Introduction to Pathology and Adaptive Changes PDF

Introduction to Pathology and Adaptive Changes 1. Types of Cellular Responses to Stress and Noxious Stimuli Introduction to Cellular Stress Responses Cells are constantly interacting with and responding to the conditions around them, which means they face various stressors—things that can disrupt...

Introduction to Pathology and Adaptive Changes 1. Types of Cellular Responses to Stress and Noxious Stimuli Introduction to Cellular Stress Responses Cells are constantly interacting with and responding to the conditions around them, which means they face various stressors—things that can disrupt their normal functioning. These stressors can be physical (like temperature changes), chemical (toxins), biological (infections), or even a lack of nutrients. The way a cell responds to these stressors depends on three main factors: the type of stressor, the intensity of the stress, and the duration of the stress (how long the stress lasts). Adaptation: ○ If the stress is mild or chronic, cells may undergo adaptive changes to survive. —for example, if there are low levels of oxygen or sustained exposure to a toxin in the cells—they often adapt to this new situation. This process is called adaptation. Think of it like a person adjusting to living at a higher altitude: they might develop more red blood cells to carry oxygen more efficiently. Similarly, cells might change their structure or function to handle the stress better. Common types of adaptive responses include hypertrophy (↑ in cell size), hyperplasia (↑ in cell number), atrophy (↓ in cell size), and metaplasia (change in cell type). These adaptations can help the cell survive in a challenging environment. Reversible Injury: ○ If the stress is severe but short-lived, cells may become injured but can recover if the stimulus is removed. This is like a person getting sick but then recovering after some rest. In this case, the cells may have damage to their structures, such as swelling of the organelles or loss of function, but if the stressor is removed quickly enough, they can bounce back and return to normal function. For example, if a cell experiences temporary oxygen deprivation (ischemia), it can recover once blood flow returns. Irreversible Injury and Cell Death: ○ If the stress is prolonged or too intense, cells may suffer irreversible damage leading to cell death (necrosis or apoptosis). For example, severe trauma, sustained ischemia, or exposure to a high concentration of toxins—cells may suffer irreversible injury. This leads to cell death, which can happen through two main mechanisms: Necrosis: This is a form of uncontrolled cell death, often due to severe damage, resulting in inflammation. It’s like a house burning down; everything is destroyed and it can affect the surrounding area. Apoptosis: This is a programmed form of cell death, where the cell essentially “decides” to die. It’s a more orderly process and is part of normal development and maintenance. Think of it like a controlled demolition of a building that no longer serves a purpose, with minimal impact on surrounding structures. 1. Initiation of Apoptosis Apoptosis can be triggered through two main pathways: Intrinsic Pathway (internal signals) and Extrinsic Pathway (external signals). Intrinsic Pathway: This pathway is triggered by internal stress signals (like DNA damage, oxidative stress, or protein misfolding) and involves components primarily located in the mitochondria. The activation of BH3-only proteins leads to the release of cytochrome C, which starts the apoptotic cascade within the cell. Extrinsic Pathway: This pathway is initiated by external signals, specifically the binding of death ligands (like Fas ligand or TNF) to their corresponding death receptors (such as Fas or TNF receptor) on the cell surface. This interaction triggers a cascade that activates initiator caspases and ultimately leads to apoptosis. a) Intrinsic Pathway (Mitochondrial Pathway)  1. Negative stimulus such as radiation, protein misfolding due to genetic mutations etc, triggers the activation of stress proteins called BH3-ONLY proteins 2. BH3-ONLY proteins have 2 functions: a. Activating Pro-apoptotic proteins such as BAX and BAK proteins b. Inhibiting Anti-apoptotic proteins such as BCL2 and BCLX 3. Activation of pro-apoptotic proteins causes these proteins to form channels on the inner mitochondrial membrane 4. These channels result in the leaking of proteins that cause apoptosis (cytochrome C and SMAC’s) into the cytoplasm. 5. Inhibition of anti-apoptotic proteins causes more and more apoptotic proteins to leak out since there is nothing stopping them from coming out of the mitochondria. 