Cell Injury and Death

Overview

Definitions

• Homeostasis:
  • Steady state Steady state Enzyme Kinetics
  • Cell is at optimal function, meeting physiologic demands.
• 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: 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 Reversible Injury Ischemic Cell Damage
  • Irreversible injury Irreversible Injury Ischemic Cell Damage (leads to cell death)
• Mechanisms of cell injury (can occur at the same time):
  • Mitochondrial damage
  • Abnormal calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes homeostasis
  • DNA damage DNA Damage Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a mutation or a block of DNA replication. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (pyrimidine dimers) or interstrand crosslinking. Damage can often be repaired (DNA repair). If the damage is extensive, it can induce apoptosis. DNA Repair Mechanisms
  • Membrane damage
  • Endoplasmic reticulum Endoplasmic reticulum A system of cisternae in the cytoplasm of many cells. In places the endoplasmic reticulum is continuous with the plasma membrane (cell membrane) or outer membrane of the nuclear envelope. If the outer surfaces of the endoplasmic reticulum membranes are coated with ribosomes, the endoplasmic reticulum is said to be rough-surfaced; otherwise it is said to be smooth-surfaced. The Cell: Organelles (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 Irreversible Injury Ischemic Cell Damage, when the cell cannot overcome the damages 
• Pathways:
  • Apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage
  • Necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage

Etiology and Types of Cell Injury

Injurious stimuli

• Physical agents:
  • Mechanical trauma
  • Temperature and atmospheric pressure Atmospheric pressure The pressure at any point in an atmosphere due solely to the weight of the atmospheric gases above the point concerned. Ventilation: Mechanics of Breathing changes
  • Radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma
  • 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 Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance)
  • Poisons (e.g., cyanide Cyanide Inorganic salts of hydrogen cyanide containing the -cn radical. The concept also includes isocyanides. It is distinguished from nitriles, which denotes organic compounds containing the -cn radical. Cyanide Poisoning, arsenic Arsenic A shiny gray element with atomic symbol as, atomic number 33, and atomic weight 75. It occurs throughout the universe, mostly in the form of metallic arsenides. Most forms are toxic. According to the fourth annual report on carcinogens, arsenic and certain arsenic compounds have been listed as known carcinogens. Metal Poisoning (Lead, Arsenic, Iron))
  • Environmental pollutants
  • Industrial hazards (e.g., asbestos)
  • Medications (toxic effects)
• Oxygen deprivation:
  • Ischemia Ischemia A hypoperfusion of the blood through an organ or tissue caused by a pathologic constriction or obstruction of its blood vessels, or an absence of blood circulation. Ischemic Cell Damage
  • 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 and Types)
• Infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease: viruses Viruses Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. Virology, 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, parasites, other biological agents
• Immunologic reactions:
  • Immune reactions to external agents
  • Autoimmune diseases Autoimmune diseases Disorders that are characterized by the production of antibodies that react with host tissues or immune effector cells that are autoreactive to endogenous peptides. Selective IgA Deficiency 
• Genetic abnormalities:
  • Congenital Congenital Chorioretinitis malformations
  • Deficient protein function from enzyme defects
  • Misfolded proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis 
• 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 Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids)

Types of cell injury

• Reversible cell injury:
  • Effect of mild or transient damage 
  • Elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy of the pathologic stimuli or restoration of critical supply leads to cell returning to steady state Steady state Enzyme Kinetics.
  • Features:
    • Cellular swelling Swelling Inflammation 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 Plasma 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 alterations (blebbing, blunting, loss of microvilli)
    • Mitochondrial swelling Swelling Inflammation 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 Cytoskeleton myelin figures ( phospholipids Phospholipids Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. Lipid Metabolism from damaged membranes)
    • Changes in nucleus Nucleus Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (cell nucleolus). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the endoplasmic reticulum. A cell may contain more than one nucleus. The Cell: Organelles (granular and fibrillar elements disaggregate) 
    • Fatty change Fatty change Yellow Fever Virus 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 Irreversible Injury Ischemic Cell Damage:
  • “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 Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Post-translational Protein Processing and adenosine Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs triphosphate (ATP) production)
    • Significant damage to membrane function

