Cell Injury and Death

The cell undergoes a variety of changes in response to injury, which may or may not lead to cell death. Injurious stimuli trigger the process of cellular adaptation Cellular adaptation In order to cope with their environment, cells undergo structural and functional changes. These cellular adaptations are reversible responses that allow cells to survive and continue to adequately function. Adaptive processes consist of increased cellular size and function (hypertrophy), increase in cell number (hyperplasia), decrease in cell size and metabolic activity (atrophy), or a change in the phenotype of the cells (metaplasia). Cellular Adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. The principal targets of cell injury are the cell membranes, mitochondria, protein synthesis machinery, and DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure. Multiple cellular abnormalities resulting from the damage result in cell death. The 2 main types of cell death are necrosis and apoptosis. Necrosis is an uncontrolled cell death characterized by inflammatory changes in a pathologic condition. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects.

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Overview

Definitions

  • Homeostasis: 
    • Steady state
    • Cell is at optimal function, meeting physiologic demands.
  • Cellular adaptation: reversible changes in cell structures or functions in response to changes in the cell’s environment

Cell injury

  • Cells cannot adapt, or the maximum adaptive response to physiologic or pathologic stimuli is exceeded.
  • Occurs with damaging stimuli, loss of critical nutrients, or mutations 
  • Factors affecting cell injury:
    • Nature, duration, and severity of injury
    • Type and adaptability of the cell
    • Simultaneous injury mechanisms stimulated by the etiology
  • Types of cell injury:
    • Reversible injury
    • Irreversible injury (leads to cell death)
  • Mechanisms of cell injury (can occur at the same time):
    • Mitochondrial damage
    • Abnormal calcium homeostasis
    • DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure damage
    • Membrane damage
    • Endoplasmic reticulum (ER) stress
    • Oxidative stress

Cell death

  • State in which cell ceases to carry out functions
  • Part of embryogenesis, organ development, and maintenance of homeostasis where damaged and unneeded cells are removed 
  • Effect of irreversible injury, when the cell cannot overcome the damages 
  • Pathways:
    • Apoptosis
    • Necrosis
Cellular response to stress and injury

Cellular response to stress and injury

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Etiology and Types of Cell Injury

Injurious stimuli

  • Physical agents:
    • Mechanical trauma
    • Temperature and atmospheric pressure changes
    • Radiation
    • Electric shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock 
  • Chemical agents and drugs:
    • Chemicals causing electrolyte derangements (e.g., glucose)
    • Poisons (e.g., cyanide, arsenic)
    • Environmental pollutants
    • Industrial hazards (e.g., asbestos)
    • Medications (toxic effects)
  • Oxygen deprivation:
    • Ischemia
    • Cardiorespiratory decompensation
    • ↓ oxygen-carrying capacity of the blood ( anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview)
  • Infections: viruses, bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview, parasites, other biological agents
  • Immunologic reactions:
    • Immune reactions to external agents
    • Autoimmune diseases 
  • Genetic abnormalities:
    • Congenital malformations
    • Deficient protein function from enzyme defects
    • Misfolded proteins 
  • Nutritional deficiencies and excess:
    • Nutritional deficiencies (vitamin deficiency)
    • Nutritional excess ( obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity, increased lipids)

Types of cell injury

  • Reversible cell injury:
    • Effect of mild or transient damage 
    • Elimination of the pathologic stimuli or restoration of critical supply leads to cell returning to steady state.
    • Features:
      • Cellular swelling due to water influx (earliest manifestation of cell injury)
      • Hydropic change or vacuolar degeneration: small, clear vacuoles within the cytoplasm (from distended ER)
      • Plasma membrane alterations (blebbing, blunting, loss of microvilli)
      • Mitochondrial swelling and appearance of amorphous densities
      • Cytosol Cytosol A cell's cytoskeleton is a network of intracellular protein fibers that provides structural support, anchors organelles, and aids intra- and extracellular movement. . The Cell: Cytosol and Cytoskeletonmyelin figures (phospholipids from damaged membranes)
      • Changes in nucleus (granular and fibrillar elements disaggregate) 
      • Fatty change from accumulation of lipid vacuoles (in organs involved in lipid metabolism Lipid Metabolism Lipid metabolism is the processing of lipids for energy use, energy storage, and structural component production. Lipid metabolism uses fats from dietary sources or from fat stores in the body. A complex series of processes involving digestion, absorption, and transport are required for the proper metabolism of lipids. Lipid Metabolism)
  • Irreversible injury:
    • “Point of no return”: cell cannot be restored → cell death 
    • Injurious stimulus is severe and/or persistent.
    • Features:
      • Inability to reverse mitochondrial dysfunction (loss of oxidative phosphorylation and adenosine triphosphate (ATP) production)
      • Significant damage to membrane function

