Module 2 - Cell Injury and Adaptations

Question 1

Mechanisms of Cell Injury Classifications

Answer 1

Classified according to:
Causative agents
- physical
- chemical
- biological
- metabolic
Cellular target
Mode of cell death
- apoptosis 
- necrosis

Question 2

Causative Agent - Physical

Answer 2

Trauma and thermal injury
- disrupt cells and denature proteins
- microwaves, lasers (breaks intramolecular bonds)
Membrane disruption
- leads to catastrophic functional impairment
- freezing (mechanical damage caused by ice crystals leads to membrane disruption)
- shearing forces - structures move relative to each other

Question 3

Causative Agent - Chemical

Answer 3

Naturally occurring or synthetic
Toxic to metabolic pathways
E.g. Cyanine is an electron transport inhibitor

Question 4

Causative Agent - Biological

Answer 4

Enzymes and toxins secreted by microorganisms
- e.g. bacterial endotoxins which create a strong immune response which damages nearby cells
Viruses
- physical rupture of infected cells
- local tissue damage from host immune response

Question 5

Cellular Target - Blockade of Metabolic Pathways

Answer 5

Inhibit protein synthesis
- enzymes and structural proteins cant be replaced
- e.g. Ricin blocks protein synthesis at ribosomes
- many antibiotics interfere with protein synthesis
Respiratory poisons (cellular respiration)
- e.g. cyanide binds to cytochrome oxidase and block electron transport chain
- cells with high oxygen requirements most sensitive
Energy failure
- glucose and oxygen deprivation
Loss of growth factor or hormonal stimulus
- many cells rely on growth factors for survival
- growth factors bind receptors on the cell surface triggering intracellular signalling
- can block pathway by decreased GF availability, decreased receptor or inhibition of intracellular pathways
- affected cells may undergo apoptosis

Question 6

Cellular Target - Failure of Membrane Integrity

Answer 6

Cell membrane damage may be due to:
Complement mediated cytolysis
Perforin mediated cytolysis
Specific blockade of ion channels
- e.g. movement of calcium blocked by some drugs
Failure of membrane ion pumps
- an agent that interferes with ATP production will compromise membrane pump activity and cell may lyse
Free radical attack
- cross linkage of membrane proteins
- if membranes or internal organelles are damaged, toxic waste products can enter cell and cause damage/death

Question 7

Cellular Target - DNA Damage

Answer 7

Includes strand breaks, base alterations, cross linking
- UV damage
- chemical damage
- endogenous errors
Dividing cells are more susceptible
Non-lethal damage inherited by daughter cells is known as neoplastic transformation

Question 8

Reversible and Irreversible Cell Injury

Answer 8

Irreversible:
- mitochondrial dysfunction
- membrane dysfunction
Reversible:
Hydropic change
- accumulation of fluid
- cytoplasm pale and swollen
Fatty change
- vacuolation of cells, accumulation of lipid droplets
Autophagy
- cellular response to stress
- cell components isolated into vacuoles, lysosomes
- way of staving off cell death

Question 9

Reversible Cell Injury - Hydropic Change/Cell Swelling

Answer 9

Can be caused by:
- interference with membrane structure
- interruption of energy supplies to membrane exchange systems
- both lead to dysregulated ion and water movement in/out of the cell
Cells can survive for weeks if:
- non membrane and internal structures rupture and
- enough membrane function is present so that metabolic processes are functioning

Question 10

Reversible Cell Injury - Causes of Fatty Changes (Liver)

Answer 10

Can be caused by:

• increase in peripheral mobilisation of free fatty acids (FFA) and cellular uptake e.g. diabetes
• increase in conversion of FFA to triglycerides e.g. alcohol
• decrease in oxidation of triglycerides to acetyl-CoA e.g. hypoxia
• decrease lipid acceptor proteins preventing export of formed triglycerides e.g. protein malnutrition

Question 11

Irreversible Damage

Answer 11

Usually due to one of the following
- free radicals
- calcium ions
- energy shortage e.g. ATP depletion
- cell membrane dysfunction e.g. increased permeability
Contains:
Apoptosis - controlled cell death
Necrosis - uncontrolled cell death, result of injury

Question 12

Necrosis

Answer 12

Death of cell or tissues following:
- bio-energetic failure
- loss of plasma membrane integrity
Can be caused by:
- ischaemia (leading to hypoxia, lack of oxygen)
- metabolic blockade
- trauma
Induces inflammation and repair

Question 13

Coagulative Necrosis

Answer 13

Most common
Can occur in most organs
- seen in hypoxic/ischaemic cell death in all tissues except the brain
Protein denaturation/coagulation is main process
- structural proteins
- enzymes (breakdown of enzymes -> loss of metabolic activity)
Produces an inflammatory response
Followed by repair and regeneration

Question 14

Morphology of Coagulative Necrosis

Answer 14

Gross
- tissue texture becomes soft as its digested by macrophages
Microscopic 
- lose nuclear stain
- lose cytoplasmic detail
- collagenous stroma resist dissolution

Question 15

Colliquative (Liquefactive) Necrosis

Answer 15

Enzymatic digestion is the main process
Combination of:
- lysis of damaged cells
- leukocytes migrating in large numbers
- release of lysosomal enzymes
Result is liquified necrotic tissue
Occurs in organs with lots of lipid e.g. brain
Site of necrosis eventually marked with a cyst
- cyst/abscess formation associated with lots of acute inflammatory cells
- walled off by fibrous capsule