Cell Injury by Mitochondrial Damage

Mitochondria Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive ribosomes, transfer RNAs; amino Acyl tRNA synthetases; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs. Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. The Cell: Organelles

• Major site of synthesis Synthesis Polymerase Chain Reaction (PCR) of adenosine Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs triphosphate or ATP 
• ATP:
  • Energy required in synthetic and degradative processes
  • Sources:
    • From oxidative phosphorylation Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Post-translational Protein Processing of adenosine Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs diphosphate 
    • From the glycolytic pathway (anaerobic)
• Subject to most injurious stimuli

Consequences of mitochondrial damage

• Adenosine Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs triphosphate (ATP) depletion: mitochondrial permeability transition pore forms → loss 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 Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Post-translational Protein Processing → reduced ATP
• ATP depletion leads to:
  • Cell swelling Swelling Inflammation: plasma membrane Plasma 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 sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia pump Pump ACES and RUSH: Resuscitation Ultrasound Protocols (Na⁺, K⁺-ATPase) fails → sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia enters the cell → water accumulation
  • Reduced cytosolic enzyme activity: ↑ glycogenolysis Glycogenolysis The release of glucose from glycogen by glycogen phosphorylase (phosphorolysis). The released glucose-1-phosphate is then converted to glucose-6-phosphate by phosphoglucomutase before entering glycolysis. Glycogenolysis is stimulated by glucagon or epinephrine via the activation of phosphorylase kinase. Glycogen Metabolism 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 pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance → 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 Synthesis Polymerase Chain Reaction (PCR): detachment of ribosomes Ribosomes Multicomponent ribonucleoprotein structures found in the cytoplasm of all cells, and in mitochondria, and plastids. They function in protein biosynthesis via genetic translation. The Cell: Organelles 
• Impaired oxidative phosphorylation Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Post-translational Protein Processing: Reactive oxygen species Reactive oxygen species Molecules or ions formed by the incomplete one-electron reduction of oxygen. These reactive oxygen intermediates include singlet oxygen; superoxides; peroxides; hydroxyl radical; and hypochlorous acid. They contribute to the microbicidal activity of phagocytes, regulation of signal transduction and gene expression, and the oxidative damage to nucleic acids; proteins; and lipids. Nonalcoholic Fatty Liver Disease ( free radicals Free radicals Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. Ischemic Cell Damage) are created, causing lipid/protein/nucleic acid damage.
• Apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage/cell death: leakage of apoptotic proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis (e.g., cytochrome c) results in organelle damage

Cell Injury by Abnormal Calcium Homeostasis

Calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes homeostasis

• Intracellular calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes (Ca²⁺): normally low (sequestered in the mitochondria Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive ribosomes, transfer RNAs; amino Acyl tRNA synthetases; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs. Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. The Cell: Organelles and ER)
• Common injurious stimuli:
  • Oxygen deprivation/ ischemia Ischemia A hypoperfusion of the blood through an organ or tissue caused by a pathologic constriction or obstruction of its blood vessels, or an absence of blood circulation. Ischemic Cell Damage
  • Toxins 

Consequences of impaired calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes homeostasis

• Release of Ca²⁺ from intracellular stores and ↑ Ca²⁺ influx through the plasma membrane Plasma 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 
• ↑ Calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes → opening of mitochondrial permeability transition pore ( mPTP MPTP Parkinson’s Disease) → 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 Proteases Proteins and Peptides → membrane and cytoskeletal protein degradation
  • Endonucleases → DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure and chromatin Chromatin The material of chromosomes. It is a complex of dna; histones; and nonhistone proteins found within the nucleus of a cell. DNA Types and Structure fragmentation Fragmentation Chronic Apophyseal Injury
  • ATPases → ATP depletion

Cell Injury by DNA and Membrane Damage

DNA damage DNA Damage Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a mutation or a block of DNA replication. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (pyrimidine dimers) or interstrand crosslinking. Damage can often be repaired (DNA repair). If the damage is extensive, it can induce apoptosis. DNA Repair Mechanisms

• Common injurious stimuli:
  • Radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma
  • Chemotherapeutic drugs
  • ROS
• May be part of aging 

