Chapter 1: Cellular adaptation These 4 cellular adaptations could be physiological response or pathological response.

Hyperplasia Is able to increase number of cells by mitosis to handle increased work load, this increases the size of tissue or organ. (example is erythrocytes for people living in high altitudes) Hypertrophy Cannot increase in number of cells so increase in size to support increased work load, this increases the size of the tissue or organ (nervous tissue & muscle cells) Muscle cells increase in number of mitochondria instead cell size increase. Atrophy (opposite of hypertrophy) Could be pathological or physiological. This could be due to decreased metabolic demand thus decrease in size. (bedridden people) Cells still alive, but volume of cells decrease size of tissue or organ decrease. Hypoplasia The opposite of hyperplasia, which is decrease in organ size But it is only used in developmental stages, in the fetus stage. Metaplasia Pseudostratified columnar cells change to squamous cells to prevent themselves from dying; squamous cells are like punch bags. (smoking) Because squamous can withstand physical or chemical assault better than pseudostraified. Phenomenon is reversible if stimuli is removed or cells are not nearly dying

Factors that causes cellular injury 1. Oxygen deprivation (hypoxia) affect aerobic respiration, thus affect ATP production, caused by blood loss. 2. Physical Agent Trauma, heat, cold 3. Chemical Agent Alcohol, drugs, environmental pollutants 4. Infectious Agent Fungus, bacteria, virus, helminth 5. Nutritional Imbalance Anaemia, kwashiorkor 6. Genetic Derangement Radiation 7. Immunological responses Excessive inflammation, autoimmune responses Cellular injury (death) could be due to 4 different mechanism, which is caused by 7 dangerous stimuli. Decreased ATP ATP is used as a source of energy to drive numerous physiological pathways in the cell. With the depletion of ATP, these pathways are unable to move forward. Membrane Damage Membrane damage caused important substances to leak out of the cell which is needed by the cell and conditions for certain processes now becomes unfavorable (plasma membrane). Membrane damage of the mitochondria can also cause cytochrome c to be released, which induces apoptosis. It can also reduce the production of ATP and this will lead to the first point (mitochondria). Lastly, lysosome membrane damage could release digestive enzymes which would digest the cell (lysosome). Increased Intracellular Calcium Calcium is controlled tightly, cells has 1,000 times lesser amount of calcium. Calcium is found in the ER and mitochondria. Calcium (a cofactor) activates certain enzymes. (ATPase breaks down ATP; phospholipase breaks down phospholipids etc)

Generation of Oxygen Radicals Produced due to UV radiation or by white blood cells to kill pathogens. Oxygen radicals damage lipids, proteins and nucleic acid. Most of the time it is taken care of by antioxidants, but a few of them will not be removed. Instead it will accumulate and cause damage to the DNA and causes wear and tear in the body (ageing).

Cell Death When a cell is injured, it is able to restore back to its original health. However if the injurious stimuli exceeds the capability of the cell to restore back to its original state, the cell will be permanently injured and would eventually lead to cell death if injurious stimuli is not removed. Necrosis vs. Apoptosis Necrosis causes cell to die by swelling until it bursts and die, the cellular components may leak out of the cell upon bursting. And they have different kinds of necrosis; it is caused only by pathological causes. Apoptosis can be physiological or pathological. Physiological is because cells need to die for normal functions of our body. The apoptotic cells will shrink in size (due to cytoskeleton collapse) and have DNA fragmenting (iCad). The cell will finally undergo blebbing and the phagocytes will engulf the apoptotic cell. Characteristics of apoptosis 1. Protein Cleavage Cytoskeletons in cells are made by actin (protein). Actin is cleaved in the cytoskeleton which caused cells collapse inwards. The cleaving is caused by executioner caspases. 2. DNA Breakdown mechanism mediated by iCAD (CAD), CAD is a molecule that chops DNA (~200 bp). iCAD is a molecule that is found in the cytoplasm. iCAD is an inhibitor which binds to CAD to inhibit it. Executioner caspase cleaves iCAD, releasing CAD which then becomes free and active. lane B. lane A is normal cell. lane C necrosis (where DNA is just all a mess) [Picture in notes]. CAD is called (caspase-activated-DNase). 3. Phospholipids Flipping Out Flipping of phospholipids at the cell membrane is an indication that the cell has become apoptotic.

Extrinsic vs. Intrinsic Extrinsic Activation of caspases is either by extrinsic or intrinsic, meaning that activation can come from a stimulus outside or inside the cell respectively. Extrinsic is by "poison" that enters the cell and it activate the caspase. An example of the poison is FasL and the cell has a receptor that detects it, Fas. Fas receptors will combine together to allow FADD to attach onto it. FADD will then attract the Pro Caspase-8; this results in an increase in concentration of Pro Caspase-8 which will automatically trigger the activation of it to produce Caspase-8. (The white part of the bottom part of FADD is also FADD, but is

the different part of the FADD). Caspase-8 will then activate the executioner caspases. Caspase-8 is also able to activate Bid which then causes cytochrome c to be released from the mitochondria by disrupting the balance of pro-apoptotic and anti-apoptotic proteins. Bid is a pro-apoptotic molecule. Intrinsic In normal circumstances, the balance of anti-apoptotic protein and pro-apoptotic protein is maintained. But this balance can be disrupted when there are more pro-apoptotic proteins than anti-apoptotic proteins. Examples of anti-apoptotic protein are Belz and Belx. Examples of pro-apoptotic protein are called Bak, Bax and Bim. These proteins are found on the membrane of mitochondria. When there is more pro-apoptotic protein, the mitochondrias membrane pore will start to open. Cytochrome c, which is found in the mitochondrias intermembrane space, will escape through the pores and will bind to Apaf-1 to form apoptotsome. Apaf-1 is found in the cytoplasm; apoptotsome is made up of many cytochome c that is binded to Apaf-1. Apoptosome is like the FADD, but it attracts Pro Caspase-9. With increasing concentration of Pro Caspase-9, it will be activated to form Caspase-9. Then the caspase will activate the executioner caspases. The Missing link Intrinsic can cause extrinsic apoptosis by formation of Caspase-8. Extrinsic can also cause intrinsic apoptosis through Bid. Bid is a molecule that is found on the cytoplasm, when it is activated, it will translocate to the membrane of the mitochondria. Bid is a pro-apoptotic molecule, so it will cause the pore of the mitochondria's membrane to increase, releasing Cytochrome C. Initiator Caspase They are Caspase 8 and Caspase 9 which is produced from extrinsic and intrinsic apoptosis. Executioner Caspase Active Caspase-8 and Active Caspase-9 will activate Caspase-3 which will activate Caspase-2 and Caspase-6. Caspase-6 then activate Caspase-8 and Caspase-10. Caspase-8 will then activate Caspase-3 and this cycle continues (positive feedback). This cycle is important to increase the number of pro-apoptotic proteins (Bid) so that the number of proapoptotic protein will be higher than anti-apoptotic protein, this will lead apoptosis.