Cell Injury by Mitochondrial Damage

Mitochandria

  • Major site of synthesis of adenosine triphosphate or ATP 
  • ATP: 
    • Energy required in synthetic and degradative processes
    • Sources:
      • From oxidative phosphorylation of adenosine diphosphate 
      • From the glycolytic pathway (anaerobic)
  • Subject to most injurious stimuli

Consequences of mitochondrial damage

  • Adenosine triphosphate (ATP) depletion: mitochondrial permeability transition pore formsloss of membrane potential Membrane potential The membrane potential is the difference in electric charge between the interior and the exterior of a cell. All living cells maintain a potential difference across the membrane thanks to the insulating properties of their plasma membranes (PMs) and the selective transport of ions across this membrane by transporters. Membrane Potential and oxidative phosphorylation → reduced ATP
  • ATP depletion leads to:
    • Cell swelling: plasma membrane sodium pump (Na⁺, K⁺-ATPase) fails → sodium enters the cell → water accumulation
    • Reduced cytosolic enzyme activity: ↑ glycogenolysis and glycolysis Glycolysis Glycolysis is a central metabolic pathway responsible for the breakdown of glucose and plays a vital role in generating free energy for the cell and metabolites for further oxidative degradation. Glucose primarily becomes available in the blood as a result of glycogen breakdown or from its synthesis from noncarbohydrate precursors (gluconeogenesis) and is imported into cells by specific transport proteins. Glycolysis to compensate for the ATP loss → depleted glycogen → ↑ lactic acid and inorganic phosphates → ↓ intracellular pH → impaired enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
    • Reduced protein synthesis: detachment of ribosomes 
  • Impaired oxidative phosphorylation: Reactive oxygen species (free radicals) are created, causing lipid/protein/nucleic acid damage.
  • Apoptosis/cell death: leakage of apoptotic proteins (e.g., cytochrome c) results in organelle damage
Mechanisms mitochondrial

Mitochondrial damage from injurious stimuli (e.g., radiation, toxins) leads to:
Bottom left: Pro-apoptotic proteins leak from the mitochondria causing apoptosis.
Top right: Incomplete oxidative phosphorylation produces reactive oxygen species (ROS). Membranes, proteins and DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure are damaged.
Bottom right: Decreased ATP results in cell swelling, reduced enzyme activity and protein synthesis.
All processes lead to severe cell injury, then necrosis occurs.

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Cell Injury by Abnormal Calcium Homeostasis

Calcium homeostasis

  • Intracellular calcium (Ca²⁺): normally low (sequestered in the mitochondria and ER)
  • Common injurious stimuli: 
    • Oxygen deprivation/ischemia
    • Toxins 

Consequences of impaired calcium homeostasis

  • Release of Ca²⁺ from intracellular stores and ↑ Ca²⁺ influx through the plasma membrane 
  • ↑ Calcium → opening of mitochondrial permeability transition pore (mPTP) → ATP depletion
  • Increased Ca²⁺ activates enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes, which produce cell injury: 
    • Phospholipases → membrane damage
    • Proteases → membrane and cytoskeletal protein degradation
    • Endonucleases → DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure and chromatin fragmentation
    • ATPases → ATP depletion
Mechanisms calcium

Effects of impaired calcium homeostasis
Injurious stimuli cause release of calcium from the mitochondrion and endoplasmic reticulum.

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Cell Injury by DNA and Membrane Damage

DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure damage

  • Common injurious stimuli: 
    • Radiation
    • Chemotherapeutic drugs
    • ROS
  • May be part of aging 

Consequences of damaged DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure

  • Triggers p53 pathway: arrests cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle in G1 phase, activating repair mechanisms
  • Apoptosis occurs:
    • If repairs cannot correct the damage 
    • To protect the tissue involved (cell dies rather than persists with an abnormal DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure, which has potential for malignant transformation)
Dna damage activates p53

DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure damage activates p53 which arrests cells in G1 phase and triggers DNA repair mechanisms DNA repair mechanisms Although DNA fidelity is highly protected, DNA can still be damaged by a number of environmental factors, reactive oxygen species, and errors in DNA replication. DNA repair is a continuous process in which the cell corrects the damage. The cell has multiple mechanisms it can use to repair DNA. DNA Repair Mechanisms. If damage is irreparable, p53 triggers apoptosis.