Question 16

Caseous Necrosis

Answer 16

Characteristic of Tuberculosis - seen in lungs
Dead cells/tissue has no structure
Histological appearance:
- amorphous eosinophilic area with haematoxylin stained nuclear debris
Granulomas form
- centre contains cells that mediate chronic inflammatory reaction
Combination of coagulative and colliquative necrosis

Question 17

Fat Necrosis

Answer 17

Direct trauma
- adipose tissue
- extracellular liberation of fat
- seen in adipose tissue of thigh, breast and other locations subject to impact
- physical injury to adipocytes releases triglycerides which eventually leads to formation of chalky material
Pancreatitis
- lysis of fat due to lipase release > leaks from pancreas into surrounding tissue
- fat split into fatty acids, combines with Ca/Na/K which precipitates as white soaps

Question 18

Gangrene

Answer 18

Not a type of necrosis but an outcome of it
If black - deposition of iron from degraded Hb
Two forms:
Dry - usually seen in toes, due to lack of blood supply
Wet - bowel necrosis

Question 19

Apoptosis

Answer 19

Physiological cellular process
- loss of a cell without releasing products that harm surrounding cells
- no inflammation
Energy dependent, biochemically specific mode of cell death
- digestion
- phagocytosis
Physiological -> growth and morphogenesis
Pathological -> disease

Question 20

Examples of Extracellular and Intracellular Triggers for Apoptosis

Answer 20

Extracellular
- detachment from extracellular matrix
- withdrawal of growth factors
- signals from other cells
Intracellular
- DNA damage
- failure of mitosis to occur correctly

Question 21

Apoptosis - Intrinsic Pathway

Answer 21

Integrates internal and external stimuli
- lack of growth factors
- biochemical stress
- DNA damage
Causes alterations in levels of pro- and anti- apoptotic members of the Bcl-2 family
- Bcl-2 inhibits apoptosis
- Bax stimulates apoptosis
Ratio of Bcl-2:Bax influences how susceptible a cell is to apoptotic stimuli
Bcl-2 governs mitochondrial outer membrane permeability (MOMP)
- caspase 9

Question 22

Apoptosis - Extrinsic Pathway

Answer 22

Ligand binding at death receptors on cell surface
Receptors include members of tumour necrosis factor family
- TNF receptor 1
- Fas
Ligand binding -> clustering of receptors on cell surface
Initiation of a signalling cascade resulting in caspase activation
- caspase 8

Question 23

Complete Repair

Answer 23

E.g. minor abrasion
Epidermis lost over a limited area
Cells at the edge capable of multiplying
Fibrin scab protects underlying area
Cells proliferate and spread as a thin sheet until defect covered
Once in place the epidermis is built up from the bottom

Question 24

Repair of Complex Tissue

Answer 24

When complex tissue is destroyed it cant always be properly reconstructed
- this is when repair occurs (opposed to healing)
Capillary endothelial cells proliferate and move into area to be repaired
- form vasculature in damaged area
Fibroblasts proliferate and secrete collagen and other ECM proteins
- myofibroblasts (contractile fibroblast)
- role in wound contraction (reduce volume of tissue that needs repair)
Combination of capillary loops and myofibroblasts - granulation tissue

Question 25

Repair of Skin - Small Incision Wound

Answer 25

Repair proceeds quickly
Fibrin deposited to bind two sides together
Capillaries proliferate to bridge gap
Fibroblasts secrete collagen
Loss of elastic tissue in dermis
Basal epidermal cells proliferate and spread over gap

Question 26

Repair of Skin - Large Wounds

Answer 26

When wound margins arent close (tissue loss):

• phagocytosis to remove debris
• granulation tissue fills defect
• tissue contracts and scar results
• epithelial regeneration to cover surface

Question 27

Repair of Bone

Answer 27

Immediately after fracture, hemorrhage within bone from ruptured vessels
Hematoma at fracture site helps repair by providing a foundation for cell growth
- fibroblasts and osteoblasts accompany capillaries
- bone deposited in irregular woven pattern called a callus
- woven bone replaced by lamellar bone
- lamellar bone remodelled according to direction of mechanical stress

Question 28

Factors Affecting Repair

Answer 28

In old age, reserve capacity is reduced and healing is slower
- ischaemia or other diseases contribute to this
Nutritional deficiencies
- Vitamin C
- malnutrition impairs healing
Corticosteroids, malignancy and local ischaemia impair healing
Diabetes

Question 29

Apoptosis vs Necrosis Features

Answer 29

Apoptosis
- induced by pathological or physiological stimuli
- affects single cells
- energy-dependent fragmentation of DNA by endonucleases
- cell membrane is maintained
- cells shrink and fragment to form apoptotic bodies with condensed chromatin
- no inflammatory response
- dead cells are phagocytized by neighbouring cells
- outcome is cell elimination
Necrosis
- always due to pathological injury
- affects cell groups
- biochemical events include energy failure, impaired ion homeostasis and lysosomes leaking enzymes
- cell membrane integrity is lost
- cells swell and lyse
- there is usually an inflammatory response
- dead cells are phagocytized by macrophages
- outcome is defence and prepare for repair