Lecture 1 Flashcards

Question

State six causes of atrophy What is sarcopenia

Answer 1

Decreased workload (atrophy of disuse) • Loss of innervation (denervation atrophy). • Diminished blood supply. •Inadequate nutrition •Loss of endocrine stimulation. •Aging (senile atrophy). •Pressure. How diminished blood supply causes atrophy: - [ ] By causing Tissue hypoxia leading to reduced oxygen in cells that is used for their cellular function leading to shrinking of the cells - [ ] It can also cause decreased workload cuz reduced blood supply to a certain part makes it difficult to use that part of the body So when the cell loses its function or is unable to perform its function, it leads to atrophy. Thymus gland is almost vanished due to atrophy in aging people Senile Atrophy: • Definition: Senile atrophy is a type of atrophy that occurs as a natural part of aging. It affects various organs and tissues, such as muscles, the brain, skin, and bones. • Mechanism: Aging leads to a gradual decrease in cell size and number due to a combination of factors, including reduced blood supply, decreased hormonal stimulation, and accumulation of cellular and molecular damage over time. • Examples: • Brain: In the elderly, there is a decrease in brain size due to the loss of neurons, which is evident in conditions like Alzheimer’s disease. • Muscles: Age-related muscle wasting, known as sarcopenia, is another example, where muscle fibers shrink and are replaced by fat and fibrous tissue. • Skin: The skin may become thinner, less elastic, and more prone to injury as cells decrease in number and collagen production declines. 2. Pressure Atrophy: • Definition: Pressure atrophy is the reduction in the size of a tissue or organ due to persistent and prolonged pressure. This pressure disrupts normal blood flow, leading to ischemia (reduced oxygen supply), which in turn causes tissue shrinkage. • Mechanism: When an organ or tissue is subjected to continuous pressure, cells can be damaged, and nutrient and oxygen supply to the cells is impaired. Over time, this causes cells to shrink or die, leading to atrophy. • Examples: • Kidneys: In hydronephrosis, where there is a blockage of urine flow, the build-up of urine puts pressure on kidney tissues, causing them to atrophy. • Skin and Subcutaneous Tissue: Prolonged pressure in bedridden patients can cause pressure ulcers (bedsores), where the skin and underlying tissues atrophy due to sustained pressure. Generally, excessive use of an organ or tissue does not cause atrophy; Pressure atrophy results from prolonged pressure on tissues, leading to a reduction in size due to impaired blood flow and oxygen supply.

Answer 2

Cell injury results when cells are stressed so severely that they are no longer able to adapt or when cells are exposed to inherently damaging agents •Injury may progress through a reversible stage and culminate in cell death •Injury is grouped into ; 1.Reversible cell injury 2.Irreversible injury and cell death

Answer 3

Reversible injury; the hallmarks of reversible injury are reduced oxidative phosphorylation(this is the process by which mitochondria produces ATP), adenosine triphosphate (ATP) depletion, and cellular swelling caused by changes in ion concentrations and water influx. In addition: ATP DEPLETION, Impaired mitochondrial function 4. Increased ROS production 5. Disrupted electron transport chain Further understanding: So oxidative phosphorylation will be reduced because there is reduced ADP generation. ADP is the substrate for ATP synthase. ATP synthase uses ADP and inorganic phosphate to produce ATP. With less ADP available, the enzyme has less substrate to work with, reducing the rate of ATP synthesis and reducing oxidative phosphorylation Reversible cell injury refers to cellular damage that can be reversed if the harmful stimulus is removed. The hallmarks of reversible cell injury primarily reflect early cellular responses to stress or injury The key features include: 1. **Cellular Swelling**: Due to the failure of ion pumps in the plasma membrane, especially the Na+/K+ ATPase pump, leading to an influx of sodium and water into the cell. 2. **Fatty Change (Steatosis)**: Accumulation of lipid droplets within the cytoplasm, often seen in organs involved in lipid metabolism, like the liver. 3. **Membrane Blebbing**: Formation of protrusions or blebs in the plasma membrane due to cytoskeletal disruption. 4. **Mitochondrial Swelling**: Swelling and distortion of mitochondria, which may lead to decreased ATP production but are not yet irreversibly damaged. 5. **Dilation of the Endoplasmic Reticulum**: Expansion of the ER, leading to detachment of ribosomes and disruption of protein synthesis. 6. **Detachment of Ribosomes from the Rough ER**: Leading to impaired protein synthesis. 7. **Chromatin Clumping**: Aggregation of nuclear chromatin due to changes in ionic balance, especially pH. 8. **Cellular and Organelle Disorganization**: Initial reversible changes in the structure and function of various organelles within the cell. 9. **Increased Plasma Membrane Permeability**: Leading to an imbalance of ions and water across the membrane, contributing to cellular swelling. 10. **Accumulation of Intracellular Ions**: Particularly calcium, which can activate various enzymatic pathways that can lead to further cell damage if not controlled. These changes are generally reversible if the injurious stimulus is removed and the cell can restore homeostasis. Reversible cell injury changes are first seen: ultra structurally, later on… light microscopy Reversible cell injury is a Redemption mechanism: Stress response: most genes are inactivated and a set of inducible genes are expressed resulting in synthesis of intracellular “stress proteins” or "heat shock proteins" (HSP) Stress proteins are involved in the cell’s defense mechanisms against stress and are produced during reversible cell injury to help the cell adapt and recover. • In the context of irreversible cell injury, while stress proteins may still be produced, their protective effects are insufficient to prevent cell death.

Answer 4

Irreversible injury; structural changes (e.g., amorphous densities in mitochondria, indicative of severe mitochondrial damage) and functional changes (e.g., loss of membrane permeability) are indicative of cells that have suffered irreversible injury. Irreversible cell injury refers to a state where cell damage has progressed to a point beyond recovery, ultimately leading to cell death. Several hallmark features characterize this irreversible injury, distinguishing it from reversible damage. These hallmarks include: ### 1. **Severe Mitochondrial Damage** - **Irreversible Mitochondrial Dysfunction**: Mitochondria lose their ability to produce ATP. Significant mitochondrial damage includes the loss of membrane potential and the formation of mitochondrial permeability transition pores, leading to the release of pro-apoptotic factors. ### 2. **Profound Membrane Damage** - **Plasma Membrane Disruption**: Loss of membrane integrity leads to an uncontrolled influx of calcium and other ions, as well as leakage of cellular contents into the extracellular space. - **Lysosomal Membrane Damage**: Release of lysosomal enzymes into the cytoplasm, causing enzymatic digestion of cellular components. ### 3. **Nuclear Changes** - **Pyknosis**: Nuclear shrinkage and increased basophilia due to chromatin condensation. - **Karyorrhexis**: Fragmentation of the nucleus into smaller pieces. - **Karyolysis**: Dissolution of the nuclear structure, resulting in a loss of chromatin staining. ### 4. **Cytoplasmic Changes** - **Increased Eosinophilia**: The cytoplasm appears more pink when stained with hematoxylin and eosin (H&E) due to the denaturation of proteins and loss of RNA. - **Cytoplasmic Vacuolization**: Formation of large vacuoles within the cytoplasm as a result of autophagy and other degradative processes. ### 5. **Release of Cellular Contents** - **Leakage of Intracellular Enzymes**: Enzymes and proteins, such as lactate dehydrogenase (LDH) and creatine kinase (CK), are released into the extracellular space and bloodstream, serving as markers of cell death and tissue damage. ### 6. **Loss of Cell Function** - **Functional Impairment**: Complete loss of specific cellular functions, such as contraction in muscle cells or electrical activity in neurons When I mentioned "increased basophilia" in the context of pyknosis, I was referring to the fact that the condensed chromatin in the nucleus becomes more intensely stained with basic dyes. Basophilia is a term used to describe the ability of a substance to attract basic dyes, such as hematoxylin and eosin (H&E). In the context of histology and cytology, basophilia is often used to describe the staining properties of cellular structures. In the case of pyknosis, the condensed chromatin becomes more basophilic because the DNA and associated proteins are packed more tightly together. This increased density of negatively charged molecules (such as phosphate groups in DNA) creates a stronger attraction for positively charged basic dyes. As a result, the pyknotic nucleus appears more intensely stained with basic dyes, often appearing dark blue or purple under a microscope. This is in contrast to the surrounding cytoplasm, which may appear more pale or eosinophilic (staining with acidic dyes). So, to summarize: - Basophilia refers to the ability of a substance to attract basic dyes. - In pyknosis, the condensed chromatin becomes more basophilic due to the increased density of negatively charged molecules. - This results in the pyknotic nucleus appearing more intensely stained with basic dyes under a microscope.

Answer 5

1.Oxygen deprivation- 2.Physical agents- too hot too cold temperatures cuz the cells were to best at optimum temp Which is often 37 degrees celcius. PHYSICAL A.Extremes of temperature - cell injury and/or cell death result if tissue is maintained at a level greater than 5°C above (hyperthermia) or 15°C below (hypothermia) normal body temperature. B. Mechanical causes; Mechanical - •abrasions (tearing of epidermal cells by friction) • contusions/bruises • lacerations • incisions • stab (pressure produced by pointed objects) C. Light - photopathy (pathologic effect produced by light): photalgia (pain in eye caused by light); photonosus (any disease due to excess light) D. Pressure - high pressure may cause injury. E.Sound - may damage hearing causing hearing impairment F.Radiation - x-rays, gamma rays, alpha and beta particles, ultra-violet rays, etc. - result in damage to DNA and mutations 3.Chemical agents and drugs: The number of chemicals capable of causing cell injury is too vast to enumerate. Some, even in very small amounts, can cause death to enough cells in the body within minutes to hours, killing the whole organism – “poisons”. 4.Infectious agents-HIV destroying cells. BIOLOGICAL (INFECTIVE) AGENTS Bacteria - production of exo- and endo-toxins and other virulence factors Viruses, Clamydiae, Rickettsiae - direct cell lysis, cytopathic effects e.g. syncytial giant cell formation, inclusions, DNA alteration. Yeasts and fungi - chronic inflammation with fibrosis, hypersensitivity reactions. Parasites - cell lysis, tissue destruction by enzymes, competition for nutrients 5.Immunologic reactions-Allergic reactions and SLE. IMMUNOLOGICAL REACTIONS Hypersensitivity reactions - complement, T lymphocytes, Macrophages, chemical mediators of inflammation Autoimmune diseases – reactions of the immune system to self antigens Immunodeficiency – inherited and acquired (e.g. HIV infection) 6.Genetic derangements: GENETIC ABNORMALITIES DNA damage may lead to cell death, alteration of metabolic pathways (including synthesis of abnormal products or reduced or total lack of synthesis), or neoplastic transformation. 7.Nutritional imbalances: 8.Ageing

Answer 6

Irreversible cell injury: Loss of membrane permeability means the cell isn’t able to control what goes in and out of it. There is lysosome rupture. Lysosomes contain certain chemicals that destroy the cell One of the reasons reversible cell injury is reversible is cuz the damage isn’t as bad and lysosomes don’t rupture Diff between reversible and irreversible cell injury

Answer 7

Mechanisms of cell injury 1.The cellular response to injurious stimuli depends on the type of injury, its duration, and its severity. 2.The consequences of cell injury depend on the type, state, and adaptability of the injured cell. 3.Cell injury results from functional and biochemical abnormalities in one or more of several essential cellular components(next slide).