Consequences of damaged DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). 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 G1 Phase The period of the cell cycle preceding DNA replication in s phase. Subphases of g1 include ‘competence’ (to respond to growth factors), g1a (entry into g1), g1b (progression), and g1c (assembly). Progression through the g1 subphases is effected by limiting growth factors, nutrients, or inhibitors. Cell Cycle, activating repair mechanisms
• Apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage occurs:
  • If repairs cannot correct the damage 
  • To protect the tissue involved (cell dies rather than persists with an abnormal DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure, which has potential for malignant transformation Transformation Change brought about to an organism’s genetic composition by unidirectional transfer (transfection; transduction, genetic; conjugation, genetic, etc.) and incorporation of foreign DNA into prokaryotic or eukaryotic cells by recombination of part or all of that DNA into the cell’s genome. Bacteriology)

Membrane damage

• Normal membrane: made of lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids, with phospholipids Phospholipids Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. Lipid Metabolism as the most abundant form
• Common injurious stimuli:
  • Bacterial infection (toxins)
  • Viral proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis
  • Complement-mediated lysis
  • Physical/chemical agents 
  • Ischemia Ischemia A hypoperfusion of the blood through an organ or tissue caused by a pathologic constriction or obstruction of its blood vessels, or an absence of blood circulation. Ischemic Cell Damage
• Other mechanisms overlap and cause membrane damage:
  • Oxygen free radicals Free radicals Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. Ischemic Cell Damage → lipid peroxidation Lipid peroxidation Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. Drug-Induced Liver Injury → phospholipid loss
  • Mitochondrial damage → reduced ATP → decreased phospholipid synthesis Synthesis Polymerase Chain Reaction (PCR)
  • Calcium-dependent phospholipases → phospholipid breakdown → loss of membrane
  • Calcium-dependent proteases Proteases Proteins and Peptides → cytoskeletal filament damage → increased cellular swelling Swelling Inflammation and rupture 

Consequences of membrane damage

• ↑ Permeability of plasma membrane Plasma 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 → 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

Cell Injury by ER Stress

Endoplasmic reticulum Endoplasmic reticulum A system of cisternae in the cytoplasm of many cells. In places the endoplasmic reticulum is continuous with the plasma membrane (cell membrane) or outer membrane of the nuclear envelope. If the outer surfaces of the endoplasmic reticulum membranes are coated with ribosomes, the endoplasmic reticulum is said to be rough-surfaced; otherwise it is said to be smooth-surfaced. The Cell: Organelles

• Site of protein synthesis Synthesis Polymerase Chain Reaction (PCR) and folding, lipid synthesis Synthesis Polymerase Chain Reaction (PCR), and free calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes storage
• Chaperones: control protein folding Protein folding Processes involved in the formation of tertiary protein structure. Proteins and Peptides 
• Misfolded proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis: usually processed for proteolysis
• Unfolded protein response:
  • Signal transduction Transduction The transfer of bacterial DNA by phages from an infected bacterium to another bacterium. This also refers to the transfer of genes into eukaryotic cells by viruses. This naturally occurring process is routinely employed as a gene transfer technique. Bacteriology pathways that sense misfolded proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis
  • ↑ 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 Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis
• Injurious stimuli:
  • Genetic abnormalities/mutations
  • Ischemia Ischemia A hypoperfusion of the blood through an organ or tissue caused by a pathologic constriction or obstruction of its blood vessels, or an absence of blood circulation. Ischemic Cell Damage/ hypoxia Hypoxia Sub-optimal oxygen levels in the ambient air of living organisms. Ischemic Cell Damage 
  • Viral infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease

Consequences of ER stress

• ER stress: Protein folding Protein folding Processes involved in the formation of tertiary protein structure. Proteins and Peptides demand exceeds protein folding Protein folding Processes involved in the formation of tertiary protein structure. Proteins and Peptides capacity.
• Unrepaired proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis accumulate → apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage
• Diseases and their associated misfolded proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis:
  • Cystic Cystic Fibrocystic Change fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans: cystic Cystic Fibrocystic Change fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans transmembrane conductance regulator (CFTR)
  • α1- antitrypsin deficiency: α1- antitrypsin
  • Alzheimer’s disease: Aβ peptide
  • Familial hypercholesterolemia Familial hypercholesterolemia Lipid Disorders: LDL receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
  • Creutzfeldt-Jacob disease: prion

