FDSC LC 2 Cell Injury and Death

The major types of causes of cell injury include:

1. Lack of oxygen (hypoxia)
2. Physical agents and trauma
3. Chemical agents and drugs
4. Infectious agents
5. Immunologic reactions
6. Genetic defects
7. Nutritional imbalances

The cell membrane itself is crucial for maintaining integrity, and its damage can lead to cell injury.

The cytoskeleton provides structural support, helps in cell shape maintenance, and is involved in intracellular transport.

Damage to the genetic apparatus can lead to impaired cell function, loss of control over cell division, and potential cell death.

Cell injury can lead to a decrease in protein synthesis, affecting the cell's ability to produce essential proteins for its function and survival.

The three main types of cellular damage are:

1. Membrane Damage
2. Protein/Cytoskeletal Damage
3. DNA Damage

Mitochondrial damage leads to:

1. Decrease in ATP production, resulting in multiple downstream effects.
2. Increase in ROS (Reactive Oxygen Species), causing damage to lipids, proteins, and DNA.

The entry of Ca2+ leads to:

1. Increased mitochondrial permeability, which can disrupt mitochondrial function.
2. Activation of multiple cellular enzymes, which can further contribute to cellular damage.

Membrane damage affects:

1. Plasma membrane: leads to loss of cellular components.
2. Lysosomal membrane: results in enzymatic digestion of cellular components.

Protein misfolding and DNA damage result in the activation of pro-apoptotic proteins, which can trigger the process of apoptosis, leading to cell death.

1. Influx of calcium into the cell and loss of calcium homeostasis
2. Mitochondrial damage
3. Depletion of ATP
4. Accumulation of oxygen-derived free radicals (oxidative stress)
5. Defects in membrane permeability

Increased intracellular Ca2+ activates several cellular enzymes, including:

1. Phospholipase - leads to a decrease in phospholipids.
2. Protease - causes disruption of membrane and cytoskeletal proteins.
3. Endonuclease - contributes to nuclear damage.
4. ATPase - results in decreased ATP levels.

These enzyme activations lead to membrane damage, nuclear damage, and overall cellular dysfunction.

The primary causes of mitochondrial injury include:

1. Increase of Ca2+ in cytosol
2. Oxidative stress
3. Breakdown of phospholipids through:
   • Phospholipase A₂ pathway
   • Sphingomyelin pathway

These processes can lead to the production of lipid breakdown products, such as free fatty acids and ceramide, which may further damage mitochondria.

The electron transport chain facilitates the transfer of electrons from NADH to oxygen, pumping protons (H+) from the mitochondrial matrix to the intermembrane space, creating an electrochemical gradient that drives ATP synthesis via ATP synthase.

ATP synthase uses the energy stored in the electrochemical gradient of protons (H+) across the inner mitochondrial membrane to synthesize ATP from ADP and inorganic phosphate (Pi).

The main components involved in the electron transport chain are:

1. Complex I (NADH dehydrogenase)
2. Coenzyme Q (ubiquinone)
3. Complex III (cytochrome bc1 complex)
4. Cytochrome c
5. Complex IV (cytochrome c oxidase)
6. Oxygen (final electron acceptor)

The citric acid cycle, located in the mitochondrial matrix, provides electrons in the form of NADH and FADH2 to the electron transport chain, which are essential for driving oxidative phosphorylation and ATP production.

The main factors that can lead to mitochondrial damage or dysfunction include:

1. O2 supply - Insufficient oxygen can impair mitochondrial function.
2. Toxins - Various toxins can disrupt mitochondrial processes.
3. Radiation - Exposure to radiation can cause damage to mitochondrial structures.

Mitochondrial damage can lead to two primary cellular outcomes:

• Necrosis: Resulting from multiple cellular abnormalities, including decreased ATP generation and increased production of reactive oxygen species (ROS).
• Apoptosis: Triggered by increased pro-apoptotic proteins and decreased anti-apoptotic proteins, leading to leakage of mitochondrial proteins.

Pro-apoptotic and anti-apoptotic proteins play a crucial role in determining cell fate during injury:

• Pro-apoptotic proteins: Their increase promotes apoptosis by facilitating mitochondrial dysfunction and protein leakage.
• Anti-apoptotic proteins: Their decrease reduces the cell's ability to resist apoptosis, further contributing to cell death.

ATP depletion is frequently caused by chemical injury and hypoxia.