Answer 8

Mechanisms of cell injury 1.The cellular response to injurious stimuli depends on the type of injury, its duration, and its severity. 2.The consequences of cell injury depend on the type, state, and adaptability of the injured cell.(example is the cells in the lungs. They are used to oxygen so oxygen deprivation in the lungs for even ten seconds will give you an exaggerated effect as compared to oxygen deprivation of the same amount of time in the liver. Hepatocytes will be more adapted to oxygen deprivation stress than the lungs ) 3.Cell injury results from functional and biochemical abnormalities in one or more of several essential cellular components

Answer 9

Important targets of injurious stimuli 1.Aerobic respiration involving mitochondrial oxidative phosphorylation and production of ATP 2.The integrity of cell membranes, on which the ionic and osmotic homeostasis of the cell and its organelles depends(attack to this area by injurious stimuli leads to high sodium in cells due to failure of Sodium potassium pumps leading to swelling of cells) 3.Protein synthesis-components in cell are held together by proteins. Example is the cytoskeleton. Problem in protein synthesis can cause deranged enzymes such as derangement in enzymes in glycolytic pathway (example streptokinase) so the cell isn’t able to produce the mediators for ATP synthesis 4.The cytoskeleton 5.The integrity of the genetic apparatus of the cell.(Example is radiation causing injury to DNA which will affect integrity of genetic apparatus Summary: Injury to membrane or cell affects these key areas or causes: 1.Mitochondrial damage leads to reduced ATP production and then loss of energy dependent cellular functions like sodium potassium atpase pumps. 2.Injury to lysosomes causing enzymatic digestion of cellular components 3. Injury to plasma membrane causing loss of integrity of plasma membrane leading to loss of cellular contents 4. Increased intracellular calcium leading to protein breakdown and dna damage 5. Release or ROS such as nitric oxide,hydrogen peroxide,hydrochloride also leading to protein breakdown and dna damage

Answer 10

Decreased ATP synthesis and depletion are frequently associated with both hypoxic and chemical (toxic) injury H Hypoxic Injury: A lack of oxygen reduces oxidative phosphorylation in mitochondria, sharply decreasing ATP production. Cells switch to anaerobic glycolysis, which is much less efficient and produces minimal ATP. • Chemical (Toxic) Injury: Toxic substances can damage mitochondria, inhibit key enzymes in ATP production pathways, increase mitochondrial membrane permeability, or cause oxidative stress, all of which impair ATP synthesis. • ATP depletion to <5-10% of normal levels result in; 1.Reduction in the activity of the plasma membrane energy-dependent sodium pump (ouabain-sensitive Na+,K+-ATPase) which leads to increased sodium,water and calcium influx and increased potassium efflux causing ER swelling and the whole cell to swell up 2.Altered cellular energy metabolism-reduced ATP means now the cell has to undergo anaerobic glycolysis instead of aerobic. More of the ATP or high amounts of it is produced from aerobic glycolysis in the cristae of the mitochondria. This anaerobic glycolysis leads to reduced glycogen,reduced ph and then clumping of nuclear chromatin 3.Failure of the Ca2+ pump leads to influx of Ca2+, with damaging effects on numerous cellular components 4.Structural disruption of the protein synthetic apparatus, manifested as detachment of ribosomes from the rough endoplasmic reticulum and dissociation of polysomes into monosomes, with a consequent reduction in protein synthesis and increased lipid deposition 5.Unfolded protein response is triggered cristae **: The folds of the inner mitochondrial membrane where the electron transport chain and ATP synthesis take place. - **Matrix**: The innermost part of the mitochondrion where the Krebs cycle occurs.

Answer 11

Increases of cytosolic Ca2+ •Oxidative stress •Breakdown of phospholipids •Lipid breakdown products Damage RESULTS IN; 1.Formation of a high-conductance channel in the mitochondrial membrane, called the mitochondrial permeability transition pore 1. *Mitochondrial Permeability Transition (MPT) pore formation*: A high-conductance channel forms in the mitochondrial membrane, allowing solutes and water to flow into the mitochondria, leading to: - Mitochondrial swelling - Mitochondrial dysfunction - Release of pro-apoptotic factors 2.Sequestration between the outer and inner membranes of the mitochondria of several proteins that are capable of activating apoptotic pathways( cytochrome c and proteins that indirectly activate apoptosis inducing enzymes called caspases). The statement you've provided refers to a critical step in the intrinsic (mitochondrial) pathway of apoptosis, where certain proteins sequestered between the outer and inner membranes of the mitochondria are released to initiate the apoptotic process. Here’s a breakdown: ### **Mitochondrial Role in Apoptosis**: 1. **Sequestration of Proteins**: - Under normal conditions, proteins like **cytochrome c** and others that can promote apoptosis are sequestered in the intermembrane space of the mitochondria (the space between the outer and inner mitochondrial membranes). 2. **Release of Cytochrome c**: - In response to apoptotic stimuli (e.g., DNA damage, oxidative stress), the mitochondrial outer membrane becomes permeable. - This permeability allows **cytochrome c** and other pro-apoptotic proteins to be released into the cytoplasm. 3. **Activation of Caspases**: - Once in the cytoplasm, cytochrome c interacts with a protein called **Apaf-1** (Apoptotic protease activating factor-1) to form a complex known as the **apoptosome**. - The apoptosome then recruits and activates **procaspase-9**, which is cleaved to form active **caspase-9**. - **Caspase-9** subsequently activates other caspases (like caspase-3), which are responsible for executing the cell death program by degrading cellular components. 4. **Apoptotic Pathway**: - The release of cytochrome c is a key event in the **intrinsic apoptotic pathway**. - This pathway is tightly regulated and ensures that cells undergo controlled, programmed cell death in response to internal stress signals. ### **Key Proteins Involved**: - **Cytochrome c**: A protein normally involved in the electron transport chain, but also crucial for the activation of the intrinsic apoptotic pathway when released into the cytoplasm. - **Caspases**: A family of protease enzymes that play essential roles in programmed cell death (apoptosis). They are activated in a cascade, leading to the systematic dismantling of the cell. ### **Summary**: - **Sequestration** of apoptotic proteins like cytochrome c within the mitochondria keeps the apoptotic machinery in check. - **Release** of these proteins into the cytoplasm triggers the activation of **caspases**, leading to apoptosis. This process ensures that cells can be efficiently and systematically eliminated when they are damaged or no longer needed, preventing potential harm to the organism. Sequestration of pro-apoptotic proteins*: Between the outer and inner mitochondrial membranes, several proteins are sequestered, including: - *Cytochrome c*: A key electron transport chain protein that can activate caspases and induce apoptosis - *Pro-apoptotic Bcl-2 family members*: Proteins like Bax, Bak, and Bid, which can activate caspases and induce apoptosis These sequestered proteins can then be released into the cytosol, triggering apoptotic pathways and ultimately leading to programmed cell death (apoptosis). S several key factors responsible for triggering apoptotic pathways are located in the mitochondria. These factors include: 1. *Cytochrome c*: A protein that's normally involved in the electron transport chain, but when released into the cytosol, it activates caspases and triggers apoptosis. 2. *Smac/DIABLO*: A protein that inhibits the activity of IAPs (inhibitors of apoptosis proteins), allowing caspases to activate and drive apoptosis. 3. *Omi/HtrA2*: A serine protease that can activate caspases and trigger apoptosis. 4. *Bcl-2 family members*: A family of proteins that regulate apoptosis by either promoting (pro-apoptotic) or inhibiting (anti-apoptotic) mitochondrial outer membrane permeabilization (MOMP). These mitochondrial factors are normally sequestered within the mitochondria, but when the mitochondria are damaged or dysfunctional, they can be released into the cytosol, triggering apoptotic pathways Sequestration of proteins refers to the process by which proteins are selectively bound or trapped by other molecules, such as lipids, nucleic acids, or other proteins, and removed from their normal cellular environment or activityh The MPT pore formation and protein sequestration are critical steps in the mitochondrial pathway of apoptosis, which is a key mechanism of cell death in response to cellular stress, injury, or damage.

Answer 12

CAUSES OF DEFECTS IN MEMBRANE PERMEABILITY •Mitochondrial dysfunction-losss of sodium potassium atpase causing cell membrane to swell up •Loss of membrane phospholipids •Cytoskeletal abnormalities. •Reactive oxygen species. •Lipid breakdown products. Here are some ways in which lipid breakdown products can disrupt membrane permeability: 1. _Lysophospholipids_: These products of phospholipid breakdown can insert into the mitochondrial membrane, causing it to become more permeable. 2. _Fatty acid derivatives_: Certain fatty acid derivatives, such as palmitate, can alter the fluidity and permeability of the mitochondrial membrane. 3. _Oxidized lipids_: Oxidized lipids, such as oxidized cholesterol, can disrupt the mitochondrial membrane structure and function, leading to increased permeability. 4. _Ceramide_: This sphingolipid breakdown product can form channels in the mitochondrial membrane, leading to increased permeability

Answer 13

Two phenomena consistently characterize irreversibility; 1.The inability to reverse mitochondrial dysfunction (lack of oxidative phosphorylation and ATP generation) or when Mitochondria is destroyed 2.Profound disturbances in membrane function.-Membrane of cell is destroyed The best available definition of cell death is the irreversible loss of integrated cellular function: Boundary functions (cell membrane) Energy production/metabolism Protein synthesis Maintenance of cell shape (Cytoskeleton) Cell function control and modulation (RNA/DNA)

Answer 14

Two light microscopic changes are recognizable; 1.Cellular swelling and bleb formation 2.Fatty change and fatty deposits especially in the hepatocytes Ultrastructural changes in reversible injury include: 1.Plasma membrane alterations 2.Mitochondrial changes 3.Dilation of the endoplasmic reticulum-this displaces the ribosomes on it 4.Nuclear alterations I checked this when I asked whether bleb formation was irreversible or reversiboe and the thing said it’s an early sign of reversible cell injury but it can also occur in latter parts of irreversible cell injury so it gave me the below to understand better. When selecting an option for an MCQ that involves bleb formation, here’s how to approach it: 1. Question Context: Determine whether the question is asking about early or late features of cell injury. If it focuses on early signs, bleb formation can be associated with both reversible and irreversible cell injury. 2. Specificity: • If the question specifies irreversible cell injury or cell death, choose that option as bleb formation can occur during the transition to irreversible damage. • If the question is general and does not specify the stage of injury, note that bleb formation can occur in both reversible and irreversible cell injury. 3. Definitive Signs: • For irreversible cell injury: Look for additional definitive signs like severe mitochondrial damage, extensive membrane rupture, or nuclear changes (e.g., pyknosis). • For reversible cell injury: If only bleb formation is mentioned without other irreversible changes, it’s more likely to indicate reversible injury or early reversible injury. Example MCQ Scenario: • Question: “Which of the following is an early sign of cell injury?” • Options: • A. Bleb formation • B. Pyknosis • C. Karyorrhexis • D. Karyolysis • Best Answer: A. Bleb formation, because it can occur early in both reversible and irreversible cell injury. • Question: “Which of the following indicates irreversible cell injury?” • Options: • A. Bleb formation • B. Cellular swelling • C. Pyknosis • D. Fatty change • Best Answer: C. Pyknosis, as it is a definitive sign of irreversible cell injury and cell death, though bleb formation is also relevant as part of the broader context of injury. Reversible and irreversible cell injury involve distinct cellular changes. Here’s a comparison: ### **Reversible Cell Injury:** - **Cellular Swelling**: Early sign, caused by impaired ion pumps (e.g., Na+/K+ ATPase) leading to an influx of water. - **Fatty Change**: Accumulation of lipid droplets in the cytoplasm due to impaired lipid metabolism. - **Loss of Microvilli**: Changes in the cell membrane structure. - **Mitochondrial Swelling**: Mild swelling and aggregation of mitochondrial granules. - **Chromatin Clumping**: Chromatin becomes more condensed and clumped, but this is reversible if the stress is removed. ### **Irreversible Cell Injury:** - **Cell Death**: Irreversible injury leads to cell death via apoptosis or necrosis. - **Severe Mitochondrial Damage**: Loss of mitochondrial function and release of pro-apoptotic factors (e.g., cytochrome c). - **Severe Plasma Membrane Damage**: Loss of membrane integrity leads to leakage of cellular contents. - **Lysosomal Membrane Damage**: Enzymes leak out, causing digestion of cell components. - **Nuclear Changes**: - **Pyknosis**: Nuclear shrinkage and increased basophilia. - **Karyorrhexis**: Fragmentation of the nucleus. - **Karyolysis**: Dissolution of the nucleus. ### Summary: - **Reversible Injury**: Characterized by early changes that are potentially recoverable if the stress is removed. It involves cellular swelling, fatty change, and mild structural changes. - **Irreversible Injury**: Characterized by severe damage leading to cell death. It involves significant mitochondrial damage, membrane rupture, and severe nuclear changes. Understanding these distinctions helps in diagnosing and managing cell damage in various pathological conditions.

