L3 - Cell Injury and Death Flashcards
How do cells survive?
- Constant energy supply
- Intact plasma membrane
- Efficient cellular activities
- Genomic integrity
- Controlled cell division
- Internal homeostatic mechanism
Disturbance of these factors can lead to cell injury or death
How are mechanisms of cell injury classified?
Classified according to:
• Causative agents
• Cellular target
• Pattern of cell death
apoptosis/necrosis
Physical causative agents
- Passive cell destruction (membrane disruption lead to catastrophic functional impairment)
- Trauma and thermal injury (Microwave leads to thermal injury, Laser breaks intramolecular bonds, Disrupt cells & denature proteins)
- Freezing (Mechanical damage leads to ice crystals and membrane disruption)
- Shearing forces (Structures move relative to each other)
Chemical and biological causative agents
- Chemical agents (Naturally occurring or synthetic, Toxic to specific metabolic pathways)
Biological agents:
- Enzymes & toxins secreted by microorganisms
- Bacterial endotoxin (lipopolysaccharide, LPS) that damage nearby cells
- Viruses (Physical rupture of infected cells , local tissue damage from immune response)
-
Cellular target: DNA damage
- Non-lethal damage inherited by daughter cells: neoplastic transformation
- Lethal damage can occur if multiple mutations accumulate
- If cells unable to repair, cell will die (Apoptosis)
- Strand breaks, base alterations, cross linking
Characteristics of irreversibility in cell damage
- Irreversible mitochondrial dysfunction (earliest sign)
- Profound membrane dysfunction
Reversible cell injury
Hydropic change:
- Accumulation of fluid
- cytoplasm pale & swollen
Fatty change:
- Vacuolation of cells, accumulation of lipid droplets
Autophagy
- Cellular response to stress, e.g. lack of nutrients or growth factors
- Cell components isolated into vacuoles, lysosomes
- can proceed to apoptosis if stimulus not removed
Reversible cell swelling/ hydropic change can be caused by
- Interference with membrane structure
- Interruption of energy supplies
- Both lead to dysregulated ion and water movement in/out of cell
Features of reversible cell swelling/hydropic change
- Cell cytoplasm - pale and swollen
- Fluid accumulation
Cells can survive for weeks after reversible swelling and hydropic change if:
- no membrane and internal structures rupture;
* Enough membrane function is present so that metabolic processes are functioning
Reversible Fatty changes (locations where it can be seen)
Seen in cells which have a high lipid content/ high lipid synthesis (Liver, heart, kidney)
Reversible Fatty changes (common causes)
- Toxins - alcohol and hydrocarbons such as chloroform - Chronic hypoxia
- Diabetes mellitus.
Irreversible cell death is due to:
- Free radicals
- Calcium ions
- Energy shortage (ATP depletion)
- Cell membrane dysfunction (increased permeability)
Ischaemia
lack of blood supply to an organ
Hypoxia
lack of oxygen
Necrosis (irreversible cell death) is caused by
- Ischemia (leading to hypoxia, lack of oxygen)
- Metabolic blockade
- Trauma
Time to death of organs with hypoxia
- Brain < 3 minutes
- Heart 1-2 hours
- Kidney 2-3 hours
- Skin fibroblasts < 24 hours
Coagulative necrosis
- protein denaturation is the main process
- enzymes in the cells are broken down, preventing normal function
- seen in hypoxic/ ischaemic cell death everywhere except the brain
- loss of nuclear stain and cytoplasmic detail after tissue has been consumed by macrophages
Caseous necrosis
- Characteristic of TB in lungs
- Dead cells/tissue has no structure
- Histology: amorphous eosinophilic area with haematoxylin-stained nuclear debris
- Granulomas have a centre that contains cells that mediate chronic inflammatory reaction
- Cheesy looking; Grey/white, soft & friable
- Combination of coagulative and colliquative necrosis
Gangrene
- Necrosis with putrefaction of tissues
- Black areas are deposition of iron sulphide from degraded haemoglobin
- Sometimes due to bacterial infection e.g. clostridia
- Can also be due to poor blood supply, e.g. to feet in diabetic patients
- Dry form > usually seen in toes, due to lack of blood supply
- Wet form > bowel gangrene
Fibrinoid necrosis
- Immune-complex-mediated hypersensitivity
- These antigen-antibody complexes stick to vessel walls, attract inflammatory cells, activate complement.
- Inflammation damages the vessel wall and wall becomes necrotic.
- The “fibrinoid” part of the name implies fibrin has a central role in this type of necrosis – it doesn’t
- The name is because the bright pink staining in an H&E (due to immune complexes and debris) looks like fibrin.
Fat necrosis (direct)
- Seen in adipose tissue of thigh, breast, other locations subject to impact
- Physical injury to adipocytes releases triglycerides > hydrolysed by serum lipases > fatty acids > saponification > formation of chalky material
Fat necrosis (pancreatitis)
- Lysis of fat due to lipase release > leaks from pancreas into surrounding tissue
- Fat split into fatty acids, combines with calcium/sodium/potassium > precipitates as white soaps
Fat necrosis (inflammatory response)
- Neutrophils and macrophages phagocytose the fat
- End result > fibrosis – can have palpable mass
Apoptosis
- No inflammatory reaction (intact cell membrane)
- Death of scattered single cells
- Form rounded membrane bound bodies
- Eventually phagocytized by unaffected neighbouring cells
- Occurs in most living cells
- Energy-dependent
Apoptosis - intrinsic pathway
- Bcl-2 inhibits apoptosis
- Bax stimulates apoptosis
- Ratio of Bcl-2: Bax influence how susceptible a cell is to apoptotic stimuli
- The Bcl-2 family govern mitochondrial outer membrane permeability
Apoptosis - extrinsic pathway
- Ligand binding at death receptors on cell surface
- Receptors include (TNF Receptor 1, Fas (CD95))
- Ligand binding leads to clustering of receptors on cell surface
- Initiation of a signaling cascade resulting in caspase activation
Factors affecting repair of tissues
- Damage to fetus can affect subsequent development (e.g. rubella, thalidomide)
- Children generally heal quickly, but there can be growth disturbance following tissue damage (e.g. pulmonary airways permanently damaged by whooping cough)
- Nutritional deficiencies (Vitamin C disturbs collagen synthesis and causes scurvy, malnutrition impairs repair)
- In old age, reserve capacity is reduced, healing is slower (ischaemia contributes to this)
