question 9

How are Free Radicals created?

Answer 9

• Formed during metabolism and by normal cell reactions
  
  • Oxidation reduction reaction during aerobc respiration
    
    • Oxygen-derived products are the most important types o free radicals i tissues and cells
  • Biotrnssfomation ocf chemical substances
    
    • Transient, highly reactive intermediate compounds are formed
  • Nitric oxide metabolism

Question 10

What are the effects of Reactive Oxygen Metabolites?

Answer 10

• Protein and membrane degradation
• DNA damage
• Inflammation
• Implicated in:
  
  • Aging
  • Neurodegeneration
  • Neoplasia
  • Cell injury and death
  • Chronic inflammation

Question 11

What are the protective mechanisms against Free Radical Injury?

Answer 11

• Vitamins A, C, and E (antioxidants): phytochemicals
• Iron ad coppor binding proteins
  
  • Ferritin
  • ceruloplasmin
  • others
• Specific enzymes:
  
  • Superoxide dismutase
  • Catalase
  • Glutathione peroxidae
  • Others

Question 12

What is Phospholipase-Induced Injury?

Answer 12

• Activted membrane phospholipases cleave phospholipids out of the membrane
  
  • These can be activated by increased cytoplasmic Ca⁺² among other activators
• Phospholipase activation can also be caused by decreased energy
  
  • Decreased energy results in interference with membrane pump function and increased cytoplasmic Ca⁺²

Question 13

What is Direct Membrane Injury

Answer 13

• Certain substances can cause direct injury to membranes
  
  • Bacterial toxins
  • Xenobiotics
  • Complement system

Question 14

How does the loss of the ability to produce energy cause cell injury?

Answer 14

• ATP is insufficient to support cell functions
• ATP is produced in 2 pathways
  
  • Oxidative phosphorylation - Mitochondria, highly efficient
  • Anaerobic glycolysis - Cytoplasm, poorly efficient

1. Failure of energy-dependent membrane pumps (NA⁺/K⁺ and Ca⁺²/Mg⁺²
2. Decreased intracellular pH
3. Decreased protein syntehesis
4. Cytoskeletal degradation
   
   • Ca⁺² induced coagulation
5. Membrane degradation
6. Leakage of organelle contents
7. Organelle dysfunction

Question 15

What role does Calcium play in Cell injury?

Answer 15

• Mitochondrial injury
• Phospholipase activation
• Protease activation
• Endonuclease activation

Question 16

What is Genetic Injury?

Answer 16

• Damag to cellular nucleic acids is common
  
  • most damage is repaired and transient
• Permanent damage to DNA is a mutation

Question 17

What are the outcomes of genetic injury?

Answer 17

• No effect on cell or tissue
• Cell dysfunction leading to disease
  
  • developmental anomalies, storage diseses
• Cell transformation leading to neoplasia
• Cell death - apoptosis

Question 18

What are the characteristics of Cell injury?

Answer 18

• Can either be sublethal or lethal
  
  • sublethal can be reversible or progress to cell death
• Sublethal:
  
  • cell swelling
  • Intrcellular accumulations
  • Neoplatic transformation
• Lethal:
  
  • Apoptosis
  • Necrosis (oncotic death)

Question 19

What is Cell Swelling?

Answer 19

• Membraneion pumps fail to maintain osmotic gradients across the membrane
  
  • water enters the cell or an intracellular organelle along an osmotic gradient
• Morphology
  
  • Affected cells or organelles are swllen and finely vacuolated
  • Hydropic change

Question 20

What are Intracellular accumulations?

Answer 20

• Abnormal metabolism, functional demands that exceed the capability of the cell, or exposure to injurious agents can lead to acuumulation of various intracellular substances
  
  • Endogenous
  • Exogenous

Question 21

What are endogenous intracellular accumulations?

Answer 21

• Excess normal or abnormal metabolic products that accumulate in a cell
• Causes:
  
  • Abnormal metabolism
  • Demand that exceeds capability of the cell
  • Cell injury that inhibits cell functions

Question 22

What are examples of endogenous Intracellular accumulations?

Answer 22

• Metabolic storage diseases
• Lipidosis
• Glycogenosis
• Intracellular Pigments
  
  • lipofuscin, iron/hemosiderin

Question 23

What is Lipidosis

Answer 23

• Metabolic pathways in cells are inhibited by injury or overwhelmed by excess demand
  
  • Triglyceride accumulation is one common manifestation of metabolic change
• It can be physiological as well as pathological
• Most apparent in those cells which metabolize large amounts of fat
• When due to cell injury, often occurs concurrently with cell swelling
• Morphology:
  
  • Cytoplasmic vacuoles of variable size

Question 24

What are physiologic causes of Lipidosis

Answer 24

• High fat ration
• Increased periparturient energy needs
• Anorexia

Question 25

What are pathologic causes of Lipidosis

Answer 25

• Hepatotoxins
• Hypoxia
• Starvation

Question 26

What is Glycogenosis?