Lack of oxygen prevents oxidative phosphorylation from proceeding, leading to a decrease in ATP levels in the cell.

Ischemia leads to decreased oxidative phosphorylation, resulting in reduced ATP production. This reduction affects the Na+ pump, causing an influx of Ca2+, H2O, and Na+, and an efflux of K+, which contributes to ER swelling, cellular swelling, and other morphological changes such as loss of microvilli and blebs.

Ischemia causes detachment of ribosomes, which leads to a decrease in protein synthesis. This is a consequence of reduced ATP levels and the overall stress on the cell due to ischemic conditions.

During ischemia, there is an increase in anaerobic glycolysis due to insufficient oxygen. This process leads to the production of lactic acid, which subsequently affects the pH of the cell, contributing to cellular damage.

The morphological changes due to ischemia include ER swelling, cellular swelling, loss of microvilli, blebs, and clumping of nuclear chromatin. These changes are indicative of cellular injury and stress caused by ischemic conditions.

1. Cellular and Organelle Swelling: Due to the lack of energy for the Na+ K+ pump, the osmotic gradient is altered.

2. Increased Intracellular Ca++: The failure of the Ca++ pump leads to elevated intracellular calcium levels, activating enzymes that can cause membrane damage.

3. Decreased pH: Increased anaerobic glycolysis results in a drop in pH, contributing to cellular damage.

4. Chromatin Clumping: This indicates DNA damage due to energy depletion.

5. Decreased Protein Synthesis: Detached ribosomes lead to a reduction in the synthesis of housekeeping proteins.

Oxidative stress is the accumulation of damage caused by oxygen-derived free radicals. It occurs when the damage exceeds the cell's ability to prevent or repair it, leading to cellular injury.

Free radicals are highly reactive and can form bonds quickly and non-specifically, leading to alterations in the structure of:

1. Proteins
2. Nucleic acids
3. Lipids

These alterations can contribute to cell injury and dysfunction.

Normal metabolism results in the formation of oxygen-derived free radicals, which can accumulate and cause oxidative stress if not adequately managed by cellular mechanisms.

Excess oxygen therapy can lead to oxidative stress, resulting in damage to cellular components such as lipids, proteins, and DNA. This can trigger inflammatory responses and contribute to cell injury.

Polymorphonuclear leukocytes (PMNs) and macrophages play a crucial role in the inflammatory response during cell injury by releasing cytokines, chemokines, and reactive oxygen species, which can further exacerbate tissue damage.

Xanthine oxidase contributes to reperfusion injury by generating reactive oxygen species upon restoration of blood flow, leading to oxidative damage and inflammation in the affected tissues.

Mixed function oxidation involves cyclic redox reactions that can produce reactive metabolites, leading to chemical toxicity by damaging cellular structures and disrupting normal cellular functions.

Radiotherapy utilizes ionizing radiation to induce DNA damage in cancer cells, leading to cell death. However, it can also affect surrounding healthy tissues, causing collateral damage and inflammation.

Mutagens are agents that cause chemical carcinogenesis by inducing mutations in the DNA, which can lead to uncontrolled cell growth and cancer development.

Mitochondrial metabolism is linked to biological aging as it produces reactive oxygen species that can damage cellular components over time, contributing to the aging process and age-related diseases.

Lipid peroxidation involves the following steps:

1. Attack on Unsaturated Fatty Acids: Double bonds of unsaturated fatty acids in membranes are attacked by oxygen-derived free radicals.

2. Formation of Peroxides: This attack leads to the formation of peroxides.

3. Reactivity of Peroxides: The unstable peroxides react with membrane lipids, causing damage and generating more peroxides.

4. Self-Sustaining Damage: This process is self-sustaining, leading to extensive damage unless free radicals are neutralized by scavengers.

5. Role of Antioxidants: Antioxidants like Vitamin E, Vitamin C, Vitamin A, and β-carotene help capture free radicals and mitigate damage.

• Changes in function/structure: Oxidation of side chains alters the protein's function and structure.
• Cross-linking: Formation of disulfide bonds leads to cross-linking of proteins.
• Enzyme inactivation: Oxidation of certain enzymes can result in their inactivation.

Free radicals interact with thymine, causing single-stranded breaks in DNA.

Free radicals cause single-stranded breaks in DNA and mutations, which have been implicated in carcinogenesis.

Free radicals have been implicated as one cause of cellular aging due to their damaging effects on DNA.