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Membrane damage

  • Normal membrane: made of lipids, with phospholipids as the most abundant form
  • Common injurious stimuli: 
    • Bacterial infection (toxins)
    • Viral proteins
    • Complement-mediated lysis
    • Physical/chemical agents 
    • Ischemia
  • Other mechanisms overlap and cause membrane damage:
    • Oxygen free radicals → lipid peroxidation → phospholipid loss
    • Mitochondrial damage → reduced ATP → decreased phospholipid synthesis
    • Calcium-dependent phospholipases → phospholipid breakdown → loss of membrane
    • Calcium-dependent proteases → cytoskeletal filament damage → increased cellular swelling and rupture 

Consequences of membrane damage

  • ↑ Permeability of plasma membrane → influx of fluids and ions + loss of cell osmotic balance
  • Injury to lysosomal membranes → lysosomal enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes disrupt cytoplasmic organelles Organelles A cell is a complex unit that performs several complex functions. An organelle is a specialized subunit within a cell that fulfills a specific role or function. Organelles are enclosed within their own lipid bilayers or are unbound by membranes. The Cell: Organelles
Mechanisms membrane

Membrane damage occurs from the following:
An injurious stimulus (top left) leads to disrupted transport functions. The injurious stimulus also affects lysosomal membranes, leaking enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes that damage the cell.
Other mechanisms: Abnormal calcium homeostasis (top right) releases enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes that degrade the membrane; mitochondrial dysfunction (lower left) reduces ATP production needed for membrane synthesis.
Reactive oxygen species (lower right) cause lipid peroxidation, leading to membrane phospholipid loss.

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Cell Injury by ER Stress

Endoplasmic reticulum

  • Site of protein synthesis and folding, lipid synthesis, and free calcium storage
  • Chaperones: control protein folding 
  • Misfolded proteins: usually processed for proteolysis
  • Unfolded protein response: 
    • Signal transduction pathways that sense misfolded proteins
    • ↑ Chaperones, ↓ protein translation Translation Translation is the process of synthesizing a protein from a messenger RNA (mRNA) transcript. This process is divided into three primary stages: initiation, elongation, and termination. Translation is catalyzed by structures known as ribosomes, which are large complexes of proteins and ribosomal RNA (rRNA). Stages and Regulation of Translation, and ↑ degradation of misfolded proteins
  • Injurious stimuli: 
    • Genetic abnormalities/mutations
    • Ischemia/hypoxia 
    • Viral infections

Consequences of ER stress

  • ER stress: Protein folding demand exceeds protein folding capacity.
  • Unrepaired proteins accumulate → apoptosis
  • Diseases and their associated misfolded proteins:
    • Cystic fibrosis Cystic fibrosis Cystic fibrosis is an autosomal recessive disorder caused by mutations in the gene CFTR. The mutations lead to dysfunction of chloride channels, which results in hyperviscous mucus and the accumulation of secretions. Common presentations include chronic respiratory infections, failure to thrive, and pancreatic insufficiency. Cystic Fibrosis: cystic fibrosis transmembrane conductance regulator (CFTR)
    • α1- antitrypsin deficiency: α1- antitrypsin
    • Alzheimer’s disease: Aβ peptide
    • Familial hypercholesterolemia: LDL receptor
    • Creutzfeldt-Jacob disease: prion
Endoplasmic reticulum (er)

Endoplasmic reticulum (ER)
Chaperones control protein folding in the ER and misfolded proteins normally undergo proteolysis. When misfolded proteins increase, unfolded protein response occurs (increasing chaperones, decreasing protein synthesis and enhancing degradation of misfolded proteins).
ER stress: If protein folding demand increases (excessive misfolded proteins), the protein folding capacity gets saturated, leading to cell apoptosis.