Answer 15

Necrosis and apoptosis There are two morphological forms of cell death: Necrosis, and Apoptosis

Answer 16

Spectrum of morphologic changes that follow cell death in living tissue Refers to death of contiguous (adjacent or neighbouring) cells in living or dead tissue It is followed by degradation of tissue by hydrolytic enzymes It is mostly accompanied by inflammatory reaction (Leucocytosis) •Morphologic appearance of necrosis is the result of denaturation of intracellular proteins and enzymatic digestion of the cell. Necrotic cells often exhibit: - Cytoplasmic swelling -karyorrhexis (1) - Nuclear pyknosis (2)(condensation) - Karyolysis (nuclear breakdown)(3) - Cell lysis (rupture) 1,2,3 are stages of necrosis As the cell dies, its components are broken down and removed by the body's clearance mechanisms. In some cases, dead cells may be replaced by myelin figures, which are composed of lipid material and can be seen in conditions such as infarction (tissue death due to lack of blood supply) •Dead cells may be replaced by myelin figures. Dead cells may be replaced by myelin figures, which are formed by the breakdown of cellular membranes and the accumulation of lipid material. Two concurrent processes mediate the changes seen in necrosis; enzymatic digestion denaturation of proteins Type of Necrosis is dependent on which process dominates

Answer 17

Necrotic cells show increased eosinophilia

Answer 18

1.Pyknosis; morphological change in nucleus characterized by nuclear condensation and nuclear shrinkage or clumping of nuclear material or chromatin into dense masses and increased basophilia(this increased basophilia means Increased Staining Intensity**: Due to the high density of chromatin, the nucleus stains more darkly with basic dyes.) 2.Karyorrhexis; nucleus undergoes fragmentation. Karyorrhexis**: This is the fragmentation of the nucleus. During karyorrhexis, the nuclear envelope breaks down, and the chromatin is fragmented into irregular pieces. This typically occurs after pyknosis, where the nucleus shrinks and condenses. Karyorrhexis** usually starts first. After the nucleus undergoes pyknosis (condensation), it fragments into pieces, which is karyorrhexis. 3. Nuclear changes in necrosis Due to nonspecific breakdown of DNA and include; Karyolysis; karyolysis is the dissolution or disintegration of the cell’s nucleus. There is fading of the basophilia of the chromatin a change that presumably reflects DNase activity. DNase digests DNA . **Karyolysis**: This is the dissolution of the nuclear material. In karyolysis, the chromatin fades and the nucleus becomes less visible due to enzymatic degradation by DNAases. The nucleus eventually disappears altogether. Following this fragmentation, the nuclear material is progressively digested by enzymes, leading to karyolysis.

Answer 19

Morphologic variants of necrosis •Coagulative necrosis; implies preservation of the basic outline of the coagulated cell for a span of at least some days.example is the heart muscle which undergoes coagulative necrosis Coagulative Necrosis: Protein denaturation predominates Commonest form of necrosis Occurs in almost all organs Mostly due to ischaemia Other common causes are potent bacterial toxins and chemicals **Coagulative Necrosis** and **Liquefactive Necrosis** are two distinct types of tissue necrosis that can result from different infections. ### Coagulative Necrosis **Characteristics**: - Coagulative necrosis is characterized by the preservation of the basic outline of the coagulated cell for a few days. The architecture of dead tissues is preserved for at least some days. - It typically occurs due to ischemia or infarction, where blood supply is cut off, leading to tissue death. **Infections Causing Coagulative Necrosis**: - **Bacterial Infections**: - **Clostridium perfringens**: Causes gas gangrene, leading to coagulative necrosis in the muscles. - **Bacillus anthracis**: Causes anthrax, which can result in black eschar with coagulative necrosis in cutaneous anthrax. - Certain bacterial infections (e.g., anthrax, clostridial infections) can cause coagulative necrosis through vascular damage, thrombosis, and ischemia - **Viral Infections**: - While viral infections more commonly cause liquefactive necrosis in certain tissues, some can indirectly lead to ischemia and subsequent coagulative necrosis (e.g., by causing vascular damage and thromboembolism). You're looking for the common viral infections that lead to ischemia. Here are some of the most common ones: 1. *Herpesviruses* (HSV, VZV) 2. *Cytomegalovirus (CMV)* 3. *Influenza* 4. *HIV* 5. *Respiratory syncytial virus (RSV)* These viruses can cause ischemia through various mechanisms, including vasculitis, endothelial dysfunction, and thrombosis. •Liquefactive necrosis is characteristic of focal bacterial or, occasionally, fungal infections, because microbes stimulate the accumulation of inflammatory cells. Focal bacteria refer to bacteria that are localized to a specific area or focus within a tissue or organ. In other words, they are concentrated in a particular region, rather than being widely distributed throughout the body. Focal bacteria can cause a range of effects, including: 1. _Local inflammation_: The immune response to the bacteria can lead to inflammation in the surrounding tissue. 2. _Tissue damage_: The bacteria can produce toxins or enzymes that damage the surrounding tissue. 3. _Abscess formation_: The bacteria can cause the formation of an abscess, a pocket of pus and debris. 4. _Granuloma formation_: The immune response to the bacteria can lead to the formation of a granuloma, a type of inflammatory nodule. Examples of focal bacteria include: 1. _Staphylococcus aureus_ (can cause abscesses or granulomas) 2. _Mycobacterium tuberculosis_ (can cause granulomas in the lungs) 3. _Bartonella henselae_ (can cause focal lesions in the skin or lymph nodes) Focal bacteria can be diagnosed through various methods, including: 1. _Imaging studies_ (e.g., X-rays, CT scans) 2. _Biopsy_ (examining a tissue sample under a microscope) 3. _Microbiological cultures_ (growing the bacteria in a laboratory) Treatment for focal bacteria typically involves antibiotics and, in some cases, surgical drainage or removal of the affected tissue. Liquefaction completely digests the dead cells. Example is in brain infections ### Liquefactive Necrosis **Characteristics**: - Liquefactive necrosis results in the transformation of the tissue into a liquid viscous mass. It is often associated with the presence of abscesses and pus due to the action of hydrolytic enzymes. - It is common in tissues with high enzymatic content, such as the brain, and in abscesses due to bacterial infections. Examples of tissues with high enzymatic content include: 1. Pancreas: The pancreas contains digestive enzymes that can break down dead tissue, leading to liquefactive necrosis. 2. Liver: The liver contains enzymes that can break down dead tissue, leading to liquefactive necrosis. 3. Spleen: The spleen contains enzymes that can break down dead tissue, leading to liquefactive necrosis. 4. Lymph nodes: Lymph nodes contain enzymes that can break down dead tissue, leading to liquefactive necrosis. 5. Adipose tissue (fat tissue): Adipose tissue contains lipases, which can break down dead tissue, leading to liquefactive necrosis. These tissues are more prone to liquefactive necrosis due to their high enzymatic content, which can facilitate the breakdown of dead cells and tissues. On the other hand, tissues with low enzymatic content, such as muscle and bone, are more likely to undergo coagulative necrosis **Infections Causing Liquefactive Necrosis**: - **Bacterial Infections**: - **Staphylococcus aureus**: Causes abscesses in various tissues leading to liquefactive necrosis. - **Streptococcus pyogenes**: Can cause severe soft tissue infections, including necrotizing fasciitis, which involves liquefactive necrosis. - **Pseudomonas aeruginosa**: Known for causing abscesses with liquefactive necrosis, especially in immunocompromised patients. - **Fungal Infections**: - **Aspergillus spp.**: Can cause aspergillosis, leading to lung abscesses with liquefactive necrosis. - **Candida spp.**: Can lead to abscesses in various organs, often involving liquefactive necrosis. - **Viral Infections**: - **Herpes Simplex Virus (HSV)**: Can cause encephalitis, leading to liquefactive necrosis in the brain. - **Cytomegalovirus (CMV)**: In immunocompromised patients, CMV infections can lead to extensive tissue necrosis, including liquefactive necrosis in organs like the lungs and the brain. •Other terms include; gangrenous necrosis(due to occlusion of blood vessel proximal to the site of the necrosis) and wet gangrene-when inflammatory cells are involved

Answer 20

Caseous necrosis •A distinctive form of coagulative necrosis encountered most often in foci of tuberculous infection •Name derives from cheesy white gross appearance of the area of necrosis •Microscopically, the necrotic focus appears as amorphous (no clear shape)granular debris enclosed within a distinctive inflammatory border known as a granulomatous reaction. Unlike coagulative necrosis, the tissue architecture is completely obliterated in caseous necrosis Caseation Necrosis Grossly, the area of necrosis is yellowish white and sharply circumscribed and the necrotic tissue is soft, granular and friable, resembling dry cheese It is seen principally in tuberculosis but also in fungal infections Granulomatous Reaction: • The necrotic area is typically surrounded by a distinctive inflammatory border known as a granuloma. A granuloma is an organized collection of immune cells that forms as a response to chronic inflammation. • The granuloma often contains epithelioid macrophages, multinucleated giant cells, and a lymphocytic cuff (a layer of lymphocytes). This type of reaction is known as a granulomatous inflammation, and it serves to wall off the necrotic area. The necrosis results from the immune system’s response to the presence of pathogens (like Mycobacterium tuberculosis) that are resistant to eradication. The immune response attempts to contain the infection, leading to tissue destruction and caseous necrosis as a byproduct.

