Cell Injury and Death Flashcards
Name 3 Causes of Cellular Injury (7 total)
(1) Hypoxia Ischaemia or lack of blood flow
(2) Physical agents Trauma, Temperature extremes, Radiation, Electric Shock
(3) Chemicals and Drugs Alcohol, Corressive Agents
(4) Infectious agents Viruses, Bacteria, parasites
(5) Immunologic reactions Autoimmune disease, hypersensitivity reactions
(6) Genetic derangements Sickle cell disease
(7) Nutritional imbalances Obesity/ Malnutrition
Biochemical Changes in Cellular Injury
- ATP ____________
- Mitochondrial _____________
- Calcium changes:________ intracellular calcium and loss of calcium homeostasis
- Oxygen and oxygen-derived_____________
Biochemical Changes in Cellular Injury
- ATP Depletion
- Mitochondrial damage and dysfunction
- Calcium changes: Increased intracellular calcium and loss of calcium homeostasis
- Oxygen and oxygen-derived free radicals
How does mitochondrial damage occur?
The inner membrane has greater surface area than outer. When the inner membrane swells under ischaemic conditions, increases surface area causing the outer membrane to rupture eventually
Where does increased calcium concentration in cell when injured arise from
influx of calcium into cell
release of Ca2+ from mitochondria and Endoplasmic Reticulum
What are Reactive Oxygen Species and what are their effects?
- Very unstable and react with inorganic and organic material
- Damage determined by rates of production and removal (Antioxidants)
- Lead to Lipid Peroxidation (membrane damage), Protein modifications (Breakdown/misfolding), DNA Damage
What are Reactive Oxygen Species and what are their effects?
Structural Changes in Reversible Cell Injury
- Cell swelling –Hydropic swelling –Impaired cellular volume regulation
- Mitochondria and Endoplasmic Reticulum (ER) swell with the detachment of ribosomes from rough ER [earliest changes]
- Surface blebs (increased calcium results in changes in the microfilaments of the cytoskeleton
- Loss of microvilli structure (e.g. proximal tubular epithelial cells)
What causes Cellular Surface Blebs?
Surface blebs (increased calcium results in changes in the microfilaments of the cytoskeleton)
Necrosis versus Apoptosis
Necrosis
- Exogenous stimuli e.g.) ischemia, Uncontrolled
- A pathological response to cellular injury
- Chromatin clumping
- Mitochondria swelling and rupture
- Plasma membrane lyses
- Cell contents spill out
•General inflammatory response is triggered
Apoptosis
- Programmed cell death: normal physiological response to specific suicide signals or lack of survival signals
- Energy dependent process
- Chromatin condenses and migrates to the nuclear membrane. Internucleosomal cleavage leads to laddering of DNA at the nucleosomal repeat length
- Cytoplasm shrinks without membrane rupture, Blebbing of plasma and nuclear membranes
- Cellular destruction of each part of the cell: Cell contents are packaged in membrane-bounded bodies, to be engulfed by neighboring cells, specifically phagocytes
- No spillage, no inflammation
_______________death of tissue due to a restricted blood supply
Infarction-death of tissue due to a restricted blood supply (Ischaemia)
Two main cuases of irreversible cell injury?
- Extensive membrane damage -rupturing
- Increased concentrations of Ca 2+ions which mediate deleterious enzymatic processes leading to cell death
Stages of Cellular Necrosis:
- ___________ –Condensation of chromatin
- ___________ –Destructive fragmentation of the nucleus –“Nucleus bursts”
- ___________ –Complete dissolution of the chromatin
Stages of Cellular Necrosis:
- Pyknosis –Condensation of chromatin
- Karyorrhexis –Destructive fragmentation of the nucleus –“Nucleus bursts”
- Karyolysis –Complete dissolution of the chromatin
Type of Necrosisz which exibits the most common pattern.
- Tissue remains firm
- Cell shape and organ structure are preserved
- No nuclei
Coagulative
Type of Necrosis in which tissue has become liquefied. Examples?
