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Hypoxia (most common cause of cell injury) –> can lead to necrosis (not…

- - - - Decreased Na+/K+ ATPase activity
        
        Increased K+ efflux, increased Na+ and Ca2+ influx
        
        Protease activation (from increased Ca2+)
        
        Cytoskeletal damage damages cell structure (lose apical-basal polarity/)
        
        Increased H2O influx (osmosis)
        
        Ultrastructural: ER and mitochondrial swelling
        
        Light microscopy: Cellular swelling and plasma membrane blebbing
        
        Phospholipid activation (from increased Ca2+)
        
        Increased phospholipid degradation yields lipid breakdown products
      - Decreased phospholipid reacylation and synthesis
        
        Phospholipid loss
        
        MEMBRANE DAMAGE
        
        Cellular contents leak out
        
        Mitochondrial damage
        
        No cellular energy
      - Increased anaerobic glycolysis
        
        Decreased glycogen (as glucose needed)
        
        Increased lactic acid
        
        Light microscopy: Decreased pH causes pyknosis (clumping of nuclear chromatin)
        
        Decreased protein synthesis
        
        Light microscopy: Karyorrhexis (nucleus fragments)
        
        Light microscopy:Karyolysis (nucleus dissolves)
      - Ribosomes detach from ER
- - - - Embolus (blood clot)
  - - - Altitude sickness
      - Haemaglobinopathies (e.g. anaemia)
  - - - The threshold by which reversible injury becomes irreversible depends on time (duration of injury)
        
        This threshold depends on the cell type
        
        Severe and progressive –> usually irreversible (purple bubbles)
        
        Biochemical changes
        
        Ultrastructural changes
        
        Light microscopy changes
        
        Gross morphologic changes
      - Decreased metabolic function (hallmark is decreased ATP)
- - - - Excess misfolded (denatured) proteins causes ER stress
        
        Cellular adaptation is called unfolded protein response (decrease protein synthesis and up-regulate HSP expression)
        
        Failure to adapt leads to irreversible injury and apoptosis
        
        Yields mature folded proteins
      - Pre-stressing many cell and tissue types (e.g. cardiomyocytes) at the right amount, with pharmacological inhibitors causes chaperone upregulation
        
        Cells like cardiomyocytes can now survive longer with greater integrity
        
        Prevent myocardial infarction in at-risk patients
- - - - Coagulative necrosis
        
        Most commonly due to ischaemia (except in brain)
        
        Typically associated with lower limb gangrene
        
        Necrotic tissue maintains solid consistency (intact tissue architecture)
        
        Necrotic region usually removed by inflammatory cells (neutrophil infiltration)
        
        Necrotic region either:
        
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      - Liquefactive necrosis
        
        Outcome of ischaemic event (stroke) or infection in the brain
        
        Characterised by massive neutrophil filtration
        
        Neutrophils secrete ROS and proteases that degrade ECM and neighbouring cells
        
        Formation of abscess (pus-filled area)
        
        Tissue architecture lost
      - Caseous necrosis
        
        Characteristic of granulomatous inflammation of tuberculosis and some fungal infections
        
        Accumulation of amorphous (unstructured) debris within necrotic area –> soft, white, cottage-cheese appearance
        
        Tissue architecture lost and viable cells within necrotic area are unrecognisable
      - Infarction
        
        Area of ischaemic necrosis in tissue/organ –> coagulative for most, liquefactive for brain
        
        Red (haemorrhagic)
        
        Venous occlusion
        
        Fluid congestion in tissue
        
        Loose/floppy tissue
        
        White
        
        Arterial occlusion
    - - On a gel, DNA is cleaved in a random fashion, generating a 'smear'
- - - - Occurs during embryonic development
      - Removal of damaged/infected cells
    - - Spinal muscular atrophy (continued loss of spinal motor neurons)
      - Follicular lymphoma
        
        BCL2 (anti-apoptotic protein) over-expressed in B cells
        
        B cell tumours in bone marrow that spreads to lymphatics
        
        Can be inhibited by Venetoclax
      - For instance, due to protein misfolding
        
        Creutzfeldt-Jacob disease
        
        PrPsc misfolding (prion) causes abnormal neuronal apoptosis
        
        Alzheimer's disease
        
        Amyloid β protein misfolding cause aggregation within neurons and neuronal apoptosis
  - - - Plasma and nuclear membrane blebbing
        
        Cell contents bud off as membrane-bound apoptotic bodies
        
        Cytoplasm/cell shrinks without membrane rupture, hence no inflammation
    - - On a gel, DNA is cleaved in a regulated fashion, in 200 bp multiples, forming a 'ladder'
  - - - Lack of survival signals (e.g. growth factors)
      - DNA damage (by mutation) detected by DNA damage sensing factors such as p53
        
        Activates a subset of BH2 family sensors called BH3-only proteins
        
        BH3-only proteins (e.g. Bim) competitively antagonise BCL2 by binding to the receptor
        
        Activates a BCL2 family effector called the BAX/BAK channel on mitochondrion
        
        Leakage of cytochrome C and other pro-apoptotic proteins
        
        Activation of initiator caspases
        
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        Consider balance between apoptotic and anti-apoptotic signals
      - Excess misfolded proteins (causes ER stress)
        
        Failure to adapt with unfolded protein response causes apoptosis
    - - FasL on CD8+ T cell binds to multiple FasR (expressed on infected, tumour or damaged cells) – receptor-ligand interaction
        
        Intracellular adapter protein (FADD) activates initiator caspases like Caspase-8 from their pro- form
        
        Initiator caspases activates executioner caspases
        
        Endonuclease activation
        
        Plasma (and nuclear) membrane blebbing
        
        Cytoskeleton degradation
      - Also with TNF/TNF receptor