Answer 21

Fat necrosis •Descriptive of areas of fat destruction, typically occurring as a result of release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity. Fat necrosis is a type of necrosis that specifically affects fatty tissues. It's characterized by the destruction of fat cells, leading to the release of fatty acids and other lipolytic products. As you mentioned, fat necrosis often occurs as a result of: 1. Release of activated pancreatic lipases: These enzymes break down fat cells, leading to their destruction. 2. Pancreatic injury or inflammation: Conditions like pancreatitis can lead to the release of pancreatic lipases, causing fat necrosis. 3. Peritoneal cavity involvement: The peritoneum is a membrane lining the abdominal cavity. When it's affected by inflammation or injury, it can lead to fat necrosis. Fat necrosis can also occur in other situations, such as: - Trauma or injury to fatty areas - Infections like cellulitis or abscesses - Cancer or radiation therapy - Certain medications or drugs •Histologically it takes the form of foci of shadowy outlines of necrotic fat cells, with basophilic calcium deposits, surrounded by an inflammatory reaction. Enzymatic Fat Necrosis Direct trauma to adipose tissue with extracellular liberation of fat and inflammatory response - traumatic fat necrosis of the breast Also, lipolytic activity of lipases released from acute injury to pancreatic acinar tissue on fat cells – acute pancreatitis Grossly, appears as firm, yellow-white deposits Grossly, the necrotic area is soft and the centre is liquefied With time, in the brain, a cystic space with walls formed by non-necrotic tissue develops With an abscess a wall of fibrous tissue infiltrated by inflammatory cells forms – pyogenic membrane

Answer 22

Ischemic and hypoxic injury •Hypoxia refers to any state of reduced oxygen availability •Ischemia is brought about by reduced blood flow due to mechanical obstruction in the arterial system or as a result of a catastrophic fall in blood pressure or loss of blood. •In contrast to hypoxia, during which glycolytic energy production can continue, ischemia compromises the delivery of substrates for glycolysis Fibrinoid necrosis is characterized by deposition of fibrin-like material which has the staining properties of fibrin. 1. Fibrin-Like Material: The term “fibrinoid” refers to the appearance of this material, which looks like fibrin (a protein involved in clot formation). The material is eosinophilic, meaning it stains intensely with eosin, a dye used in histological staining. Eg: in vasculitis, peptic ulcer, arterioles in hypetension

Answer 23

In ischemic tissues, anaerobic energy generation stops after glycolytic substrates are exhausted, or glycolytic function becomes inhibited by the accumulation of metabolites that would have been removed otherwise by blood flow Ischemia injures tissues faster than hypoxia for several reasons: 1. *Reduced substrate delivery*: Ischemia reduces blood flow, which means that tissues not only receive less oxygen but also less glucose, amino acids, and other essential nutrients. This impairs cellular metabolism and energy production. 2. *Accumulation of metabolic waste*: With reduced blood flow, waste products like lactic acid, urea, and creatinine build up in tissues, leading to cellular toxicity and damage. 3. *Increased inflammation*: Ischemia triggers an inflammatory response, which can lead to tissue damage and exacerbate injury. 4. *Disrupted cellular homeostasis*: Ischemia disrupts the balance of ions, water, and electrolytes within cells, leading to cellular swelling, damage, and death. 5. *Faster energy depletion*: Ischemia depletes cellular energy stores (ATP) faster than hypoxia, as both oxygen and substrates are limited. 6. *More severe acidosis*: Ischemia leads to a more severe acidotic state (increased lactic acid and decreased pH), which damages cellular structures and functions. In contrast, hypoxia alone (without ischemia) may still allow for some glucose and substrate delivery, enabling cells to maintain basic metabolic functions and survive for a longer period. Keep in mind that both ischemia and hypoxia can cause tissue injury, but ischemia tends to be more severe and rapid due to the combination of reduced substrate delivery, metabolic waste accumulation, and disrupted cellular homeostasis. •For this reason, ischemia tends to injure tissues faster than does hypoxia. Here's a clinical question based on our previous discussion: Clinical Question: A 40-year-old male patient presents with severe leg pain and numbness after a traumatic injury. His leg is pale, cool to the touch, and has a decreased pulse. Which type of injury is most likely to cause tissue damage faster, considering the patient's presentation? A) Hypoxic injury B) Ischemic injury C) Traumatic injury D) Neurogenic injury Answer: B) Ischemic injury Explanation: The patient's presentation suggests ischemia, which is characterized by reduced blood flow to the affected limb, leading to decreased oxygen and substrate delivery. This causes tissue damage faster than hypoxia alone, as ischemia impairs both oxygen and substrate delivery, leading to cellular energy depletion, metabolic waste accumulation, and disrupted cellular homeostasis. The patient's symptoms, such as pale and cool skin, decreased pulse, and numbness, are consistent with ischemic injury. Let me know if you have any further questions or if you'd like me to clarify anything!

Answer 24

CK and LDH There is increased leakage of enzymes CK and LDH There is also loss of phospholipid,cytoskeletal alterations,free radicals,lipid breakdown

Answer 25

Ischaemia-reperfusion injury •New damaging processes are set in motion during reperfusion, causing the death of cells that might have recovered otherwise Proposed mechanisms for this injury include: 1.Increased generation of oxygen free radicals from parenchymal and endothelial cells and from infiltrating leukocytes. 2.Mitochondrial permeability transition 3.Inflammation and activation of the complement pathway During reperfusion, there is a sudden increase in oxygen delivery to the tissues, which can lead to an overproduction of reactive oxygen species (ROS). This occurs for several reasons: 1. *Replenished oxygen*: After a period of ischemia, the tissues are oxygen-depleted. When blood flow is restored, oxygen rushes in, and the sudden increase can lead to an overabundance of ROS. 2. *Mitochondrial dysfunction*: Ischemia can damage mitochondria, making them more prone to generating ROS during reperfusion. 3. *Activation of enzymes*: Reperfusion triggers the activation of enzymes like xanthine oxidase, NADPH oxidase, and cyclooxygenase, which can produce ROS as a byproduct. 4. *Inflammation*: Reperfusion initiates an inflammatory response, which leads to the production of ROS by immune cells like neutrophils and macrophages. 5. *Disrupted cellular metabolism*: Reperfusion can cause a sudden shift from anaerobic to aerobic metabolism, leading to an increase in ROS production. The excessive ROS production during reperfusion can overwhelm the body's natural antioxidant defenses, leading to oxidative stress, cellular damage, and tissue injury. Does that help clarify things? Let me know if you have further questions! Mitochondrial permeability transition*: Reperfusion can cause mitochondrial membranes to become permeable, leading to the release of pro-apoptotic factors and the disruption of cellular energy production. 3. *Inflammation and complement activation*: Reperfusion triggers an inflammatory response, activating the complement pathway and leading to the production of pro-inflammatory cytokines and chemokines.

Answer 26

A pathway of cell death that is induced by a tightly regulated intracellular program in which cells destined to die activate enzymes that degrade the cells' own nuclear DNA and nuclear and cytoplasmic proteins. Proapoptotic and anti-apoptotic genes regulate apoptosis. Pro-BAX Anti-BCL2 •The cell's plasma membrane remains intact, but its structure is altered in such a way that the apoptotic cell becomes an avid target for phagocytosis The Bcl-2 family is a group of proteins that regulate apoptosis (programmed cell death) by controlling the mitochondrial pathway. The Bcl-2 family members can be divided into two main subgroups: 1. _Anti-apoptotic_ (pro-survival) members: - Bcl-2 - Bcl-xL - Bcl-w - Mcl-1 2. _Pro-apoptotic_ (pro-death) members:(pro as in promax as in pro bax as in bax is a pro apoptotic member) - Bax - Bak - Bad - Bid - Bim - Puma - Noxa Bax, specifically, is a pro-apoptotic member of the Bcl-2 family. It can form homodimers or heterodimers with other Bcl-2 family members, leading to the formation of pores in the mitochondrial outer membrane, which ultimately triggers apoptosis. The Bcl-2 family members interact with each other and with other proteins to regulate the mitochondrial pathway of apoptosis. The balance between pro-apoptotic and anti-apoptotic Bcl-2 family members determines the cellular fate: survival or death. As an anti-apoptotic protein, Bcl-2 inhibits the activation of caspases, which are enzymes that carry out the process of apoptosis. By inhibiting caspases, Bcl-2 prevents cell death and promotes cell survival.

Answer 27

Cell death by this pathway does not elicit an inflammatory reaction in the host but necrosis does elicit inflammatory reactions. Apoptotic bodies are formed and the immune system and macrophages and things recognize them and get involved and destroy the cell with the apoptotic bodies on them •Responsible for numerous physiologic, adaptive, and pathologic events. Apoptosis is important for Actively dividing cells with high turnover rates cuz some of the cells must definitely die physiologically for other cells to take their place and so if those older cells are not programmed to die, how will the new cells take their place?

Answer 28

The programmed destruction of cells during embryogenesis-aplasia means cells are dying off and is important during embryogenesis so that certain structures can give way for other better ones to work. Example is regression of the tail seen in formation of embryo •Hormone-dependent involution(reduction in size of organ) in the adult- •Cell deletion in proliferating cell populations •Death of host cells that have served their useful purpose, such as neutrophils in an acute inflammatory response(neutrophils have lifespan of 4-6 hours in the blood vessel and 4-5 days in the tissues ) •Elimination of potentially harmful self-reactive lymphocytes •Cell death induced by cytotoxic T cells

Answer 29

-Cell death produced by a variety of injurious stimuli can induce apoptosis if the insult is mild, but large doses of the same stimuli result in necrotic cell death. •Cell injury in certain viral diseases, such as viral hepatitis •Pathologic atrophy in parenchymal organs after duct obstruction •Cell death in tumors, most frequently during regression but also in actively growing tumors

Answer 30

Cell shrinkage. The cell is smaller in size(but is bigger in size in necrosis cuz of the cell swelling that occurs only in necrosis ); the cytoplasm is dense; and the organelles, although relatively normal, are more tightly packed. •Chromatin condensation. This is the most characteristic feature of apoptosis. (But in necrosis there is karyolysis,pyknosis and karyohexxis) The chromatin aggregates peripherally, under the nuclear membrane, into dense masses of various shapes and sizes. The nucleus itself may break up, producing two or more fragments. Plasma membrane is disrupted in necrosis but is maintained in apoptosis Formation of cytoplasmic blebs and apoptotic bodies. The apoptotic cell first shows extensive surface blebbing, then undergoes fragmentation into membrane-bound apoptotic bodies composed of cytoplasm and tightly packed organelles, with or without nuclear fragments. •Phagocytosis of apoptotic cells or cell bodies, usually by macrophages. while both apoptosis and necrosis may exhibit chromatin condensation, the hallmark of apoptosis lies in the consistent and peripheral pattern of chromatin aggregation under the nuclear membrane, which is a critical histological feature used to distinguish it from necrosis. Timing: Chromatin condensation in apoptosis is typically an early and consistent feature, occurring as part of the programmed cell death process. • Pattern: In apoptosis, chromatin condensation is uniform and peripheral, whereas in necrosis, it may be irregular and accompanied by other nuclear changes depending on the type of necrosis. the loss of membrane integrity(The cell membrane becomes permeable and eventually ruptures, causing uncontrolled leakage of cellular contents.), cell swelling(oncosis), and inflammatory response( The release of cellular contents into the extracellular space triggers an inflammatory response. )are what make necrosis distinct from apoptosis. Hallmarks of Apoptosis: 1. Cell Shrinkage: Cells condense rather than swell, maintaining plasma membrane integrity. 2. Membrane Blebbing: The cell surface forms blebs, and the cell breaks apart into apoptotic bodies. 3. No Inflammation: Apoptotic bodies are phagocytosed without triggering inflammation. 4. Nuclear Changes: • Pyknosis: Chromatin condenses, similar to necrosis. • Karyorrhexis: The condensed nucleus fragments, but these fragments are packaged into apoptotic bodies rather than leaking into the extracellular space.