Answer 26

• Glycogen accumulates due to abnormal metabolism
  
  • Hepatocytes of animals with diabetes mellitus
• Cells look “swollen”

Question 27

What is hemosiderin?

Answer 27

• Intracellular aggregates of ferritin (iron protein conjugate)
• Commonly associated with:
  
  • increased RBC senescence
  • Hemolysis

Question 28

What is Lipfuscin-ceroid accumulation?

Answer 28

• Endogenous
• Undegradable remnants of oxidized membrane lipids
  
  • It can accumulate as a part of aging or due to excessive membrane oxidatoin

Question 29

What are Exogenous Intracellular accumulations

Answer 29

• Substances that accumulate are not native to the cell environment
• Include:
  
  • Viral proteins and nucleic acids (“inclusions”)
  • Carbon
  • Non-nutritive minerals (eg. lead)

Question 30

What is transformation

Answer 30

• A type of sublethal injury
• As a result of genetic injury some cells undergo neoplastic transformation
• Transformed cells may have abnormal grwoth, often abnormal function, and abnormal morphology
• They are not “injured” in the traditional sense, they are detrimentally changed

Question 31

What is the Morphology of transformation

Answer 31

• Cells may appear normal
  
  • some degree of hyperplasia may be present
• Some cells appear poorly differentiated
  
  • Anaplasia
• Some cells have variable sizes/shapes/appearance
  
  • Pleomorphism

Question 32

What is lethal cell injury?

Answer 32

• An insult to the cell exceeds the cell’s ability to adapt or respond
  
  • Lethl injury is immediate
• Sublethal injury can progress to lethal injury
  
  • The severity of the insult may dertermine the outcome for the cell
    
    • Many of the causes of lethal injury are the same as those for sublethal injury
• Patterns of cell deth:
  
  • Apoptosis
  • Necrosis

Question 33

What is apoptosis?

Answer 33

• Physiological cell death
  
  • The mechanism to remove damaged or unneeded cells in the least disruptive way possible
• Maintains homeostasis, but can also be involved in pathological states
• An ACTIVE process that requires energy from the cell

Question 34

What are the Physiologic causes of apoptosis?

Answer 34

• Patterned death during embryogenesis
• Hormone/cytokine-induced death
  
  • Tissue involution
• Maintain balance in proliferating populations
• Removal of cells following completion of their purpose
  
  • Inflammatory cells following the end of the stimulus
• Removal of self-reactive lymphocytes

Question 35

What are the Pathologic causes of apoptosis?

Answer 35

• Unrepaired DNA damage
  
  • damaged or transformed cells
• Heat
• Hypoxia
  
  • mitochondrial injury
• Viral infection
• Physical pressure
  
  • Ureteral or secretory duct obstruction

Question 36

What is Necrosis?

Answer 36

• Death due to injury that disrupts the ability of the cell to continue to function
• Autolysis of a cell/tissue in a living animal
• A passive process, does not require energy from the cell

Question 37

What is Autolysis?

Answer 37

• Self-digestion of a cell o tissue
• Occurs in any cell or tissue that has died

Question 38

What is postmortem autolysis

Answer 38

• self-digestion of cells/tissues/organs after an animal dies

Question 39

What are the causes of necrosis?

Answer 39

• Direct injury to the cell:
  
  • Hypoxia
  • Direct membrane injury
• Many of the same factors that initiate apoptosis when the stimulus is mild, initiate necrosis when more severe

Question 40

What are the mechanisms of necrosis

Answer 40

• Degradative activity of lytic enzymes
  
  • Lyosomal enzymes degrade cell components
    
    • Enzymes may come from the sme cell (autolysis)
    • Enzymes may come from other cells (heterolysis)

Question 41

What is the morphology of necross?

Answer 41

• Eosinophilia - protein denaturation
• Smooth, homogenous (“ground glass”) cytoplasm
  
  • Deterioration of organelles
• Cytoplasmi vacuolation
• Nuclear degeneration
  
  • Karyolysis, Karyorrhexis, pyknosis
• Inflammation in response to necrosis

Question 42

Compare Apoptosis and Necrosis

Answer 42

• Apoptosis:
  
  • Cells shrink and form apoptotic bodies
  • Requires energy
  • Complex and active process
  • NO inflammation
  • Physiologic and pathologic
• Necrosis:
  
  • Cells swell and lyse
  • NO energy required
  • Simple and passive process
  • Inflammation
  • Pathologic

Question 43

What is post mortem autolysis?

Answer 43

• Cell and tissue degredation that occurs following the death of an animal
  
  • the changes that occu in cells are similar to those assocaiated with antemortem necrosis
• PM autolysis occurs in a predicable fashion
  
  • different types of cells degrade at different rates
• All cells are affected and are at the same stage of autolysis
• There is no inflammation or host response