Cell Injury by Oxidative Stress

Free radicals Free radicals Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. Ischemic Cell Damage

• Molecular species with single unpaired electron in the outer orbit
• Highly reactive: attack adjacent molecules ( proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis, carbohydrates Carbohydrates A class of organic compounds composed of carbon, hydrogen, and oxygen in a ratio of cn(H2O)n. The largest class of organic compounds, including starch; glycogen; cellulose; polysaccharides; and simple monosaccharides. Basics of Carbohydrates, nucleic acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance)
• ROS: an oxygen-derived free radical Free Radical Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. Nitroimidazoles
• Principal free radicals Free radicals Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. Ischemic Cell Damage:
  • Superoxide anion Superoxide anion Highly reactive compounds produced when oxygen is reduced by a single electron. In biological systems, they may be generated during the normal catalytic function of a number of enzymes and during the oxidation of hemoglobin to methemoglobin. In living organisms, superoxide dismutase protects the cell from the deleterious effects of superoxides. Chronic Granulomatous Disease (O₂^–)
  • Hydrogen peroxide Hydrogen peroxide A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. Myeloperoxidase Deficiency (H₂O₂)
  • Hydroxyl radical (^•OH): most reactive ROS
  • Peroxynitrite (ONOO⁻)
• Injurious stimuli:
  • Ischemia-reperfusion injury
  • Chemical and radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma injury
  • Aging
  • Phagocytosis Phagocytosis The engulfing and degradation of microorganisms; other cells that are dead, dying, or pathogenic; and foreign particles by phagocytic cells (phagocytes). Innate Immunity: Phagocytes and Antigen Presentation of microbes

Oxidative stress

• Accumulation of ROS → oxidative stress:
  • From increased production of free radicals Free radicals Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. Ischemic Cell Damage
  • From decreased scavenging of ROS
• The following generate free radicals Free radicals Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. Ischemic Cell Damage:
  • Reduction-oxidation reactions:
    • O₂ is reduced with transfer of electrons to H₂ to form water molecules.
    • Partially reduced intermediates → free radicals Free radicals Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. Ischemic Cell Damage
  • Exposure to ionizing radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma and ultraviolet rays Ultraviolet rays That portion of the electromagnetic spectrum immediately below the visible range and extending into the x-ray frequencies. The longer wavelengths (near-uv or biotic or vital rays) are necessary for the endogenous synthesis of vitamin D and are also called antirachitic rays; the shorter, ionizing wavelengths (far-uv or abiotic or extravital rays) are virucidal, bactericidal, mutagenic, and carcinogenic and are used as disinfectants. Basal Cell Carcinoma (BCC)
  • Polymorphonuclear neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation produce free radicals Free radicals Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. Ischemic Cell Damage during inflammatory response.
  • Metabolism of exogenous chemicals (e.g., carbon tetrachloride Carbon tetrachloride A solvent for oils, fats, lacquers, varnishes, rubber waxes, and resins, and a starting material in the manufacturing of organic compounds. Poisoning by inhalation, ingestion or skin absorption is possible and may be fatal. Drug-Induced Liver Injury)
  • Reactions with transition metals (e.g., iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements or copper Copper A heavy metal trace element with the atomic symbol cu, atomic number 29, and atomic weight 63. 55. Trace Elements)
  • Nitric oxide Nitric Oxide A free radical gas produced endogenously by a variety of mammalian cells, synthesized from arginine by nitric oxide synthase. Nitric oxide is one of the endothelium-dependent relaxing factors released by the vascular endothelium and mediates vasodilation. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic gmp. Pulmonary Hypertension Drugs reaction (with superoxide) in macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation, producing peroxynitrite (ONOO⁻), a free radical Free Radical Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. Nitroimidazoles

Consequences of oxidative stress

• Membrane damage by lipid peroxidation Lipid peroxidation Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. Drug-Induced Liver Injury:
  • ROS attack unsaturated fatty acids Unsaturated fatty acids Fatty acids in which the carbon chain contains one or more double or triple carbon-carbon bonds. Fatty Acids and Lipids of the membrane.
  • Lipid hydroperoxides are produced → ↓ function of membranes
• DNA damage DNA Damage Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a mutation or a block of DNA replication. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (pyrimidine dimers) or interstrand crosslinking. Damage can often be repaired (DNA repair). If the damage is extensive, it can induce apoptosis. DNA Repair Mechanisms or fragmentation Fragmentation Chronic Apophyseal Injury 
• Oxidative modification of proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis: ↑ protein cross-linking leads to ↑ degradation and ↓ activity

