Adaptation, Injury and Death of the Cell Flashcards
Cell injury:
impair the ability of the cell to maintain homeostasis
4 commons target areas of injury within the cell:
- Mitochondia (make ATP, energy)
- Plasma membrane (protect the inside from exposing to things in the circulation)
- Endoplasmic Reticulum (ER) (make proteins)
- Nuclei (genetic material)
General Principles regarding cell injury:
- Many diff. causes - all impair ability of the cell to maintain homeostasis
- All parts of the cell are interdependent
- No distinct indicator of the boundary between reversible and lethal injury (Slow process)
- Extent of injury depend on type, duration and severity of the cause.
- Extent of injury will depend on the type, health, adaptability of the affected cell.
Cause of Cell Injury:
- Hypoxia
- Physical Injury (mechanical, thermal, electrical, radiation–>UV)
- Chemical Injury (ex. Cirrhosis caused by ethanol)
- Biological agents (infectious diseases, viruses, Bacteria)
- Immune Reactions (Cell-mediated, complement)
- Genetic abnormalities (Congenital or acquired)
- Inadequate nutrition (obesity, starvation)
Hypoxia:
Inadequate access of oxygen to the cell.
Ischemia:
Inadequate blood supply, lack of oxygen AND nutrients to cells. Can’t get rid of CO2 and metabolites.
Erythrocyte impaired can cause:
Hypoxia. RBCs cannot carry the oxygen. Anemia and CO poisoning impair the ability of hemoglobin to transport oxygen.
Mechanism of ATP depletion during Injury cell
decrease O2–> Decrease in oxidative phosphorylation (mitochondria) –> inadequate ATP production.
Lead to 1. decrease sodium pump (Swelling) 2. increase glycolysis –> decrease pH (Clumping of nuclear chromatin) 3. Detachment of ribosomes (decrease protein synthesis)
Decrease sodium pump lead to:
ER and cellular swelling (dragging water inside bc sodium move in and cannot go out)
Increase Ca++ (protease activation lead to cytoskeletal damage)
Increase anaerobic glycolysis lead to:
decrease glycogen, increase lactic acid, decrease pH (to compensate decrease of ATP)
Reversible injury of Hypoxia
- Blebs coming off of the surface of the cell
- Autophagy by lysosomes (free radical leakage inside the cell)
- Mitochondrial and ER swelling
- Aggregation, clumping
If the hypoxia gets worse or for longer period of time (Irreversible injury)
- Lysis of ER (due to free radical leakage, enzymatic digestion of cell component)
- Defects in cell membrane
- Rupture of lysosomes and autolysis
- Enzyme leakage (free radical leakage)
- Increase of mitochondrial permeability (due to high level of calcium) and Activate cell enzymes (membrane damage, nuclei damage)
Most vulnerable cell to ischemia:
Neuron
Production of Reactive O2 Species (unpaired electrons) by:
- Produce by all cell
- neutrophils and macrophages (during phagocytosis)
Plasma membrane damage:
Loss of cellular component
Lysosomal membrane damage:
Enzymatic digestion of cellular components
A higher level of Calcium during hypoxia come from:
Mitochondrial, smooth ER
Extracellular
2 main morphologic correlate of reversible cell injury are:
- Cell swelling
2. Fatty change
4 principle biochemical mechanism of cell injury
- Mitochondrial damage (decrease ATP/Increase Reactive O2 species (ROS))
- Entry of Ca++ (increase mitochondrial permeability/activation of cellular enzyme)
- Membrane damage (loss of cellular component/enzymatic digestion of cellular components)
- Protein, misfolding, DNA damage (Activation of pro-apoptotic protein)
Cell injury by Free Radical :
- Lipid peroxidation –> Membrane Damage
- Protein modification –> Breakdown/misfolding
- DNA damage –> Mutation
Free radical can be generated by:
Metabolism, inflammation, air pollution, smoking, ionizing radiation, UV light
Inactivation of free radicals by:
- Enzymes intracellular (Superoxide dismutase - SOD) can convert them to harmless particles.
- Antioxidants extracellular (contribute electrons to neutralize the free radical)
2 types of Cell death (Irreversible cell injury)
- Necrosis
2. Apoptosis
Necrosis involves:
Autolysis Inflammation (trigger by the influx of inflammatory cell due to leakage of intracellular component)
4 types of necrosis:
- Coagulative necrosis
- Liquefactive necrosis (eg. abscess)
- Caseous necrosis (combination of both coagulative necrosis and liquefactive necrosis) eg. tuberculosis
- Gangrene (due to bacterial attack)
Difference between necrosis and apoptosis:
There is inflammation followed necrosis and last much longer than apoptosis.
Apoptosis is a normal part of life, but is also involves in abnormal ways in certain injuries. Apoptosis is initiated by:
- Mitochondria (loss of growth factors (survival signals), DNA damage, accumulation of misfolded proteins)
- Death Receptors on the surface of the cells (external)
Usually, viable cell receptor (on the surface of the cell) are activated by survival signals (growth factor), it trigger:
production of anti-apoptotic proteins (Bcl-2 or BC-XL).
When the cell is injure, there is lack of survival signals, it trigger:
Antagonist of Bcl-2 (anti-apoptotic proteins are decreased) and activation of Bax/Bak channels on the membrane of the mitochondria (lead to release cytochrome C from mitochondria (major activator of apoptosis - pro-apoptotic protein) –> caspases –>apoptosis.
How the caspases sequence of enzyme is trigger to lead to apoptosis?
FASL (ligand) --> FAS (receptors) --> (receptor trimerize) FADD - FAS Activating Death Domain (inside of the membrane) --> Pro Caspase 8 --> Apoptosis OR TNF (tumor necrosis factor) --> TNFRI --> TRADD --> FADD --> Pro Caspase 8 --> Apoptosis
What can block the enzyme cascade sequences leading to apoptosis?
NF-kB (increase the gene expression and allows the cell to survive)
End result of caspases:
Nucleus destoyed, cytoskeleton is brokendown, and the cell form blebs.
Blebs are parts of the cell surrounded by its membrane. Blebs have proteins on the surface which are:
Ligands for phagocytosis.
Too little apoptosis and cell proliferate can be the cause of:
Cancer and autoimmune disease.
In cancer, 4 thing occurs:
- Activation of oncogene encoding factor (bcl-2) preventing cell death
- Bcl-2 is produced in abnormally large amounts
- Signals causing programmed cell death are blocked
- Inappropriate longevity of the cell
In response to Endoplasmic reticulum (ER) stress, the cell can do 2 things:
- Cellular Adaptation: decrease synthesis, increase the nb of chaperones to make more mature and correctly folded proteins.
- Failure of Adaptation: Apoptosis.
Intracellular Accumulations (Fats, carbohydrates, lipids, calcium…) is due to:
-Abnormal metabolism (hepatocytes accumulate lipids)
Defects in protein folding and transport (excess of abnormal protein)
-Lack of enzymes
-Ingestion of indigestible materials (ex. silica, people work with coal and stone)
T or F: Intracellular accumulation normally lead to cell death.
False. Do not necessary lead to cell death, but make the cell appear strange.