Reactive oxygen species (ROS) have several pathologic effects on cellular components:

• Lipid peroxidation: ROS react with fatty acids, leading to oxidation and generation of lipid peroxidases, which disrupt plasma membranes and organelles.
• Protein modifications: Oxidation of proteins results in loss of enzymatic activity and abnormal folding.
• DNA damage: ROS can cause mutations and breaks in DNA, leading to potential cellular dysfunction or death.

Antioxidant mechanisms play a crucial role in the removal of free radicals:

1. Superoxide Dismutase (SOD): Located in mitochondria, it converts superoxide (O2) into hydrogen peroxide (H2O2).

2. Glutathione Peroxidase: Also found in mitochondria, it converts hydroxyl radicals (OH) and hydrogen peroxide (H2O2) into water (H2O).

3. Catalase: Located in peroxisomes, it converts hydrogen peroxide (H2O2) into water (H2O) and oxygen (O2).

NADPH oxidase converts oxygen (O2) into superoxide (O2-), initiating the respiratory burst that enhances the neutrophil's ability to kill pathogens.

Hydrogen peroxide (H2O2) is produced from superoxide and is further converted to hypochlorous acid (HOCl) and hydroxyl radicals (-OH) by myeloperoxidase, which are potent antimicrobial agents that help in destroying phagocytosed bacteria.

The main components involved in the respiratory burst include:

1. NADPH oxidase - Converts O2 to superoxide.
2. SOD (Superoxide Dismutase) - Converts superoxide to hydrogen peroxide (H2O2).
3. Myeloperoxidase - Converts H2O2 to hypochlorous acid (HOCl) and hydroxyl radicals (-OH).
4. Neutrophil granules - Contain degradative enzymes that attack phagocytosed bacteria.

The respiratory burst is significant because it enhances the neutrophil's ability to kill pathogens through the production of reactive oxygen species (ROS) that are toxic to bacteria, thereby playing a crucial role in the immune response.

Defects in membrane permeability lead to:

• Activation of phospholipases in the cytosol.
• Inability to repair the cell membrane due to a lack of ATP, which prevents reacylation of phospholipids and diminishes their synthesis.

The key processes leading to membrane damage include:

1. Reactive oxygen species (ROS) causing lipid peroxidation.
2. Phospholipase activation leading to phospholipid degradation.
3. Protease activation resulting in cytoskeletal damage.

These processes contribute to overall membrane damage and loss of phospholipids.

Reversible cell injury occurs when the damage to the cells is not too severe, allowing the cells to repair themselves and recover from the injury.

Irreversible cell injury is characterized by reaching a point of no return, where the cells cannot recover from the accumulated damage and ultimately die.

A normal cell appears healthy with intact organelles, including a nucleus, mitochondria, and endoplasmic reticulum, all suspended in a light blue cytoplasm. In contrast, a cell undergoing reversible injury shows signs of stress, such as swelling of the endoplasmic reticulum and mitochondria, formation of membrane blebs, and clumping of chromatin, indicating initial damage but potential for recovery.

Irreversible cell injury is characterized by severe damage, including swelling of the endoplasmic reticulum, loss of ribosomes, ruptured lysosomes, and the presence of myelin figures. The final stage of necrosis involves fragmentation of the cell membrane and nucleus, nuclear condensation, and swollen mitochondria with amorphous densities, indicating significant structural breakdown.

Normal mitochondria appear as elongated organelles with a characteristic double membrane and distinct cristae structure.

Swollen mitochondria show an increase in size and altered internal structure, indicating potential cellular stress or injury.

Mitochondria swelling can be a reversible change, suggesting that the cell may recover its normal shape and function if the stressor is removed.

Swollen mitochondria appear enlarged and may show signs of dilation or stress in their internal structure, including changes in cristae arrangement.

Normal renal tubules (NL) have intact cells and open lumens. In reversible damage, tubules show swollen cells and slightly narrowed lumens. In irreversible damage, there is significant cellular damage, including cell lysis and debris, with severely occluded lumens.

The stages include:

1. Normal epithelium with brush border - Healthy kidney tubule cell structure.
2. Proliferation, differentiation, and reestablishment of polarity - Cells divide and attempt to rebuild.
3. Spreading and dedifferentiation of viable cells - Cells lose specialized functions.
4. Sloughing of viable and dead cells, with luminal obstruction - Cells detach and block the tubule.
5. Necrosis - Cell death occurs.
6. Apoptosis - Programmed cell death.
7. Loss of polarity and brush border - Breakdown of cell structure.
8. Ischemia and reperfusion - Lack of blood flow followed by restoration.