Antioxidants

• Defense against free radicals Free radicals Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. Ischemic Cell Damage (ROS scavengers)
• Immediately eliminate ROS produced during mitochondrial respiration Respiration The act of breathing with the lungs, consisting of inhalation, or the taking into the lungs of the ambient air, and of exhalation, or the expelling of the modified air which contains more carbon dioxide than the air taken in. Nose Anatomy (External & Internal) and energy generation
• Low amount of free radicals Free radicals Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. Ischemic Cell Damage may be present but are unable to induce damage.
• Non-enzymatic mechanism:
  • Vitamins A, C, E
  • Glutathione
  • Ferritin Ferritin Iron-containing proteins that are widely distributed in animals, plants, and microorganisms. Their major function is to store iron in a nontoxic bioavailable form. Each ferritin molecule consists of ferric iron in a hollow protein shell (apoferritins) made of 24 subunits of various sequences depending on the species and tissue types. Hereditary Hemochromatosis
  • Transferrin Transferrin An iron-binding beta1-globulin that is synthesized in the liver and secreted into the blood. It plays a central role in the transport of iron throughout the circulation. Heme Metabolism
  • Ceruloplasmin Ceruloplasmin A multi-copper blood ferroxidase involved in iron and copper homeostasis and inflammation. Wilson Disease
• Enzymatic mechanism:
  • Glutathione peroxidase: catalyzes breakdown of hydroxyl radicals
  • Superoxide dismutase Superoxide dismutase An oxidoreductase that catalyzes the reaction between superoxides and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. Myeloperoxidase Deficiency (SOD): converts superoxide to hydrogen peroxide Hydrogen peroxide A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. Myeloperoxidase Deficiency (H₂O₂)
  • Catalase Catalase An oxidoreductase that catalyzes the conversion of hydrogen peroxide to water and oxygen. It is present in many animal cells. A deficiency of this enzyme results in acatalasia. Nocardia/Nocardiosis: breaks down H₂O₂

Cell Death by Apoptosis

Programmed cell death ( apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage)

• 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 A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure and proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis in cells that are destined to die
• Features:
  • ↓ Cell size, eosinophilic cytoplasm
  • Chromatin Chromatin The material of chromosomes. It is a complex of dna; histones; and nonhistone proteins found within the nucleus of a cell. DNA Types and Structure condensation ( chromatin Chromatin The material of chromosomes. It is a complex of dna; histones; and nonhistone proteins found within the nucleus of a cell. DNA Types and Structure aggregates peripherally)
  • Cytoplasmic blebs Blebs Ischemic Cell Damage and apoptotic bodies
  • Phagocytosis Phagocytosis The engulfing and degradation of microorganisms; other cells that are dead, dying, or pathogenic; and foreign particles by phagocytic cells (phagocytes). Innate Immunity: Phagocytes and Antigen Presentation of apoptotic cells by macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation

Apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage 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 Regression Corneal Abrasions, Erosion, and Ulcers ( weaning Weaning Techniques for effecting the transition of the respiratory-failure patient from mechanical ventilation to spontaneous ventilation, while meeting the criteria that tidal volume be above a given threshold (greater than 5 ml/kg), respiratory frequency be below a given count (less than 30 breaths/min), and oxygen partial pressure be above a given threshold (pao2 greater than 50mm hg). Weaning studies focus on finding methods to monitor and predict the outcome of mechanical ventilator weaning as well as finding ventilatory support techniques which will facilitate successful weaning. Present methods include intermittent mandatory ventilation, intermittent positive pressure ventilation, and mandatory minute volume ventilation. Invasive Mechanical Ventilation)
  • 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: Histology (may cause autoimmune disease)
  • Removal of neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation 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: Histology in bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis) 
• Pathologic conditions:
  • DNA damage DNA Damage Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a mutation or a block of DNA replication. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (pyrimidine dimers) or interstrand crosslinking. Damage can often be repaired (DNA repair). If the damage is extensive, it can induce apoptosis. DNA Repair Mechanisms: Apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage prevents survival of cells with DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure mutations (protective effect).
  • Removal of improperly folded proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis
  • Ductal obstruction (e.g., kidney, parotid gland Parotid gland The largest of the three pairs of salivary glands. They lie on the sides of the face immediately below and in front of the ear. Salivary Glands: Anatomy): Atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation occurs by apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage. 
  • Infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease (particularly viral illness): Cytotoxic Cytotoxic Parvovirus B19 T lymphocytes T lymphocytes Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions induce apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage to eliminate infected cells.