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Cell Injury by Oxidative Stress

Free radicals

  • Molecular species with single unpaired electron in the outer orbit Orbit The orbit is the cavity of the skull in which the eye and its appendages are situated. The orbit is composed of 7 bones and has a pyramidal shape, with its apex pointed posteromedially. The orbital contents comprise the eye, extraocular muscles, 5 cranial nerves, blood vessels, fat, the lacrimal apparatus, among others. The Orbit and Extraocular Muscles
  • Highly reactive: attack adjacent molecules (proteins, carbohydrates Carbohydrates Carbohydrates are one of the 3 macronutrients, along with fats and proteins, serving as a source of energy to the body. These biomolecules store energy in the form of glycogen and starch, and play a role in defining the cellular structure (e.g., cellulose). Basics of Carbohydrates, nucleic acids Nucleic Acids Nucleic acids are polymers of nucleotides, organic molecules composed of a sugar, a phosphate group, and a nitrogenous base. Nucleic acids are responsible for storage, replication, and expression of genetic information. The 2 nucleic acids most commonly seen in eukaryotic cells are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Nucleic Acids)
  • ROS: an oxygen-derived free radical
  • Principal free radicals:
    • Superoxide anion (O2)
    • Hydrogen peroxide (H₂O₂)
    • Hydroxyl radical (OH): most reactive ROS
    • Peroxynitrite (ONOO⁻)
  • Injurious stimuli: 
    • Ischemia-reperfusion injury
    • Chemical and radiation injury
    • Aging
    • Phagocytosis of microbes

Oxidative stress

  • Accumulation of ROS → oxidative stress:
    • From increased production of free radicals
    • From decreased scavenging of ROS
  • The following generate free radicals:
    • Reduction-oxidation reactions:
      • O₂ is reduced with transfer of electrons to H₂ to form water molecules.
      • Partially reduced intermediates → free radicals
    • Exposure to ionizing radiation and ultraviolet rays
    • Polymorphonuclear neutrophils produce free radicals during inflammatory response.
    • Metabolism of exogenous chemicals (e.g., carbon tetrachloride)
    • Reactions with transition metals (e.g., iron or copper)
    • Nitric oxide reaction (with superoxide) in macrophages, producing peroxynitrite (ONOO⁻), a free radical

Consequences of oxidative stress

  • Membrane damage by lipid peroxidation:
    • ROS attack unsaturated fatty acids of the membrane.
    • Lipid hydroperoxides are produced → ↓ function of membranes
  • DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure damage or fragmentation 
  • Oxidative modification of proteins: ↑ protein cross-linking leads to ↑ degradation and ↓ activity

Antioxidants

  • Defense against free radicals (ROS scavengers)
  • Immediately eliminate ROS produced during mitochondrial respiration and energy generation
  • Low amount of free radicals may be present but are unable to induce damage.
  • Non-enzymatic mechanism:
    • Vitamins A, C, E
    • Glutathione
    • Ferritin
    • Transferrin
    • Ceruloplasmin
  • Enzymatic mechanism:
    • Glutathione peroxidase: catalyzes breakdown of hydroxyl radicals
    • Superoxide dismutase (SOD): converts superoxide to hydrogen peroxide (H₂O₂)
    • Catalase: breaks down H₂O₂
Oxidative stress causes cell injury

Oxidative stress causes cell injury by lipid peroxidation of membranes, oxidative modification of proteins, and DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure damage.

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Cell Death by Apoptosis

Programmed cell death (apoptosis)

  • Activated enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes degrade DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure and proteins in cells that are destined to die
  • Features:
    • ↓ Cell size, eosinophilic cytoplasm
    • Chromatin condensation (chromatin aggregates peripherally)
    • Cytoplasmic blebs and apoptotic bodies
    • Phagocytosis of apoptotic cells by macrophages

Apoptosis in different conditions

  • Physiologic conditions:
    • Fetal development: 
      • Cells die off after their purpose has been fulfilled.
      • Removal of supernumerary cells during development
    • Involution of tissues with hormone withdrawal:
      • Endometrial shedding in menstrual cycle Menstrual cycle The menstrual cycle is the cyclic pattern of hormonal and tissular activity that prepares a suitable uterine environment for the fertilization and implantation of an ovum. The menstrual cycle involves both an endometrial and ovarian cycle that are dependent on one another for proper functioning. There are 2 phases of the ovarian cycle and 3 phases of the endometrial cycle. Menstrual Cycle
      • Lactating breast regression (weaning)
    • Removal of self-reactive lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes (may cause autoimmune disease)
    • Removal of neutrophils in an inflammatory response
    • Control of cell proliferation, maintaining a constant number of cell populations (immature lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes in bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow
  • Pathologic conditions:
    • DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure damage: Apoptosis prevents survival of cells with DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure mutations (protective effect).
    • Removal of improperly folded proteins
    • Ductal obstruction (e.g., kidney, parotid gland): Atrophy occurs by apoptosis. 
    • Infections (particularly viral illness): Cytotoxic T lymphocytes T lymphocytes T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells induce apoptosis to eliminate infected cells.