Damage to cells is reversible up to a certain point. Beyond this point, resupplying oxygen will not allow the cell to recover, leading to cell death.

There is no single change or type of damage that definitively marks the transition from reversible to irreversible cell injury; it remains a subject of ongoing study.

Necrosis is cell death resulting from either exogenous or endogenous damage, leading to membrane damage and leaking of cellular contents. In contrast, apoptosis is programmed cell death that can occur due to external or internal damage, physiological processes, or developmental cues, resulting in cell fragmentation and subsequent phagocytosis.

Necrosis refers to uncontrolled cell death that does not require signals or activation of genes, unlike apoptosis, which is a programmed cell death process. Necrosis is characterized by various changes in the cell, including cytoplasmic and nuclear alterations.

The cytoplasmic changes seen in necrosis include:

1. Eosinophilia - increased staining due to protein denaturation.
2. Glassy appearance - a shiny, homogeneous look due to loss of cellular structure.
3. Vacuolation - formation of vacuoles within the cytoplasm.

The nuclear changes associated with necrosis include:

1. Pyknosis - nuclear shrinkage and increased basophilia.
2. Karyorrhexis - fragmentation of the nucleus.
3. Karyolysis - dissolution of the nucleus due to enzymatic degradation.

The four stages of nuclear changes during necrosis are:

1. Normal - Intact nucleus with granular and mottled internal structures.
2. Pyknosis - Dark and shrunken nucleus.
3. Karyorrhexis - Fragmented nucleus into multiple dark spots.
4. Karyolysis - Nucleus is dissolved or faded away and no longer visible.

The different types of necrosis include:

1. Coagulative - Typically occurs in solid organs, characterized by the preservation of the basic tissue architecture.
2. Liquefactive - Involves the transformation of tissue into a liquid viscous mass, often seen in brain infarcts.
3. Caseous - Characterized by cheese-like (caseous) necrosis, commonly associated with tuberculosis infections.
4. Enzymatic Fat - Associated with pancreatic damage, leading to fat necrosis due to the action of lipases.
5. Fibrinoid - Involves the deposition of fibrin-like proteinaceous material in the walls of blood vessels, often seen in immune-mediated vascular damage.
6. Gangrenous - Refers to necrosis associated with loss of blood supply, often leading to tissue death and infection.

Coagulative necrosis is usually seen in death due to ischemia, hypoxia, and reperfusion injury in most organs, except the brain.

In coagulative necrosis, the basic outline of the cell is preserved, but there are no nuclei, giving it a ghost-like appearance.

Normal Cardiac Muscle:

• Elongated, pink cells
• Centrally located, dark nuclei
• Aligned in parallel rows
• Clear striations of muscle fibers

Cardiac Muscle After MI (2-3 Days):

• Muscle fibers appear pale and indistinct
• Nuclei are absent or shrunken
• Infiltration of inflammatory cells (small, dark dots)

Liquefactive necrosis is the death of brain tissue that occurs due to a lack of supporting connective tissue. It is commonly seen in abscesses, where the center consists of enzymatically digested neutrophils (pus), and can also occur in other conditions that generate pus.

Under the microscope, liquefactive necrosis appears amorphous and granular, characterized by a loss of cells and tissue structure.

A hemorrhagic infarction indicates a region of tissue death caused by inadequate blood supply and bleeding. This results in a mottled appearance due to the presence of blood and tissue necrosis, leading to swelling and distortion of surrounding brain tissue.

The compressed ventricles in a brain infarct suggest a mass effect due to the infarction, indicating significant swelling and distortion of the surrounding brain tissue, which can lead to increased intracranial pressure and further neurological damage.

A hemorrhagic infarction disrupts the normal architecture of the cerebral cortex, as indicated by the indistinct appearance of the gyri and sulci in the affected area, reflecting extensive damage to brain tissue.

Liquefactive necrosis is characterized by the transformation of tissue into a liquid viscous mass. In brain tissue, this type of necrosis often occurs due to ischemia or infection, leading to the following features:

• Dense areas: Composed of inflammatory cells and necrotic tissue, often with dark nuclei.
• Winding light-colored areas: Indicate the liquefaction process where tissue has been destroyed.
• Fibrous regions: Less dense areas with elongated structures, suggesting a healing or scarring process.
• Scattered dark dots: Likely represent nuclei of inflammatory cells or remnants of necrotic cells.

