Module 2 - Cell Injury and Adaptations Flashcards
Mechanisms of Cell Injury Classifications
Classified according to: Causative agents - physical - chemical - biological - metabolic Cellular target Mode of cell death - apoptosis - necrosis
Causative Agent - Physical
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
Causative Agent - Chemical
Naturally occurring or synthetic
Toxic to metabolic pathways
E.g. Cyanine is an electron transport inhibitor
Causative Agent - Biological
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
Cellular Target - Blockade of Metabolic Pathways
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
Cellular Target - Failure of Membrane Integrity
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
Cellular Target - DNA Damage
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
Reversible and Irreversible Cell Injury
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
Reversible Cell Injury - Hydropic Change/Cell Swelling
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
Reversible Cell Injury - Causes of Fatty Changes (Liver)
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
Irreversible Damage
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
Necrosis
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
Coagulative Necrosis
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
Morphology of Coagulative Necrosis
Gross - tissue texture becomes soft as its digested by macrophages Microscopic - lose nuclear stain - lose cytoplasmic detail - collagenous stroma resist dissolution
Colliquative (Liquefactive) Necrosis
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
Caseous Necrosis
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
Fat Necrosis
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
Gangrene
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
Apoptosis
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
Examples of Extracellular and Intracellular Triggers for Apoptosis
Extracellular - detachment from extracellular matrix - withdrawal of growth factors - signals from other cells Intracellular - DNA damage - failure of mitosis to occur correctly
Apoptosis - Intrinsic Pathway
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
Apoptosis - Extrinsic Pathway
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
Complete Repair
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
Repair of Complex Tissue
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
Repair of Skin - Small Incision Wound
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
Repair of Skin - Large Wounds
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
Repair of Bone
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
Factors Affecting Repair
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
Apoptosis vs Necrosis Features
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