Mechanisms of Apoptosis

Caspases:

  • Cystein aspartic acid proteases
  • Exist in inactive form, requiring enzymatic cleavage to be activated
  • Active caspases: a marker for cells undergoing apoptosis
  • Phases of apoptosis:
    • Initiation: activation of caspases → cascade of other caspases
      • Intrinsic pathway
      • Extrinsic pathway
    • Execution: terminal caspases → cellular fragmentation

Intrinsic pathway (initiation):

  • Mitochondrial pathway
  • In viable cells, growth factors and survival signals reduce mitochondrial leakage of cytochrome c by producing anti-apoptotic proteins (principal members):
    • BCL2
    • BCL-XL
    • MCL-1
  • In damaged cells, loss of survival signals, DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure damage, protein misfolding: 
    • Allow cytochrome c leakage from the mitochondria by producing pro-apoptotic proteins (main members):
      • BAX
      • BAK 
    • Activate apoptosis initiators (BH3-only proteins): BAD, BIM, BID, Puma, Noxa
  • Events:
    • Increased permeability of the mitochondrial outer membrane → release of cytochrome c into the cytoplasm 
    • Cytochrome c initiates apoptosis.
    • In the cytoplasm, cytochrome c binds with apoptosis-activating factor-1 (APAF-1), forming a structure, apoptosome.
    • Apoptosome leads to self-cleavage and activation of caspase-9, the initiator caspase.
    • Activated caspase-9 → cascade of executioner caspases 

Extrinsic pathway (initiation):

  • Death receptor-initiated pathway
  • Plasma membrane death receptors initiate this pathway.
  • Death receptors: 
    • Members of tumor necrosis factor Tumor necrosis factor Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) ( TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF)) family with a cytoplasmic death domain (delivers the apoptotic signals)
    • Best known death receptors: 
      • Type 1 TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) receptor (TNFR1)
      • Fas (CD95)
  • Events:
    • FasL (Fas ligand on T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells and cytotoxic T lymphocytes T lymphocytes T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells) binds to Fas → a signal for apoptosis is given to the cell.
    • 3 or more Fas molecules combine to form the protein, Fas-associated death domain (FADD).
    • FADD binds pro-caspase-8.
    • Caspase-8 (or caspase-10) is activated → stimulates executioner caspases 

Execution phase:

  • Both pathways converge in the execution phase.
  • Events:
    • Starts with sequential activation of executioner caspases.
    • Inhibitor of deoxyribonuclease (DNase) is cleaved → active DNase → nuclear proteolysis and fragmentation
    • Cytoskeleton Cytoskeleton A cell's cytosol is the liquid inside the cell membrane that surrounds the organelles and cytoskeleton. The cytosol is a complex solution where many biochemical processes take place. The Cell: Cytosol and Cytoskeleton proteins break down.
    • Cell fragments → cytoplasmic blebs form → become apoptotic bodies
    • Apoptotic bodies are eaten by phagocytes.
  • Efferocytosis
    • Apoptotic cell phagocytosis
    • Rapid clearance with reduced production of pro-inflammatory cytokines → limited inflammatory reactions even with substantial apoptosis
Apoptotic pathway

Intrinsic and extrinsic apoptotic pathway
Intrinsic pathway starts with release of cytochrome c, eventually activating caspase 9. The extrinsic pathway starts with activation of Fas (death receptor), which leads to an active caspase 8/10. These caspases go through the execution phase, finally forming apoptotic bodies which undergo phagocytosis.