Answer 31

Biochemical features of apoptosis •Protein Cleavage; protein hydrolysis involving the activation of several members of a family of cysteine proteases named caspases. •DNA Breakdown; by Ca2+- and Mg2+-dependent endonucleases. •Phagocytic Recognition; apoptotic cells express phosphatidylserine in the outer layers of their plasma membranes. Thrombospondin, an adhesive glycoprotein, is also expressed on the surfaces of some apoptotic bodies Apoptosis, also known as programmed cell death, is characterized by several biochemical features, including: 1. *Protein Cleavage*: Protein hydrolysis (cleavage of procaspases) leads to the activation of caspases.Procaspases are inactive precursors of caspases, and they require cleavage by other proteases or by autocatalytic processes to become active. This cleavage removes inhibitory domains and allows the caspase to adopt an active conformation. 2. *DNA Breakdown*: Ca2+- and Mg2+-dependent endonucleases fragment DNA into smaller pieces, resulting in a characteristic "ladder-like" pattern on gel electrophoresis. 3. *Phagocytic Recognition*: Apoptotic cells exhibit changes in their plasma membranes, including: - Externalization of phosphatidylserine (PS) from the inner leaflet to the outer leaflet, which serves as an "eat me" signal for phagocytic cells. - Expression of thrombospondin, an adhesive glycoprotein, on the surfaces of some apoptotic bodies, facilitating their recognition and clearance by phagocytes. Additionally, other biochemical features of apoptosis include: - *Mitochondrial Outer Membrane Permeabilization (MOMP)*: Disruption of the mitochondrial outer membrane, leading to the release of cytochrome c and other pro-apoptotic factors. - *Caspase Cascade*: Activation of initiator caspases (e.g., caspase-8, caspase-9) and executioner caspases (e.g., caspase-3, caspase-6, caspase-7), resulting in a cascade of proteolytic events. - *Cell Shrinkage*: Reduction in cell volume due to the loss of water and ions. - *Membrane Blebbing*: Formation of membrane-bound blebs, which can contain fragmented DNA and other cellular components. These biochemical features contribute to the characteristic morphological changes associated with apoptosis, including cell shrinkage, nuclear condensation, and membrane blebbing.

Answer 32

Apoptosis is induced by a cascade of molecular events that may be initiated in distinct ways and culminate in the activation of caspases •Divided into an initiation phase, during which caspases become catalytically active, and an execution phase, during which these enzymes act to cause cell death.

Answer 33

Initiation of apoptosis •Occurs principally by signals from two distinct but convergent pathways — the extrinsic, or death receptor-initiated, pathway and the intrinsic, or mitochondrial, pathway •Both pathways converge to activate caspases. •Pathways interconnected at numerous steps

Answer 34

The extrinsic (Death Receptor-Initiated) Pathway •Initiated by engagement of cell surface death receptors on a variety of cells •Death receptors are members of the tumor necrosis factor receptor family that contain a cytoplasmic domain involved in protein-protein interactions that is called the death domain because it is essential for delivering apoptotic signals Dbdbdn •Best-known death receptors are the type 1 TNF receptor (TNFR1) and a related protein called Fas (CD95) B The extrinsic pathway of apoptosis, also known as the death receptor-initiated pathway, is an important mechanism by which cells can initiate programmed cell death in response to external signals. Here’s a breakdown of its key components and processes: ### Key Components of the Extrinsic Pathway: 1. **Death Receptors**: - Death receptors are cell surface receptors that belong to the tumor necrosis factor (TNF) receptor superfamily. - Examples include TNF receptor 1 (TNFR1) and Fas receptor (CD95/APO-1). - These receptors contain an extracellular domain for ligand binding and an intracellular death domain. 2. **Ligand Binding**: - The pathway is initiated when specific ligands bind to their corresponding death receptors. Examples of ligands include TNF-alpha (binds to TNFR1) and Fas ligand (FasL, binds to Fas). 3. **Death Domain Interaction**: - Upon ligand binding, the death receptors undergo a conformational change that allows them to recruit and bind cytoplasmic adaptor proteins. - The intracellular domain of death receptors contains a death domain, which interacts with a similar death domain found in adaptor proteins such as FADD (Fas-associated death domain protein). 4. **Formation of Death-Inducing Signaling Complex (DISC)**: - The recruitment of FADD and other adaptor proteins to the death domain of activated death receptors forms the DISC. - Within the DISC, procaspase-8 (an inactive precursor of caspase-8) is recruited and activated through proximity-induced autoproteolysis. 5. **Activation of Caspases**: - Caspase-8 activation within the DISC leads to the activation of downstream effector caspases, such as caspase-3 and caspase-7. - Activated effector caspases then initiate the proteolytic cleavage of various cellular substrates, resulting in the characteristic biochemical and morphological changes associated with apoptosis. ### Function and Regulation: - **Cellular Response**: The extrinsic pathway of apoptosis is involved in regulating immune responses, eliminating infected or damaged cells, and maintaining tissue homeostasis. - **Regulation**: The activation of death receptors and subsequent apoptosis can be regulated by various factors, including inhibitors of apoptosis proteins (IAPs) and cellular FLICE-like inhibitory protein (cFLIP), which can modulate caspase activation and cell fate decisions. In summary, the extrinsic pathway of apoptosis is initiated by the binding of ligands to death receptors on the cell surface, leading to the formation of the DISC and activation of caspases that ultimately induce programmed cell death. This pathway is crucial for immune surveillance and maintaining tissue integrity by eliminating unwanted or damaged cells. The **extrinsic (death receptor-initiated) pathway** is a way for cells to safely break down when they are no longer needed or if they are damaged. Here’s how it works with some key terms simplified: 1. **Death Receptors**: On the surface of cells, there are special parts called **death receptors**. These receptors are like buttons that can be pressed to tell the cell it’s time to die in a controlled way. These death receptors belong to a family called the **tumor necrosis factor (TNF) receptor family**. 2. **The Death Signal**: Sometimes, the body sends a **death signal** to cells that are damaged, infected, or no longer needed. This signal binds to the death receptors on the cell’s surface, like pressing the button to say, “You need to start shutting down.” 3. **The Death Domain**: When the death signal binds to the death receptor, it activates a special part inside the cell called the **death domain**. This part is crucial because it helps the cell receive the message to start breaking down. 4. **Formation of the DISC**: After the death domain is activated, it helps form a complex inside the cell called the **Death-Inducing Signaling Complex (DISC)**. Think of the DISC as a team of workers that gather together to start the cell’s breakdown process. The DISC brings together important proteins that are needed to start **apoptosis** (the programmed and controlled cell death process). 5. **Starting Apoptosis**: The DISC activates special proteins called **caspases** inside the cell. Caspases are like tiny scissors that start cutting up parts of the cell in a very controlled way. This controlled cutting up is what begins **apoptosis**. During apoptosis, the cell shrinks, breaks apart into small pieces called **apoptotic bodies**, and is safely cleaned up by other cells. So, the **extrinsic pathway** uses **death receptors** to receive a death signal, activates the **death domain**, forms the **DISC** to gather the right proteins, and then activates **caspases** to safely dismantle the cell without causing harm to the surrounding area. The **extrinsic pathway** is like a special "goodbye signal" for a cell to know when it's time to stop working and break down safely, kind of like when a leaf falls from a tree in autumn. Here's how it works: 1. **Death Receptors as Doorbells**: Imagine that each cell has doorbells on its surface called **death receptors**. These doorbells are special because they only ring when a certain "goodbye" signal comes. 2. **Pressing the Doorbell**: When a cell is not needed anymore, or it might cause problems (like getting sick), a "goodbye" signal comes along and presses these doorbells on the cell's surface. 3. **The Death Domain**: Behind each doorbell is a button called a **death domain**. This button helps the cell understand, "Oh, it's time for me to safely break down." 4. **The Safe Goodbye Process**: Once the death domain gets the message, it starts a process inside the cell that breaks it down into tiny, safe pieces. This way, the cell says goodbye without causing any harm around it. This whole process is like the cell’s way of cleaning up nicely without making a mess—much like how you put away your toys when you’re done playing, so everything stays neat and tidy.

Answer 35

The Intrinsic (Mitochondrial) Pathway •Result of increased mitochondrial permeability and release of pro-apoptotic molecules into the cytoplasm, without a role for death receptors •The essence of this intrinsic pathway is a balance between pro-apoptotic and protective molecules that regulate mitochondrial permeability and the release of death inducers that are normally sequestered within the mitochondria. Intrinsic pathway •Growth factors and other survival signals stimulate the production of anti-apoptotic members of the Bcl-2 family of proteins •The two main anti-apoptotic ones are Bcl-2 and Bcl-x which reside in mitochondrial membranes and the cytoplasm •When cells are deprived of survival signals or subjected to stress, Bcl-2 and/or Bcl-x are lost from the mitochondrial membrane and are replaced by pro-apoptotic members of the family, such as Bak, Bax, and Bim. Intrinsic pathway •When Bcl-2/Bcl-x levels decrease, the permeability of the mitochondrial membrane increases, and several that can activate the caspase cascade leak out •One of these proteins is cytochrome c, well known for its role in mitochondrial respiration. In the cytosol, cytochrome c binds to a protein called Apaf-1 (apoptosis activating factor-1, homologous to Ced-4 in C. elegans), and the complex activates caspase-9

Answer 36

The Execution Phase •Mediated by a proteolytic cascade ( caspases) •Executioner caspases act on many cellular components. •They cleave cytoskeletal and nuclear matrix proteins and thus disrupt the cytoskeleton and lead to breakdown of the nucleus •In the nucleus, the targets of caspase activation include proteins involved in transcription, DNA replication, and DNA repair.

Answer 37

The Execution Phase •Mediated by a proteolytic cascade ( caspases) •Executioner caspases act on many cellular components. •They cleave cytoskeletal and nuclear matrix proteins and thus disrupt the cytoskeleton and lead to breakdown of the nucleus •In the nucleus, the targets of caspase activation include proteins involved in transcription, DNA replication, and DNA repair.

Answer 38

Removal of dead cells •At early stages of apoptosis, dying cells secrete soluble factors that recruit phagocytes. •This facilitates prompt clearance of apoptotic cells before they undergo secondary necrosis and release their cellular contents **Soluble factors** that recruit phagocytes during apoptosis include: 1. **Chemokines**: - **Fractalkine (CX3CL1)** and **Monocyte Chemoattractant Protein-1 (MCP-1)** help attract phagocytes like macrophages to apoptotic cells. 2. **Eicosanoids**: - **Prostaglandins** modulate inflammation and assist in recruiting phagocytes. 3. **Phosphatidylserine**: - Although not soluble, it is exposed on apoptotic cells and recognized by phagocytes with the help of soluble factors like **Milk Fat Globule-EGF Factor 8 (MFG-E8)**. 4. **Collectins**: - **Mannose-binding lectin (MBL)** binds to apoptotic cells, facilitating their recognition and removal by phagocytes. These factors ensure apoptotic cells are efficiently cleared by phagocytes, preventing inflammation and tissue damage.