Liquefactive
Brain infarction –Proteolytic enzymes from the microglial cells liquefy the brain tissue.
Abscess –proteolytic enzymes released from neutrophils liquefy the surrounding tissue.
Type of necrosis in which tissue maintains a cheese-like apearance
The dead tissue appears as a soft and white proteinaceous dead cell mass.
What is this type of necrosis associated with?
Caseous
Frequently associated with tuberculosis
Type of Necrosis characteristic of Ischemia of lower limb and GI tract.
Differences between wet and dry?
Gangrene
Dry gangrene: Coagulative necrosis that resembles mummified tissue
Wet gangrene: superimposed infection then liquefactive necrosis ensues.
How are debris of necrosis dealt with?
What are consewiences of it not being properly dealt with?
- Necrotic (dead) cells and their debris can eventually disappear by a combined process of (a) enzymatic digestion (b) fragmentation and some phagocytosis by leucocytes e.g. neutrophils and macrophages
- If necrotic cells and cellular debris are not promptly resorbed, they tend to attract calcium salts and other minerals and become calcified
Extrinsic versus Intrisinc Apoptosis
Extrinsic -Death Receptors/Death domain (membrane surface receptors)
Intrinsic –Mitochondria
Extrinsice Receptor Mediated Apoptosis Pathways
Causes for release of mitochondrial death signals
Altered cell cycle –p53 (tumour supressor gene)
Damage to mitochondrial membrane
Change in membrane potential
Why is p53 known as the emergency break or gate-keeper of the cell cycle?
What triggers its increase?
- p53-is a transcription factor
- is increased if DNA is damaged
- Controls transition from G1 to S Stage
-
blocks the cell cycle (allowing time to repair DNA)
- or induces apoptosis (cell death)
Approx. half of all human tumours contain somatic mutations in _____ promoting tumour progression by permitting replication of damaged DNA and increasing genomic instability.
Approx. half of all human tumours contain somatic mutations in p53 promoting tumour progression by permitting replication of damaged DNA and increasing genomic instability.
Cell Cycle alteration –p53 activation
What are known as the “Central Executioner of Cell Death” and how do they function?
Caspases (Cystein-dependent Aspartate-specific Prote_ases)_
When activated, chew up other proteins in the cell
What are caspases Initiators and Effectors?
Initiator: caspase 8 and 9
Effector: caspase 3 and 7
Describe the structure and activation of Capsases
Role in Alzheimers and Cancer?
- Caspases start packaged away in linear protein, inactivated
- When triggered by cell death signalling, Nips at Asp residue, folds over into active protease
- Proteases love actin, main strutural filament of cell
Alzeimers patients have inaproporate activation of caspases that degrade neurons in brain
Cancer cells inhibit caspases and cell death
Regulation of Apoptosis
Caspase Independent Cell Death Pathways?
Two inhibitors of Cellular Apoptosis?
B-Cell Lymphoma-2 (Bcl-2)
Inhibitors of Apoptosis (IAPs)
Most predominant over-expressed protein in cancer?
Bcl-2 Family of proteins
What is the role of BCl-2 Proteins?
Stabilize mitochondrial membrane
Anti-oxidants (prevent cancer proliferation)
Most predominant over-expressed protein in cancer
Blocking BCL-2 can be beneficial for targeting cancer cells
_______________________:
A newly discovered group of anti-apoptotic proteins
Seven members identified so far: NAIP, cIAP-1, cIAP-2, XIAP, Survivin, Livin and Apollon
Bind to and inhibit caspases 3, 7, 9
Inhibitors of Apoptosis Proteins (IAP)
How are apoptotic cells phagocytosed?
Both professional and semi-professional phagocytes e.g: macrophages, epithelia.
Recognition of surface changes on apoptotic cell eg phospholipid asymmetry, bridging molecules.
Stages of Apoptotic Cell Death