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Clinical correlation

  • Tumor suppressor genes: 
    • Prevent uncontrolled cell proliferation and lead cells to apoptosis. 
    • Inactivation → malignant neoplasm
  • Follicular lymphoma:
    • Associated with chromosomal translocations involving BCL2 gene
    • Has BCL2 over-expression
    • Increased anti-apoptotic mechanisms → expansion of malignant cells

Cell Death by Necrosis

Process of necrosis

  • Uncontrolled cell death after irreversible injury:
    • Cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane is disrupted; lysosomal enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes enter and digest the cell.
    • Cellular contents are released and circulate into the extracellular space. 
    • Circulating contents elicit an inflammatory reaction and recruit leukocytes to the site of necrosis.
  • Clinical correlation (tests for tissue-specific injury represent circulating intracellular contents):
    • Troponin: from damaged cardiac muscle cells
    • Alkaline phosphatase: from bile duct epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium
    • Transaminases: from hepatocytes

Cellular changes

  • Cytoplasmic changes
    • Eosinophilic cytoplasm: due to denatured cytoplasmic proteins (which bind to eosin dye) 
    • Vacuolated cytoplasm: Enzymes digest organelles Organelles A cell is a complex unit that performs several complex functions. An organelle is a specialized subunit within a cell that fulfills a specific role or function. Organelles are enclosed within their own lipid bilayers or are unbound by membranes. The Cell: Organelles, leaving “moth-eaten” appearance.
    • Myelin figures: large whorled phospholipid precipitates (from the damaged membrane), which are phagocytosed or degraded to fatty acids
  • Nuclear changes (1 of 3 patterns):
    • Karyolysis: reduced basophilia due to DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure loss (effect of DNAse)
    • Pyknosis: nuclear shrinkage and increased basophilia (condensation of chromatin into a dense basophilic mass)
    • Karyorrhexis: fragmentation of the nucleus
Table: Necrosis and apoptosis
Features of necrosisFeatures of apoptosis
Cell size Enlarged (swelling) Reduced (shrinkage)
Nucleus Pyknosis, karyorrhexis, karyolysis Fragmentation into nucleosome-size fragments
Plasma membrane Disrupted Intact but altered structure (orientation of lipids)
Cellular contents Enzymatic digestion; leak out of the cell Intact; released in apoptotic bodies
Adjacent inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation Frequent No
Physiologic or pathologic role Pathologic (result of irreversible cell injury) Physiologic: elimination of unwanted cells
Pathologic: cell injury from DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure and protein damage

Patterns of Necrosis

Coagulative necrosis:

  • Cell outlines and tissue architecture maintained for several days
  • Injury also denatures enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes, so initial proteolysis is blocked.
  • Eventually, leukocyte enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes break down the dead cells.
  • Often in ischemia or hypoxic injury
  • Infarct: localized area of coagulative necrosis 
  • Seen in myocardial and renal infarction

Liquefactive necrosis:

  • Colliquative necrosis
  • Tissue is digested and dissolved into a viscous liquid.
  • Seen in bacterial and fungal infections, which stimulate leukocytes and the release of hydrolytic enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
  • Pus: creamy-yellow necrotic material 
  • Default necrosis mechanism used by hypoxic central nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System cells
  • Coagulative and liquefactive necrosis: not mutually exclusive
  • Damaged cardiac myocytes undergo coagulative necrosis; as leukocytes set in and enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes are released, liquefactive necrosis occurs.

Caseous necrosis :

  • Caseous: “cheese-like”
  • Fragmented cells and debris surrounded by an inflammatory border: granuloma
  • Seen in tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis and some fungal infections
  • Mycolic acid from the mycobacterial cell wall induces granuloma formation.

Fat necrosis:

  • Change in adipose tissue Adipose tissue Adipose tissue is a specialized type of connective tissue that has both structural and highly complex metabolic functions, including energy storage, glucose homeostasis, and a multitude of endocrine capabilities. There are three types of adipose tissue, white adipose tissue, brown adipose tissue, and beige or "brite" adipose tissue, which is a transitional form. Adipose Tissue due to trauma or enzymatic release
  • Release of pancreatic lipases into the pancreatic parenchyma and the peritoneum Peritoneum The peritoneum is a serous membrane lining the abdominopelvic cavity. This lining is formed by connective tissue and originates from the mesoderm. The membrane lines both the abdominal walls (as parietal peritoneum) and all of the visceral organs (as visceral peritoneum). Peritoneum and Retroperitoneum → destruction of adipocytes 
  • Liberated fatty acids combine with calcium, producing chalky-white areas (fat saponification).
  • Seen in acute pancreatitis Acute pancreatitis Acute pancreatitis is an inflammatory disease of the pancreas due to autodigestion. Common etiologies include gallstones and excessive alcohol use. Patients typically present with epigastric pain radiating to the back. Acute Pancreatitis, fat necrosis of the breast Fat necrosis of the breast Fat necrosis of the breast is an inflammatory, benign condition resulting from injury to the breast tissue. Forms of injury include blunt traumatic injury as well as trauma from surgical procedures, biopsies, and radiation therapy. Fat Necrosis of the Breast