Answer 39

Lysosomal catabolism; Primary lysosomes are membrane-bound intracellular organelles that contain a variety of hydrolytic enzymes, including acid phosphatase, glucuronidase, sulfatase, ribonuclease, and collagenase •These enzymes are synthesized in the rough endoplasmic reticulum and then packaged into vesicles in the Golgi apparatus Primary lysosomes fuse with membrane-bound vacuoles that contain material to be digested, forming secondary lysosomes or phagolysosomes •Lysosomes with undigested debris may persist within cell as residual bodies or may be extruded. Lipofuscin pigment granules represent undigested material derived from intracellular lipid peroxidation

Answer 40

Heterophagy and autophagy are two distinct processes involving the degradation and recycling of cellular components, but they differ in their mechanisms and targets: 1. **Autophagy**: - **Definition**: Autophagy is a cellular process that involves the degradation and recycling of unnecessary or dysfunctional cellular components through the lysosomal machinery. - **Mechanism**: It begins with the formation of a double-membrane structure called an autophagosome around the targeted cellular material, which can include damaged organelles, misfolded proteins, or other cytoplasmic components. - **Function**: Autophagy plays a critical role in maintaining cellular homeostasis by removing cellular debris and promoting cell survival during stress conditions such as nutrient deprivation or infection. - **Types**: There are several types of autophagy, including macroautophagy (the most studied form), microautophagy, and chaperone-mediated autophagy. 2. **Heterophagy**: - **Definition**: Heterophagy refers to the process of engulfing and digesting extracellular material, such as microorganisms or particles, by a cell. - **Mechanism**: It involves the formation of phagosomes, which are single-membrane vesicles that engulf the extracellular material. - **Function**: Heterophagy is primarily involved in immune responses, where cells like macrophages and neutrophils engulf and digest pathogens through phagocytosis. - **Example**: Macrophages engulf bacteria during infection, forming phagosomes that fuse with lysosomes to form phagolysosomes, where the bacteria are degraded by lysosomal enzymes. ### Key Differences: - **Origin of Material**: Autophagy targets intracellular components, while heterophagy targets extracellular material. - **Mechanism**: Autophagy involves the formation of autophagosomes and fusion with lysosomes, whereas heterophagy involves the formation of phagosomes. - **Cellular Function**: Autophagy maintains cellular homeostasis and responds to stress, while heterophagy is primarily involved in immune defense and clearing external threats. In summary, autophagy and heterophagy are both essential processes for cellular health and immune function, each serving distinct roles in cellular maintenance and defense mechanisms.

Answer 41

Intracellular accumulations May be; 1.A normal cellular constituent accumulated in excess, such as water, lipids, proteins, and carbohydrates; 2.An abnormal substance, either exogenous, such as a mineral or products of infectious agents, or endogenous, such as a product of abnormal synthesis or metabolism 3.A pigment N Substances may accumulate either transiently or permanently •The substance may be located in either the cytoplasm (frequently within phagolysosomes) or the nucleus. •In some instances, the cell may be producing the abnormal substance, and in others it may be merely storing products of pathologic processes occurring elsewhere in the body.

Answer 42

Intracellular accumulations Attributable to three types of abnormalities; 1.A normal endogenous substance is produced at a normal or increased rate, but the rate of metabolism is inadequate to remove it. 2.A normal or abnormal endogenous substance accumulates because of genetic or acquired defects in the metabolism, packaging, transport, or secretion of these substances 3.An abnormal exogenous substance is deposited and accumulates

Answer 43

All major classes of lipids can accumulate in cells: triglycerides, cholesterol/cholesterol esters, and phospholipids •The terms steatosis and fatty change describe abnormal accumulations of triglycerides within parenchymal cells •The cause of steatosis include toxins, protein malnutrition, diabetes mellitus, obesity, and anoxia Fatty Change (Steatosis): Refers to abnormal accumulation of lipid within cytoplasm of parenchymal cells Conditions when there is so much excess fat or damage to the liver The result: -Of a disturbance of ribosomal function (detachment of ribosomes from RER) -Proteins are required for export of lipids from the cells e.g. CCl4 toxicity)

Answer 44

Steatosis and fatty change both refer to the abnormal accumulation of lipids within cells, most commonly in the liver. Here are some key points: ### Steatosis - **Definition**: Steatosis is the abnormal retention of lipids within a cell, which can disrupt cellular function. - **Common Causes**: Alcohol abuse, obesity, diabetes, and metabolic syndrome are common causes. It can also result from certain medications, toxins, and genetic conditions. - **Pathophysiology**: Excessive fatty acids enter the liver, leading to their conversion into triglycerides, which accumulate within hepatocytes (liver cells). - **Consequences**: While initially reversible, prolonged steatosis can progress to more severe liver conditions, such as non-alcoholic steatohepatitis (NASH), fibrosis, and eventually cirrhosis. ### Fatty Change - **Definition**: Fatty change is a term often used interchangeably with steatosis. It specifically refers to the appearance of fat droplets within the cytoplasm of cells. - **Histological Appearance**: On microscopic examination, fatty change is characterized by clear vacuoles within the cell cytoplasm. In the liver, this typically involves hepatocytes. - **Reversibility**: Fatty change can be reversible if the underlying cause is addressed. However, chronic fatty change can lead to permanent cellular damage and scarring. ### Diagnosis and Management - **Diagnosis**: Diagnosis typically involves imaging studies (e.g., ultrasound, CT scan, MRI) and may be confirmed with a liver biopsy showing fatty infiltration. - **Management**: Addressing the underlying cause is crucial. This may involve lifestyle changes (diet, exercise, weight loss), managing diabetes, discontinuing alcohol or offending drugs, and monitoring liver function. Understanding the mechanisms and implications of steatosis and fatty change is important for the prevention and management of liver disease.

Answer 45

Certainly! The uptake and secretion of lipids and their accumulation in tissues involve a complex interplay of various biochemical pathways and molecules. Here’s a detailed explanation of how these components are interconnected: ### 1. **Dietary Intake and Digestion** - **Dietary Fats**: Triglycerides and cholesterol esters are ingested and broken down by pancreatic lipases in the intestine. - **Absorption**: Fatty acids, monoglycerides, and cholesterol are absorbed by enterocytes (intestinal cells). ### 2. **Formation of Chylomicrons** - **Triglyceride Reassembly**: Within enterocytes, absorbed fatty acids and monoglycerides are re-esterified to form triglycerides. - **Chylomicron Assembly**: These triglycerides, along with cholesterol and apoproteins (such as apoB-48), form chylomicrons, which enter the lymphatic system and then the bloodstream. ### 3. **Transport in the Blood** - **Chylomicrons**: Transport dietary triglycerides to peripheral tissues. - **Lipoprotein Lipase (LPL)**: An enzyme on the surface of endothelial cells hydrolyzes triglycerides in chylomicrons into free fatty acids and glycerol. - **Free Fatty Acids (FFAs)**: Taken up by tissues (muscle for immediate energy or adipose for storage). ### 4. **Storage in Adipose Tissue** - **Triglyceride Formation**: In adipocytes, FFAs are re-esterified with glycerol (derived from glucose metabolism via alpha-glycerol phosphate) to form triglycerides. - **Lipid Droplets**: Stored as lipid droplets within adipose cells. ### 5. **Mobilization of Stored Lipids** - **Hormone-Sensitive Lipase (HSL)**: Activated during fasting or exercise, HSL breaks down stored triglycerides into FFAs and glycerol. - **FFA Release**: FFAs are released into the bloodstream, bound to albumin, for transport to energy-demanding tissues. ### 6. **Liver Processing** - **FFA Uptake**: The liver takes up FFAs from the blood. - **Triglyceride Synthesis**: FFAs are converted back into triglycerides and packed into Very Low-Density Lipoproteins (VLDL). - **VLDL Secretion**: VLDL transports endogenously synthesized triglycerides and cholesterol esters to peripheral tissues. ### 7. **Conversion to Ketone Bodies (During Starvation)** - **Beta-Oxidation**: In the liver, FFAs undergo beta-oxidation to produce acetyl-CoA. - **Ketogenesis**: Excess acetyl-CoA is converted into ketone bodies (acetoacetate, beta-hydroxybutyrate) which are released into the bloodstream as an alternative energy source. ### 8. **Cholesterol Metabolism** - **Cholesterol Esters**: Formed by the esterification of cholesterol with fatty acids. - **Lipoprotein Role**: Cholesterol esters are transported by lipoproteins (e.g., LDL and HDL) to and from tissues. ### 9. **Lipid Accumulation and Steatosis** - **Excess FFAs**: Chronic excess of FFAs can lead to their accumulation in the liver as triglycerides, causing hepatic steatosis (fatty liver). - **Pathological Consequences**: Lipid accumulation can lead to cell dysfunction, inflammation, and fibrosis, potentially progressing to conditions like non-alcoholic fatty liver disease (NAFLD) and cirrhosis. ### Summary - **Dietary lipids** are absorbed and transported by chylomicrons. - **Lipoprotein lipase** facilitates the uptake of fatty acids into tissues. - **Fatty acids** are stored as triglycerides in adipose tissue and mobilized during energy demand. - The **liver** plays a central role in processing and distributing lipids via VLDL and producing ketone bodies during fasting. - **Cholesterol esters** are transported by lipoproteins to maintain cellular function. - **Lipid accumulation** can result from metabolic imbalances, leading to conditions like steatosis. Understanding these interconnected pathways is crucial for managing metabolic health and preventing lipid-related diseases.

Answer 46

Cholesterol esters are formed when cholesterol is esterified with fatty acids, making them more hydrophobic and suitable for transport and storage in lipoproteins. Cholesterol and cholesterol esters Accumulation of these are seen in; •Atherosclerosis •Xanthomas •Inflammation and necrosis: During inflammation and cell injury, cellular membranes break down, releasing free cholesterol and cholesterol esters. • Foam Cells: Macrophages ingest these lipids and transform into foam cells, contributing to the inflammatory response and tissue necrosis. •Cholesterolosis.: Cholesterolosis refers to the accumulation of cholesterol-laden macrophages (foam cells) in the gallbladder. • Appearance: The gallbladder mucosa exhibits yellowish cholesterol deposits, often referred to as “strawberry gallbladder” due to its appearance. •Niemann-Pick disease, type C: Niemann-Pick disease, type C, is a lysosomal storage disorder caused by mutations in the NPC1 or NPC2 genes, which are involved in cholesterol trafficking within cells. • Pathophysiology: The defective transport leads to the accumulation of unesterified cholesterol and other lipids in lysosomes, affecting various organs, particularly the liver, spleen, and brain.

Answer 47

Proteins •Intracellular accumulations of proteins can occur due to various reasons, including increased synthesis, defective degradation, or impaired transport. Intracellular accumulations of proteins usually appear as rounded, eosinophilic droplets, vacuoles, or aggregates in the cytoplasm •Reabsorption droplets in proximal renal tubules are seen in renal diseases associated with proteinuria •Defects in protein folding may underlie some of these depositions: Defective Protein Folding • Mechanism: Proteins must fold into specific three-dimensional structures to function properly. Defects in protein folding can lead to the accumulation of misfolded proteins. • Pathology: Misfolded proteins can aggregate and form inclusions within cells. Diseases associated with defective protein folding include neurodegenerative disorders like Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS). •synthesis of excessive amounts of normal secretory protein ( Russell bodies): Excessive Synthesis of Normal Secretory Proteins (Russell Bodies) • Context: Seen in plasma cells producing large amounts of immunoglobulins. • Mechanism: When plasma cells synthesize excessive amounts of immunoglobulins, the proteins accumulate in the rough endoplasmic reticulum (ER). These accumulations appear as large, eosinophilic inclusions called Russell bodies. • Pathology: While Russell bodies are generally not harmful, they indicate an overactive immune response and can be seen in conditions such as chronic inflammation or multiple myeloma.