The histological images indicate liquefactive necrosis, which is characterized by the transformation of tissue into a liquid viscous mass due to the action of enzymes and inflammatory cells.

Caseous necrosis is characterized by the accumulation of mononuclear cells that mediate chronic inflammation and granuloma formation. The lipid in the wall of the offending organism cannot be fully broken down, leading to the persistence of dead cells as amorphous, coarsely granular, eosinophilic debris.

Caseous necrosis appears grayish, whitish, or yellowish, and is described as soft, friable, and cheesy in texture.

Caseous necrosis is characteristic of a few organisms, notably Mycobacterium tuberculosis (TB) and certain fungi.

Caseous necrosis is a type of tissue necrosis characterized by the presence of cheese-like (caseous) material. It is commonly observed in the lungs and kidneys, often associated with infections such as tuberculosis. In the lungs, it appears as a central yellow-white area within the tissue, while in the kidneys, it manifests as large white, cheese-like masses that distort the overall structure.

Caseous necrosis is characterized by a large, amorphous, granular area of pink-staining necrotic tissue, resembling cheese. It is surrounded by a ring of inflammatory cells, including lymphocytes and macrophages, which attempt to wall off the necrosis and contain the infection.

The key histological features of caseous necrosis in the lung include:

• Pale pink, amorphous mass: This represents the necrotic tissue.
• Dense inflammatory infiltrate: Characterized by dark purple nuclei of immune cells surrounding the necrotic area.
• Disruption of lung structure: Alveoli and capillaries are replaced by necrotic material and inflammatory cells.

Enzymatic fat necrosis occurs due to the action of lipases on fat, which releases fatty acids that react with calcium to form a soap-like substance.

Grossly, enzymatic fat necrosis appears white and chalky. Microscopically, it shows material in fat cells instead of the normal clear appearance, and if there is enough calcium, the deposits will be basophilic.

Enzymatic fat necrosis is most commonly seen in pancreatitis, but it can also occur in inflammation of fat.

Fibrinoid necrosis is characterized by the injury in blood vessels with an accumulation of plasma proteins, leading to the wall staining intensely eosinophilic. This condition is somewhat of a misnomer as it is challenging to distinguish between the buildup of plasma proteins and true necrosis.

Key histological features of fibrinoid necrosis include:

1. Vessel wall damage: The vessel wall appears smudged and disrupted.
2. Fibrin deposition: Brightly stained pink material indicating fibrin deposition is present.
3. Irregular lumen: The vessel lumen is irregular and filled with the pink material.
4. Inflammatory response: Surrounding tissue shows dense packing of inflammatory cells, primarily small lymphocytes.

Gangrenous necrosis is not a specific pattern of cell death; it usually refers to a limb that has died due to loss of circulation, and it can also apply to the bowel. When gangrene is combined with a superimposed bacterial infection, it is referred to as wet gangrene.

Diabetes is the most common cause of dry gangrene, leading to necrosis due to poor blood supply.

The causes of dry gangrene include:

1. Diabetes
2. Snake bite
3. Cold agglutination

Ischemia is caused by the reduction of available oxygen, leading to tissue death, which can result in conditions such as heart attack and stroke.

Reperfusion is the restoration of blood flow and oxygenation to tissues, often achieved through clot-breaking therapy (TPA) during heart attacks and strokes or in transplantation.

Reperfusion injury leads to a large amount of reactive oxygen species (ROS) damage, including O₂, ·OH, ONOO·, and lipid peroxide radicals.

The serum blood tests used to detect myocardial infarction include:

1. Creatine Kinase-MB (CK-MB) fraction
2. Troponin L (Tel)
3. Troponin T (ToT)

Reactive oxygen species (ROS) can react with various cellular components leading to:

1. Lipid Peroxide Radicals:

   • Disruption of plasma membranes and organelles.

2. Proteins:

   • Causes abnormal folding of proteins, affecting enzyme activity.

3. DNA:

   • Results in mutations and breaks in DNA.

Liquefactive necrosis is a type of tissue death characterized by the transformation of tissue into a liquid viscous mass. In the brain, it often occurs due to ischemia or infection, leading to the following manifestations:

• Tissue Breakdown: The affected area becomes disorganized and shows significant tissue breakdown.
• Discoloration: Areas may exhibit reddish-brown discoloration due to hemorrhage or inflammation.
• Microscopic Appearance: Under a microscope, liquefactive necrosis shows irregular shapes and spaces, with a pink and purple staining pattern indicating cellular destruction.