Fibrinoid necrosis:

  • Microscopic change
  • Deposition of immune complexes in the walls of vessels
  • Fibrinoid: fibrin combined with immune complexes deposited in the vessel walls (homogeneously pink in hematoxylin and eosin stains)

Gangrenous necrosis:

  • Not a pattern of necrosis; a clinical description used when a limb becomes necrotic due to ischemia 
  • Indicates coagulative necrosis of multiple layers of tissue (dry gangrene)
  • With superimposed bacterial infection, liquefaction necrosis occurs due to enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes from bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview and leukocytes (wet gangrene).

Dystrophic calcification:

  • Necrotic cells: eliminated by enzymatic digestion and phagocytosis
  • Inadequately reabsorbed necrotic cells become a nidus of calcium and mineral deposition.

Other Cellular Mechanisms

Necroptossis

  • Programmed necrosis
  • Caspase-independent cell death
  • Similar to necrosis in morphology, with apoptotic type of cell death 
  • Clinical correlation:
    • Physiologic: mammalian growth plate
    • Pathologic: steatohepatitis, Parkinson’s disease

Pyroptosis

  • Apoptosis accompanied by cytokine IL-1 (interleukin-1: fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever-inducing cytokine)
  • Pathway of apoptosis releases inflammatory mediators.
  • Clinical correlation: death of cells infected by microbes 

Ferroptosis

  • Iron-dependent pathway of cell death, characterized by lipid peroxidation
  • Results in the loss of membrane permeability (ruptured mitochondrial membrane)
  • Occurs with excessive iron or ROS, which glutathione-dependent defenses cannot handle
  • Clinical correlation: cancer, neurodegenerative diseases, and stroke

Autophagy

  • “Auto”: self; “phagy”: eat → cell eats its contents
  • Survival mechanism, such as in atrophic cells in states of nutrient deprivation
  • Triggers cell death, if unable to cope with stress
  • Mechanism:
    • Nucleation and formation of a phagophore, an isolation membrane derived from the ER or mitochondria or plasma membrane
    • The organelles Organelles A cell is a complex unit that performs several complex functions. An organelle is a specialized subunit within a cell that fulfills a specific role or function. Organelles are enclosed within their own lipid bilayers or are unbound by membranes. The Cell: Organelles are sequestered by the phagophore and a vesicle, autophagosome, forms.
    • Mature autophagosome fuses with a lysosome (autophagolysosome), resulting in the degradation of contents.
  • Clinical correlation:
    • Cancer
    • Neurodegenerative disorders (e.g., Alzheimer’s disease)
    • Infectious disease
    • Inflammatory bowel disease
Schematic diagram of the steps of autophagy

Schematic diagram of the steps of autophagy
1. Formation of the phagophore or isolation membrane (vesicle nucleation and elongation step).
2. Expansion of the phagophore into an autophagosome.
3. Fusion of the autophagosome with a lysosome forming an autophagolysosome.
4. Sequestered material is degraded inside the autophagolyosome and recycled.

Image by Lecturio.

References

  1. Adigun, R., Basit, H., Murray, J. (2020). Cell liquefactive necrosis. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK430935/#!po=1.85185
  2. Kemp W.L., Burns Burns A burn is a type of injury to the skin and deeper tissues caused by exposure to heat, electricity, chemicals, friction, or radiation. Burns are classified according to their depth as superficial (1st-degree), partial-thickness (2nd-degree), full-thickness (3rd-degree), and 4th-degree burns. Burns D.K., Brown T.G. (Eds.) (2008). Cellular pathology. Pathology: The Big Picture. McGraw-Hill.
  3. Lin, J., Walter, P., Benedict Yen, T. (2008). Endoplasmic reticulum stress in Disease Pathogenesis. Annual Rev Patho 3, 399–425. https//:doi.org/10.1146/annurev.pathmechdis.3.121806.151434
  4. Kumar V, Abbas A, Aster J, Robbins, S. Robbins, and Cotran (Eds.) (2020). Pathologic Basis of Disease (10th ed.). Elsevier, Inc.

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