Answer 48

PIGMENTS •Pigments are colored substances, which are normal or abnormal constituents of cells •They are exogenous or endogenous Exogenous pigment; includes carbon or coal dust in anthracosis and tattoos Endogenous pigment; includes melanin, lipofuscin, hemosiderin and bilirubin Carbon dust in **anthracosis** is considered an **exogenous pigment** because it originates from outside the body (the environment) and is introduced into the body through **inhalation**. - **Anthracosis** occurs when **carbon particles** (commonly from coal dust, pollution, or cigarette smoke) are inhaled and deposited in the lungs and lymph nodes. - These carbon particles are **not produced by the body**, which is why they are categorized as **exogenous pigments**. - The body cannot metabolize or break down these particles, so they accumulate, leading to discoloration of the affected tissues, such as in the lungs. Similarly, **tattoos** are also classified as containing exogenous pigments because the ink used in tattoos is introduced into the skin from an external source.

Answer 49

Pathologic calcification •Pathologic calcification is the abnormal tissue deposition of calcium salts, together with smaller amounts of iron, magnesium, and other mineral salts. Two types; 1.Dystrophic calcification 2.Metastatic calcification

Answer 50

Dystrophic calcification •Deposition occurs locally in dying tissues, it occurs despite normal serum levels of calcium and in the absence of derangements in calcium metabolism •It is encountered in areas of necrosis, whether they are of coagulative, caseous, or liquefactive type, and in foci of enzymatic necrosis of fat. •Calcification is almost inevitable in the atheromas of advanced atherosclerosis Dystrophic Calcification • Context: Occurs in necrotic or damaged tissues despite normal serum calcium levels. • Examples: Calcification in atherosclerotic plaques, damaged heart valves, and areas of caseous necrosis in tuberculosis. Dystophic calcification: -Calcium salts are deposited in severely injured or dead tissues although Ca++ and PO4-- levels are within normal limits. -Denatured proteins may preferentially bind PO4-- which in turn react with Ca++ to form a precipitate of calcium phosphate

Answer 51

Morphology •Histologically calcium salts have a basophilic, amorphous granular, sometimes clumped, appearance. •Heterotopic bone may be form with time •Progressive acquisition of outer layers may create lamellated configurations, called psammoma bodies Pathological calcification can be identified histologically by its characteristic features: • Basophilic, amorphous granular appearance: Calcium deposits are blue-staining(basophilic), amorphous, and granular under H&E (hematoxylinand eosin) staining. • Heterotopic bone formation: Chronic calcification can lead to the formation of bone tissue in abnormal locations. Over time, chronic calcification can induce a local osteogenic response, leading to the formation of bone in soft tissues. • Histology: This newly formed bone resembles normal bone histologically, • Psammoma bodies: These are laminated, calcified structures commonly seen in certain tumors and chronic conditions. These structures are formed by the progressive layering of calcium and other minerals around a central nidus, often seen in slow-growing tumors or chronic inflammatory conditions. • Common Locations: Psammoma bodies are commonly found in certain types of cancers such as: • Papillary Thyroid Carcinoma • Serous Papillary Cystadenocarcinoma of the Ovary • Meningiomas • Mesotheliomas

Answer 52

Metastatic Calcification • Context: Occurs in normal tissues due to hypercalcemia (elevated serum calcium levels). • Causes: Hyperparathyroidism, chronic renal failure, vitamin D intoxication, and certain cancers. • Common Sites: Lungs, kidneys, stomach, and blood vessels. Occurs widely throughout the body but principally affects the interstitial tissues of the gastric mucosa, kidneys, lungs, systemic arteries, and pulmonary veins •These tissues lose acid and therefore have an internal alkaline compartment that predisposes them to metastatic calcification Metastatic calcification •Occurs in normal tissues whenever there is hypercalcemia •Four principal causes of hypercalcemia: 1.Increased secretion of parathyroid hormone (PTH) 2.Destruction of bone tissue, 3.Vitamin D-related disorders, 4.renal failure Metastatic calcification:Ca++ deposits occur in otherwise undamaged tissue due to raised circulating Ca++

Answer 53

Amorphous refers to a structure that lacks a defined, regular, or crystalline form. In the context of pathological calcification, “amorphous” describes the appearance of calcium deposits that do not have a distinct shape or organized pattern. These deposits appear as irregular, granular aggregates under the microscope. In histological sections stained with hematoxylin and eosin (H&E), amorphous calcium deposits stain blue (basophilic), making them distinguishable from other tissue components.look like grains instead of well formed crystals Dystrophic Calcification: Amorphous calcium deposits can be seen in areas of necrosis or tissue damage. These deposits often appear irregular and granular within the affected tissue. • Metastatic Calcification: In conditions of hypercalcemia, amorphous calcium deposits can form in normal tissues, such as the lungs, kidneys, and stomach. These deposits are not organized into a crystalline structure

Answer 54

Here’s how the pathogenesis typically unfolds: 1. Initiation (or Nucleation): This phase involves the initial formation of calcium phosphate crystals. It can occur either intracellularly (within cells) or extracellularly (outside cells). 2. Propagation: Once initiated, the crystals can grow and propagate, leading to further deposition of calcium phosphate minerals. This process can disrupt normal tissue architecture and function. 3. Final Common Pathway: Ultimately, the deposition results in the formation of crystalline calcium phosphate minerals, often in the form of apatite, which is a mineral form of calcium phosphate commonly found in bone. Pathological calcification can occur in various tissues and organs, such as blood vessels (arterial calcification), kidneys (nephrocalcinosis), joints (calcific tendinitis), Pathogenesis •Final common pathway is the formation of crystalline calcium phosphate mineral in the form of an apatite •Two major phases: initiation (or nucleation) and propagation occurring either intracellularly and extracellularly

Answer 55

The response of cells to some extent depends on: • the nature • the intensity of the stimulus, which varies from the extremely subtle to the extremely severe, and • its duration May also be conditioned or influenced by: • Extracellular and intracellular environment • Pattern and level of metabolic activity .Level of cell differentiation: The relatively undifferentiated neuronal cell layers of the developing infant brain are more resistant to hypoxic injury than the fully differentiated neurones in the adult • Genomic expression, determines the inherent adaptability of cells: E.g. xeroderma pigmentosa - lack of repair enzymes due to inexpression of specific gene G-6-PD deficiency - inability to protect against oxidant injury following exposure to certain chemicals. Sickle cell disease - structurally abnormal haemoglobin results in sickling of red cells and haemolysis in conditions of low oxygen tension

Answer 56

The response of cells to some extent depends on: • the nature • the intensity of the stimulus, which varies from the extremely subtle to the extremely severe, and • its duration May also be conditioned by: • Extracellular and intracellular environment • Pattern and level of metabolic activity

Answer 57

PHYSOLOGIC: occurs as part of morphogenesis during embryonic development, through early life to old age - termed involution • Branchial clefts, notochord, thyroglossal duct, Müllerian duct which atrophies in males cuz it gives rise to female reproductive organs (males), Wolffian duct atrophies in females cuz it gives rise to male reproductive organs (females): undergo atrophy in the embryo and foetus • Umbilical vessels, ductus arteriosus, fetal layer of adrenal cortex: in the neonate • Thymus in early adulthood Uterus and endometrium in females (due to loss of hormonal stimulation), testes in males, bone (osteoporosis), gums, mandible (especially in the edentulous), cerebrum and lymphoid tissue in late adulthood and old age. Physiological atrophy refers to the natural shrinkage or reduction in size of organs or tissues that occurs as part of the body's normal aging process or due to a decrease in hormonal stimulation. Here’s how it affects various organs: ### **1. Uterus and Endometrium in Females:** - **Cause:** Loss of hormonal stimulation, particularly estrogen, after menopause. - **Effect:** The uterus and the lining of the endometrium decrease in size and thickness, leading to a smaller, less active uterus. ### **2. Testes in Males:** - **Cause:** Decreased hormonal stimulation, specifically lower levels of testosterone, typically with aging. - **Effect:** The testes reduce in size and function, leading to a decrease in sperm production and sometimes a reduction in sexual function. ### **3. Bone (Osteoporosis):** - **Cause:** Age-related decline in bone density due to hormonal changes, particularly reduced levels of estrogen in women and testosterone in men. - **Effect:** Bones become less dense and more fragile, increasing the risk of fractures. ### **4. Gums:** - **Cause:** Natural aging process, often exacerbated by poor oral hygiene or gum disease. - **Effect:** The gums may recede, leading to exposure of the tooth roots, which can cause sensitivity and increase the risk of tooth loss. ### **5. Mandible (Especially in the Edentulous):** - **Cause:** Loss of teeth (edentulism) reduces the mechanical stimulation required to maintain bone mass. - **Effect:** The jawbone, particularly the mandible, undergoes atrophy, leading to bone loss and a change in facial structure. ### **6. Cerebrum:** - **Cause:** Age-related neuronal loss and decreased synaptic activity. - **Effect:** Brain tissue, particularly in the cerebral cortex, may shrink, which can contribute to cognitive decline and memory loss. ### **7. Lymphoid Tissue:** - **Cause:** Aging leads to a gradual involution of lymphoid tissues, including the thymus. - **Effect:** There is a reduction in immune function due to the atrophy of lymphoid tissues, which may lead to increased susceptibility to infections. These examples illustrate how physiological atrophy affects different parts of the body due to aging or changes in hormonal levels, often resulting in diminished function.

Answer 58

PHYSOLOGIC: occurs as part of morphogenesis during embryonic development, through early life to old age - termed involution • Branchial clefts, notochord, thyroglossal duct, Müllerian duct (males), Wolffian duct (females): undergo atrophy in the embryo and foetus • Umbilical vessels, ductus arteriosus, fetal layer of adrenal cortex: in the neonate • Thymus in early adulthood Uterus and endometrium in females (due to loss of hormonal stimulation), testes in males, bone (osteoporosis), gums, mandible (especially in the edentulous), cerebrum and lymphoid tissue in late adulthood and old age.

Answer 59

PATHOLOGIC A.Withdrawal of Trophic Stimulus: 1.reduced workload or disuse - Generally, reduced functional activity is associated with reduced catabolism which in turn has a negative feedback effect on anabolism and leads to decrease in size of cells. E.g. skeletal muscle following immobilisation of a fractured limb obstruction of pancreatic duct leads to cessation of secretion of digestive enzymes and apoptosis of the exocrine cells leads to reduction in size of the pancreas 2. denervation - due to destruction of lower motor neurons or their axons. E.g. skeletal muscle in polio, motor neurone disease- denervated muscle may lose half their mass. Initially at least, anabolic processes within the affected muscle proceed at a normal rate but is exceeded by catabolism due increased lysosome numbers and activity. 3.loss of hormonal stimulus - breast, uterus, testis; adrenal, thyroid and gonads in hypopituitarism; skin, hair follicles and sebaceous glands in hypothyroidism B.Decreased Nutrition: loss of/reduced blood supply, malnutrition and severe starvation C.Radiation Induced: ischaemic in part and chromosomal damage preventing mitosis in part D.Hormone Induced: testis by oestrogen, epidermis by steroids, adrenal by steroids E.Other Factors: pressure - may be due to effect on blood supply, but pressure on bone causes increased osteoclastic activity with bone resorption Cerebral atrophy in Alzheimer's disease Underlying these morphologic changes are biochemical changes, which alter the function of the cells involved

Answer 60

PATHOLOGIC A.Withdrawal of Trophic Stimulus: 1.reduced workload or disuse - Generally, reduced functional activity is associated with reduced catabolism which in turn has a negative feedback effect on anabolism and leads to decrease in size of cells. E.g. skeletal muscle following immobilisation of a fractured limb obstruction of pancreatic duct leads to cessation of secretion of digestive enzymes and apoptosis of the exocrine cells leads to reduction in size of the pancreas 2. denervation - due to destruction of lower motor neurons or their axons. E.g. skeletal muscle in polio, motor neurone disease- denervated muscle may lose half their mass. Initially at least, anabolic processes within the affected muscle proceed at a normal rate but is exceeded by catabolism due increased lysosome numbers and activity. 3.loss of hormonal stimulus - breast, uterus, testis; adrenal, thyroid and gonads in hypopituitarism; skin, hair follicles and sebaceous glands in hypothyroidism B.Decreased Nutrition: loss of/reduced blood supply, malnutrition and severe starvation C.Radiation Induced: ischaemic in part and chromosomal damage preventing mitosis in part D.Hormone Induced: testis by oestrogen, epidermis by steroids, adrenal by steroids E.Other Factors: pressure - may be due to effect on blood supply, but pressure on bone causes increased osteoclastic activity with bone resorption Cerebral atrophy in Alzheimer's disease Underlying these morphologic changes are biochemical changes, which alter the function of the cells involved

Answer 61

Atrophy of organs and tissues is achieved by: -Reduction in sizes of the constituent cells through reduction in number of intracellular organells -Reduction in number of cells In striated muscle (skeletal and cardiac) atrophy is achieved by reduction in size of cells only as cells once lost cannot be replaced because striated muscle cannot divide to reproduce itself.