Cytokines and cell adhesion molecules lead to the accumulation of neutrophils, which contribute to further injury during ischemia/reperfusion injury.

The mitochondria are primarily responsible for ATP production during aerobic respiration through oxidative phosphorylation.

The activation of the complement pathway is a significant factor in the processes involved in ischemia/reperfusion injury, contributing to inflammation and tissue damage.

Apoptosis is a regulated mechanism of cell death that eliminates unwanted and irreparably damaged cells with minimal host reaction.

Key characteristics of apoptosis include:

1. Enzymatic degradation of proteins and DNA.
2. Initiation by caspases.
3. Removal of dead cells by phagocytes.

Apoptosis is a pathway of cell death induced by a tightly regulated suicide program, where cells activate enzymes to degrade their own nuclear DNA and proteins. Key characteristics include:

• Intact plasma membrane, but altered to target the cell for phagocytosis.
• Rapid clearance of dead cells before leakage of contents, preventing inflammatory reactions.
• Can occur physiologically or pathologically.

Apoptosis plays a crucial role in shaping the developing embryo by removing unnecessary cells, thus allowing for proper formation of tissues and organs.

Apoptosis is involved in the regression of hormone-dependent tissues, such as the endometrium during menstruation, by eliminating cells that are no longer needed.

Apoptosis helps maintain immune tolerance by eliminating self-reactive lymphocytes that could potentially cause autoimmune diseases.

Apoptosis aids in the immune response by allowing cytotoxic T cells to clear viral-infected or neoplastic transformed cells, thus preventing the spread of infection or malignancy.

Apoptosis is essential for the resolution of inflammation by removing inflammatory cells that have completed their function, preventing chronic inflammation.

Apoptosis is a mechanism through which cytotoxic anticancer drugs induce cell death in tumors, effectively reducing tumor size and preventing cancer cell proliferation.

Low doses of agents like radiation, extreme temperatures, and certain drugs can cause DNA damage that triggers apoptosis, whereas higher doses typically lead to necrosis due to overwhelming cellular injury.

In transplant rejection, apoptosis plays a critical role as the immune system targets and eliminates foreign cells, leading to the death of transplanted tissue.

Duct obstruction can lead to atrophy by reducing nutrient supply and causing cellular stress, which may trigger apoptosis in the affected tissues.

Some viral diseases can induce apoptosis in infected cells as a defense mechanism to limit viral replication and spread, thereby contributing to the pathologic condition.

The two main pathways that initiate apoptosis are the intrinsic pathway, which starts through the release of cytochrome C, and the extrinsic pathway, which is activated by receptor signaling.

During the initiation phase of apoptosis, intracellular signals commit the cell to the apoptotic pathway by producing and activating the first wave of initiator caspases.

In the execution phase of apoptosis, execution caspases catabolize the cytoskeleton and activate endonucleases, leading to the breakdown of DNA.

During the removal phase of apoptosis, macrophages remove the round dead fragments of cells that have undergone apoptosis.

The key triggers for the mitochondrial (intrinsic) apoptotic pathway include:

1. Growth factor withdrawal
2. DNA damage (caused by radiation, toxins, or free radicals)
3. Protein misfolding (resulting from endoplasmic reticulum stress)

In the case of DNA damage, the protein p53 activates pro-apoptotic forms of Bcl-2, which in turn stimulates the proteins Bax and Bak. This leads to the release of Cytochrome c from the mitochondria, initiating the apoptotic process.

The Bcl-2 family proteins regulate the release of Cytochrome c from the mitochondria. They include:

• Pro-apoptotic proteins (e.g., Bax, Bak) that promote apoptosis
• Regulators (e.g., Bcl-2, Bcl-x) that inhibit apoptosis

The activation of executioner caspases leads to several critical outcomes:

1. Endonuclease activation, resulting in DNA fragmentation
2. Breakdown of the cytoskeleton, leading to the formation of cytoplasmic blebs
3. Formation of apoptotic bodies, which are then phagocytosed by phagocytes

The mitochondrial (intrinsic) pathway is triggered by internal cellular stressors such as growth factor withdrawal, DNA damage, and protein misfolding, leading to mitochondrial changes and cytochrome c release. In contrast, the death receptor (extrinsic) pathway is initiated by external signals through receptor-ligand interactions, such as Fas and TNF receptors, activating caspases directly without mitochondrial involvement.