6. Upon leaking into the cytoplasm, Cytochrome C binds to APAF-1 (Apoptotic Protease Activating Factor-1) leading to the formation of apoptosome 𝐶𝑦𝑡𝑜𝑐ℎ𝑟𝑜𝑚𝑒 𝐶 + 𝐴𝑃𝐴𝐹 − 1 = 𝐴𝑝𝑜𝑝𝑡𝑜𝑠𝑜𝑚𝑒 7. Apoptosome binds with initiator caspase (Pro-caspase 9) activating it and turning it into Caspase 9 8. Caspase 9 then binds with executioner caspases (caspases 3 and 6) activating them also 9. Executioner caspases then cause apoptosis by different methods such as a. Proteolytic cleavage of structural proteins b. DNA fragmentation c. Degradation of cell signalling proteins d. Formation of apoptotic bodies Cytotoxic T- lymphocytes/ CD 8 T-cells cause apoptosis of infected/ damaged/ tumor cells. Normally all cells including damaged cells have proteins called FAS receptors on their membranes while CD 8 T-cells have molecules called FAS ligands. For apoptosis to occur, FAS ligands on CD 8 T-cells bind with the FAS receptors on the damaged/infected cell and thus initiating apoptosis. Apoptosis cal occur via 2 pathways if the stimulus originates from outside the cell. The extrinsic pathway and the granzyme/ perforin pathway. b) Extrinsic Pathway 1. Death ligands such as FAS ligand and Tumor necrosis Factors (TNF) binds to their respective death receptors on tumor cells (ie FAS-receptor and TNF- receptors) 2. The binding of these receptors cause death receptors to aggregate and form clusters leading to the recruitment of other signalling molecules 3. The aggregation of death receptors leads to the recruitment of adaptor proteins such as FADD (Fas Associated Death Domain). FADD acts as a bridge between the FAS ligands and the initiator caspases. 4. FADD binds to Pro-cascase 8 (or sometimes pro- caspase 10) causing the formation of a complex called DISC (Death Inducing Signalling Complex) through which the activation of caspase-8 (caspase 10) occurs 5. Once caspase 8 is activated, it operates in 2 ways: a. Directly activating executioner caspases (3,6 and 7) b. Alternatively, bind to and activate BH§-only proteins which trigger the intrinsic pathway by promoting the release of cytochrome C from the mitochondria 6. The activated executioner caspases (3, 6, and 7) then carry out the processes that lead to apoptosis, including: Proteolytic cleavage of structural proteins. DNA fragmentation. Degradation of cell signaling proteins. Formation of apoptotic bodies. c) Granzyme/ Perforin Pathway  1. Cytotoxic T cells or NK cells recognize and bind to target cells that display abnormal antigens, such as those from viral infections or tumors. 2. Upon recognition, the cytotoxic cells release perforin, a pore-forming protein, from their cytoplasmic granules. Perforin creates pores in the membrane of the target cell. 3. Once the pores are formed, granzymes, which are serine proteases also released from the granules, enter the target cell through these pores. 4. Inside the target cell, granzymes, particularly granzyme B, activate the intrinsic apoptotic pathway by cleaving and activating pro-apoptotic proteins and caspases: a. Granzyme B can directly cleave and activate caspase 3, an executioner caspase. b. It can also cleave Bid, a pro-apoptotic BH3-only protein, which promotes the release of cytochrome C from the mitochondria, further activating the intrinsic pathway. 5. The activation of executioner caspases (like caspase 3) leads to the typical features of apoptosis, including: Cleavage of structural proteins. DNA fragmentation. Degradation of signaling proteins. Formation of apoptotic bodies 2. Adaptive Responses to Stress Adaptive changes occur when cells undergo modifications in response to stress to maintain function or avoid injury. The four main types of adaptive responses are: Hypertrophy: An increase in cell size, often seen in cells that are unable to divide. For example, muscle hypertrophy in response to increased workload. Hyperplasia: An increase in the number of cells, often seen in tissues capable of cell division, such as the liver or skin. Atrophy A decrease in cell size and function due to a reduction in workload, loss of innervation, diminished blood supply, or aging. So basically no nourishment. For example, during weight loss adipocytes reduce in size and number due to a decreased function. Ie, weeks of dieting and exercises causes the adipocytes to decrease in size because most of the energy in these cells is used up. And then after months or years of constant dieting and exercise, most of these cells will undergo apoptosis and decrease in number since only a few of them will be needed unlike before (reduced size and number due to reduced function). Metaplasia: A reversible change in which one type of adult cell is replaced by another type, often as a protective mechanism. For example, the replacement of normal ciliated columnar epithelial cells in the respiratory tract by stratified squamous epithelium in smokers.