Answer 62

Atrophy of organs and tissues is achieved by: -Reduction in sizes of the constituent cells through reduction in number of intracellular organells -Reduction in number of cells In striated muscle (skeletal and cardiac) atrophy is achieved by reduction in size of cells only as cells once lost cannot be replaced because striated muscle cannot divide to reproduce itself.

Answer 63

Epithelial Metaplasia 1.Squamous metaplasia: commonest -bronchus:smokers, bronchiectasis, chronic bronchitis -nasal sinuses - chronic sinusitis -endometrium - post menopausal -prostatic ducts with advanced age -gall bladder in chronic cholelithiasis -bladder - calculi, schistosomiasis -salivary gland ducts - in sialolithiasis -transitional and columnar nasal epithelium - in vitamin A deficiency -pleura and peritoneum - chronic inflammation 2. Glandular Metaplasia -intestinal metaplasia in stomach in chronic gastritis -pyloric metaplasia in gall bladder in cholecystitis -columnar cell metaplasia in pleura and peritoneum 3.Connective tissue metaplasia 4.Osseous metaplasia: old scars, TB foci in lung, terminal ileum and mesenteric nodes, naevi in skin, muscle, thrombi 5.Chondroid metaplasia: in same sites as osseous metaplasia 6.Myeloid metaplasia :(extramedullary haemo-poiesis) spleen, liver, lymph nodes

Answer 64

Epithelial Metaplasia 1.Squamous metaplasia: commonest -bronchus:smokers, bronchiectasis, chronic bronchitis -nasal sinuses - chronic sinusitis -endometrium - post menopausal -prostatic ducts with advanced age -gall bladder in chronic cholelithiasis -bladder - calculi, schistosomiasis -salivary gland ducts - in sialolithiasis -transitional and columnar nasal epithelium - in vitamin A deficiency -pleura and peritoneum - chronic inflammation 2. Glandular Metaplasia -intestinal metaplasia in stomach in chronic gastritis -pyloric metaplasia in gall bladder in cholecystitis -columnar cell metaplasia in pleura and peritoneum 3.Connective tissue metaplasia 4.Osseous metaplasia: old scars, TB foci in lung, terminal ileum and mesenteric nodes, naevi in skin, muscle, thrombi 5.Chondroid metaplasia: in same sites as osseous metaplasia 6.Myeloid metaplasia :(extramedullary haemo-poiesis) spleen, liver, lymph nodes

Answer 65

Results from sub-lethal injury to the DNA of a cell Increased rate of cell division associated with lack of maturation or loss of differentiation with loss of specialised normal cellular features. Most frequently seen in epithelia. In a dysplastic epithelium there is also loss of normal architectural relationships between cells (loss of polarity) Cells showing dysplasia have: large nuclei compared to amount of cytoplasm normally present (increased nuclear-cytoplasmic ratio) thickened and irregular nuclear membrane and nuclei are more variable in shape and size than is normal (pleomorphic). Dysplasia often arises in metaplastic tissues Likely that the stimulus/stimuli causing the metaplasia also cause the changes in dysplasia.

Answer 66

Results from sub-lethal injury to the DNA of a cell Increased rate of cell division associated with lack of maturation or loss of differentiation with loss of specialised normal cellular features. Most frequently seen in epithelia. In a dysplastic epithelium there is also loss of normal architectural relationships between cells (loss of polarity) Cells showing dysplasia have: large nuclei compared to amount of cytoplasm normally present (increased nuclear-cytoplasmic ratio) thickened and irregular nuclear membrane and nuclei are more variable in shape and size than is normal (pleomorphic). Dysplasia often arises in metaplastic tissues Likely that the stimulus/stimuli causing the metaplasia also cause the changes in dysplasia.

Answer 67

HEAT SHOCK PROTEINS A universal cell defence mechanism H.S.P.s allows survival under conditions that would lead to cell death H.S.P.s bind to damaged cell proteins, structural or enzymatic, mark them for destruction and so are also called “molecular chaperones” If H.S.P.s cannot limit cell damage, the cells cease to produce structural proteins and begin to lose ability to generate the energy required to preserve electrolyte gradients and sustain other membrane functions

Answer 68

1.Hydropic change 2.Hyaline deposition 3.Mucin deposition 4.Fatty change (Steatosis) 5.Calcification 6.Protein Inclusions-ABNORMAL INCLUSIONS Cells and tissues may respond to sub-lethal injury by accumulating substances in abnormal quantities Most commonly such accumulations consist of molecules that are normally present 7.Pigments 8.Hereditary enzyme defects Cellular swelling is the commonest form of

Answer 69

CELLULAR SWELLING: The commonest form of response to injury is cell swelling - Hydropic change or degeneration Preservation of electrolyte gradients is impaired Abnormal accumulation of fluid and swelling of the endoplasmic reticulum, the Golgi apparatus, and the mitochondria Thus, hydropic change is the first change resulting from disturbances of membrane integrity Affected organ or tissue is swollen and pale, with a tense capsule, but soft parenchymal consistency. In hydropic change: Mitochondria become dilated with disturbance of cristae Rough endoplasmic reticulum becomes dilated with the loss of surface ribosomes Loss of cytoplasmic free ribosomes Internal membrane systems are dilated

Answer 70

Protein Inclusions Accumulation of protein deposits is less common than fatty change Excess production or reduced output can cause formation of protein inclusions Examples: Immunoglobulin may accumulate in plasma cells, producing refractile eosinophilic hyaline droplets called Russel bodies Pigment Inclusions These include: bilirubin in the brain in kernicterus melanin in freckles and melasma (facial pigmentation commonly seen in pregnancy) haemosiderin (haemochromatosis and haemosiderosis) in liver and other organs ceroid and lipofuscin (brown atrophy) Hereditary Enzyme Defects: Glycogen storage diseases You're likely thinking of **Negri bodies** and **Nissl bodies**. Here's a brief explanation of each: ### 1. **Negri Bodies**: - **What They Are**: Negri bodies are eosinophilic, round or oval inclusions found in the cytoplasm of nerve cells, particularly in the brain. - **Associated With**: They are a hallmark of rabies infection and are typically found in the neurons of the hippocampus and cerebellum in individuals infected with the rabies virus. - **Significance**: The presence of Negri bodies in brain tissue is diagnostic of rabies and helps confirm the infection. ### 2. **Nissl Bodies**: - **What They Are**: Nissl bodies (or Nissl substance) are large granular structures composed of rough endoplasmic reticulum and ribosomes found in the cytoplasm of neurons. - **Function**: They are involved in protein synthesis, particularly for the production of neurotransmitters and other proteins essential for neuron function. - **Significance**: Nissl bodies are important in understanding the metabolic activity of neurons and are used as a marker to identify neurons in histological studies. These two structures are important in different contexts: Negri bodies are pathological and associated with rabies, while Nissl bodies are normal components of neurons involved in protein synthesis. Mnemonic: • “Negri in Rabies, Nissl in Nerves” • Negri Bodies: “Negri” sounds like “agri” (as in aggressive, rabid), helping you remember that Negri bodies are associated with rabies. • Nissl Bodies: “Nissl” sounds like “neural,” reminding you that Nissl bodies are found in neurons

Answer 71

Liquefactive or Colliquative Necrosis: Enzymatic digestion predominates There is focal degradation of tissue that rapidly undergoes softening and liquefaction Characteristic of: -brain tissue following ischaemic necrosis or massive cerebral trauma -focal bacterial infections with massive accumulation of polymorphs - abscess formation Gangrenous Necrosis Refers to coagulative necrosis with putrefaction When liquefactive changes are present it is called wet gangrene (eg. gangrenous appendicitis) Dry gangrene results from gradual arterial or small vessel occlusion and coagulative changes predominate. With time a line of demarcation appears between necrotic and viable tissue ( In diabetics)

Answer 72

OUTCOMES OF NECROSIS Depends on the: 1.tissue or organ involved 2.extent of necrosis 3.functional reserve of the tissue or organ and 4.capacity of surviving cells to proliferate and replace the lost cells (regeneration) 1.Resolution: Complete restoration to normal (Parenchymal cells) Factors to consider: Area affected must be small and tissue must have the ability to regeneration. Eg: Epithelia and hepatocytes 2.Organisation Resolution is uncommon and more commonly the necrotic tissue is removed and replaced by fibrous tissue The process you're describing pertains to the **organization** phase of tissue repair, particularly in the context of necrosis and inflammation. ### Key Points about Organization: 1. **Necrotic Tissue Removal**: - After tissue necrosis, the dead cells and debris are typically removed by phagocytes, such as macrophages. This is part of the inflammatory response where the body works to clear out the damaged tissue. 2. **Replacement by Fibrous Tissue**: - Once the necrotic tissue has been removed, the area is often filled with **fibrous tissue** (scar tissue). This process is known as **organization**. The fibrous tissue is formed by fibroblasts, which produce collagen and extracellular matrix components. - **Scar Formation**: The replacement of necrotic tissue with fibrous tissue helps to restore structural integrity to the affected area, though it does not fully restore the original function of the tissue. 3. **Resolution vs. Organization**: - **Resolution** is the ideal outcome where inflammation subsides, and the tissue returns to normal without significant scarring. However, in many cases of significant necrosis or injury, full resolution is uncommon. Instead, organization with the formation of scar tissue is more common. ### Clinical Examples: - **Chronic Inflammation**: In chronic inflammation, such as in chronic ulcers or tuberculosis, organization with scar formation is often seen as part of the healing process. - **Myocardial Infarction**: After a heart attack, necrotic heart muscle tissue is replaced by fibrous tissue as part of the healing process. In summary, organization is the process where necrotic tissue is removed and replaced with fibrous tissue, leading to scar formation. This process is common in situations where resolution of the inflammation and return to normal tissue structure are not achievable.

Answer 73

OUTCOMES OF NECROSIS Depends on the: 1.tissue or organ involved 2.extent of necrosis 3.functional reserve of the tissue or organ and 4.capacity of surviving cells to proliferate and replace the lost cells (regeneration) 1.Resolution: Complete restoration to normal (Parenchymal cells) Factors to consider: Area affected must be small and tissue must have the ability to regeneration. Eg: Epithelia and hepatocytes 2.Organisation Resolution is uncommon and more commonly the necrotic tissue is removed and replaced by fibrous tissue