Survival signals, such as growth factors, bind to receptors on the cell membrane, leading to the production of anti-apoptotic proteins like BCL2. This prevents the leakage of cytochrome c from the mitochondria, allowing the cell to remain viable.

Apoptosis is triggered by a lack of survival signals and can be induced by factors such as irradiation. This results in DNA damage, activation of sensors (BH3-only proteins), antagonism of BCL2, activation of the BAX/BAK channel, leakage of cytochrome c, and ultimately activation of caspases that execute apoptosis.

The extrinsic pathway of apoptosis is initiated by death receptors such as Fas (CD95) and TNF (tumor necrosis factor). These receptors activate adaptor proteins that bind to caspases, leading to cell death.

The intrinsic pathway of apoptosis involves the dimerization of Bax and Bak, which form channels in the mitochondrial membrane. This process leads to the permeability of the membrane, resulting in the leakage of Cytochrome c and subsequent activation of caspases.

The presence of a condensed nucleus in the epidermis layer indicates apoptosis occurring in the skin cells.

The white arrows in tumor tissue stained with pink dye signify cells that are undergoing apoptosis.

White blood cells are involved in the phagocytosis of apoptotic cells, helping to clear them from the tissue.

At doses greater than 2000 R, ionizing radiation can lead to significant cellular damage, including:

1. Radiolysis of H₂O: This process generates reactive species such as hydroxyl radicals (•OH).
2. Energy transfer to macromolecules: This can disrupt cellular structures and functions.
3. DNA damage: Ionizing radiation can cause direct damage to DNA, leading to mutations.
4. Formation of protein and lipid adducts: This can affect cellular integrity and function.
5. Cell death mechanisms: The damage can trigger apoptosis (programmed cell death) or necrosis (uncontrolled cell death).

The two pathways of viral infection are:

1. Pathway A:

   • Virus infects the cell and replicates in the cytoplasm or nucleus.
   • Reduced nutrients and energy, along with the activation of p53 and caspases, can lead to:
     • Necrosis
     • Apoptosis

2. Pathway B:

   • Virus enters the cell and replicates.
   • Antibodies bind to viral antigens, leading to complement fixation and attack on the cell membrane by activated complement.
   • This process, along with caspase activation and granzyme release mediated by T lymphocytes, can also result in:
     • Necrosis
     • Apoptosis

Necroptosis is a form of programmed cell death that is recognized as important in both physiologic and pathologic conditions. It occurs during the formation of the mammalian bone growth plate, and is involved in diseases such as steatohepatitis, acute pancreatitis, reperfusion injury, and neurodegenerative diseases like Parkinson disease. Additionally, it serves as a backup mechanism in host defense against certain viruses that encode caspase inhibitors (e.g., CMV).

The necroptosis pathway involves several key steps:

1. TNF binds to TNFR1.
2. Formation of the RIP1 complex with RIP1.
3. Formation of the RIP1-RIP3 complex with RIP1, RIP3, and Caspase 8.
4. The pathway branches into:
   • Failure to activate caspase 8 leads to:
     • Formation of RIP1/HIP3 and then the Necrosome.
     • Metabolic alterations resulting in decreased ATP and increased ROS.
     • Lipid peroxidation, leading to membrane damage and organelle swelling.
     • Protein oxidation and DNA damage.
     • Loss of cell and organelle integrity, culminating in cell death by Necroptosis.
   • Activation of caspase 8 leads to degradation of cellular macromolecules and cell death by Apoptosis.

Chemicals can injure cells directly or indirectly through their metabolites. Here are some examples of their effects on different cellular regions:

The normal liver shows distinct structures such as:

1. Portal triad
2. Hepatocytes and sinusoidal
3. Central vein

In contrast, a liver with necrosis exhibits regions of cell death and inflammation, indicated by blue arrows in histological sections.

Smooth ER is involved in the metabolism of various chemicals and compounds, synthesizing phospholipids and detoxifying harmful substances.

Smooth ER undergoes hypertrophy, becoming more efficient in its functions as an adaptive response to substances like barbiturates.

The hypertrophy of Smooth ER can be dangerous, particularly when it involves the P-450 mixed function oxidase system, which can lead to increased toxicity of certain compounds.