Mechanisms of Apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage

Caspases:

• Cystein aspartic acid proteases Proteases Proteins and Peptides
• Exist in inactive form, requiring enzymatic cleavage to be activated
• Active caspases: a marker for cells undergoing apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage
• Phases of apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage:
  • Initiation: activation of caspases → cascade of other caspases
    • Intrinsic pathway Intrinsic pathway The intrinsic pathway is mainly responsible for the amplification of factor X activation Hemostasis
    • Extrinsic pathway Extrinsic pathway The extrinsic pathway is the primary physiological mechanism by which clotting is initiated Hemostasis
  • Execution: terminal caspases → cellular fragmentation Fragmentation Chronic Apophyseal Injury

Intrinsic pathway Intrinsic pathway The intrinsic pathway is mainly responsible for the amplification of factor X activation Hemostasis (initiation):

• Mitochondrial pathway
• In viable cells, growth factors and survival signals reduce mitochondrial leakage of cytochrome c by producing anti-apoptotic proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis (principal members):
  • BCL2
  • BCL-XL
  • MCL-1
• In damaged cells, loss of survival signals, DNA damage DNA Damage Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a mutation or a block of DNA replication. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (pyrimidine dimers) or interstrand crosslinking. Damage can often be repaired (DNA repair). If the damage is extensive, it can induce apoptosis. DNA Repair Mechanisms, protein misfolding:
  • Allow cytochrome c leakage from the mitochondria Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive ribosomes, transfer RNAs; amino Acyl tRNA synthetases; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs. Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. The Cell: Organelles by producing pro-apoptotic proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis (main members):
    • BAX
    • BAK 
  • Activate apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage initiators (BH3-only proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis): BAD, BIM, BID, Puma, Noxa
• Events:
  • Increased permeability of the mitochondrial outer membrane → release of cytochrome c into the cytoplasm 
  • Cytochrome c initiates apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage.
  • 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 Extrinsic pathway The extrinsic pathway is the primary physiological mechanism by which clotting is initiated Hemostasis (initiation):

• Death receptor-initiated pathway
• Plasma membrane Plasma 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 death receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors initiate this pathway.
• Death receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors:
  • Members of tumor Tumor Inflammation necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage factor ( 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 Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors:
    • Type 1 Type 1 Spinal Muscular Atrophy 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 Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors ( TNFR1 TNFR1 A tumor necrosis factor receptor subtype that has specificity for tumor necrosis factor alpha and lymphotoxin alpha. It is constitutively expressed in most tissues and is a key mediator of tumor necrosis factor signaling in the vast majority of cells. The activated receptor signals via a conserved death domain that associates with specific tnf receptor-associated factors in the cytoplasm. Tumor Necrosis Factor (TNF))
    • Fas (CD95)
• Events:
  • FasL ( Fas ligand Fas ligand A transmembrane protein belonging to the tumor necrosis factor superfamily that was originally discovered on cells of the lymphoid-myeloid lineage, including activated T-lymphocytes and natural killer cells. It plays an important role in immune homeostasis and cell-mediated toxicity by binding to the fas receptor and triggering apoptosis. Tumor Necrosis Factor (TNF) on T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions and cytotoxic Cytotoxic Parvovirus B19 T lymphocytes T lymphocytes Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions) binds to Fas → a signal for apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage 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 Sequential Computed Tomography (CT) activation of executioner caspases.
  • Inhibitor of deoxyribonuclease Deoxyribonuclease Enzymes which catalyze the hydrolases of ester bonds within DNA. Staphylococcus (DNase) is cleaved → active DNase → nuclear proteolysis and fragmentation Fragmentation Chronic Apophyseal Injury
  • Cytoskeleton Cytoskeleton The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. The Cell: Cytosol and Cytoskeleton proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis break down.
  • Cell fragments → cytoplasmic blebs Blebs Ischemic Cell Damage form → become apoptotic bodies
  • Apoptotic bodies are eaten by phagocytes.
• Efferocytosis:
  • Apoptotic cell phagocytosis Phagocytosis The engulfing and degradation of microorganisms; other cells that are dead, dying, or pathogenic; and foreign particles by phagocytic cells (phagocytes). Innate Immunity: Phagocytes and Antigen Presentation
  • Rapid clearance with reduced production of pro-inflammatory cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response → limited inflammatory reactions even with substantial apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage

Clinical correlation Correlation Determination of whether or not two variables are correlated. This means to study whether an increase or decrease in one variable corresponds to an increase or decrease in the other variable. Causality, Validity, and Reliability

• Tumor Tumor Inflammation suppressor genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure:
  • Prevent uncontrolled cell proliferation and lead cells to apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage. 
  • Inactivation → malignant neoplasm
• Follicular lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum:
  • Associated with chromosomal translocations involving BCL2 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics
  • Has BCL2 over-expression
  • Increased anti-apoptotic mechanisms → expansion of malignant cells

Cell Death by Necrosis

Process of necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage

• Uncontrolled cell death after irreversible injury Irreversible Injury Ischemic Cell Damage:
  • 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 Leukocytes White blood cells. These include granular leukocytes (basophils; eosinophils; and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). White Myeloid Cells: Histology to the site of necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage.
• Clinical correlation Correlation Determination of whether or not two variables are correlated. This means to study whether an increase or decrease in one variable corresponds to an increase or decrease in the other variable. Causality, Validity, and Reliability (tests for tissue-specific injury represent circulating intracellular contents):
  • Troponin: from damaged cardiac muscle Cardiac muscle The muscle tissue of the heart. It is composed of striated, involuntary muscle cells connected to form the contractile pump to generate blood flow. Muscle Tissue: Histology cells
  • Alkaline phosphatase Alkaline Phosphatase An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. Osteosarcoma: from bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy 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: Histology
  • Transaminases Transaminases A subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins. Autoimmune Hepatitis: from hepatocytes Hepatocytes The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. Liver: Anatomy

Cellular changes

• Cytoplasmic changes:
  • Eosinophilic cytoplasm: due to denatured cytoplasmic proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis (which bind BIND Hyperbilirubinemia of the Newborn to eosin dye) 
  • Vacuolated cytoplasm: Enzymes digest organelles, leaving “moth-eaten” appearance.
  • Myelin figures: large whorled phospholipid precipitates (from the damaged membrane), which are phagocytosed or degraded to fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance
• Nuclear changes (1 of 3 patterns):
  • Karyolysis Karyolysis Ischemic Cell Damage: reduced basophilia due to DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure loss (effect of DNAse)
  • Pyknosis Pyknosis Ischemic Cell Damage: nuclear shrinkage and increased basophilia (condensation of chromatin Chromatin The material of chromosomes. It is a complex of dna; histones; and nonhistone proteins found within the nucleus of a cell. DNA Types and Structure into a dense basophilic mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast)
  • Karyorrhexis Karyorrhexis Ischemic Cell Damage: fragmentation Fragmentation Chronic Apophyseal Injury of the nucleus Nucleus Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (cell nucleolus). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the endoplasmic reticulum. A cell may contain more than one nucleus. The Cell: Organelles

Patterns of Necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage

Coagulative necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage:

• 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 Ischemia A hypoperfusion of the blood through an organ or tissue caused by a pathologic constriction or obstruction of its blood vessels, or an absence of blood circulation. Ischemic Cell Damage or hypoxic injury
• Infarct Infarct Area of necrotic cells in an organ, arising mainly from hypoxia and ischemia Ischemic Cell Damage: localized area of coagulative necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage 
• Seen in myocardial and renal infarction Renal Infarction Imaging of the Urinary System

Liquefactive necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage:

• Colliquative necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage
• Tissue is digested and dissolved into a viscous liquid.
• Seen in bacterial and fungal infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease, which stimulate leukocytes Leukocytes White blood cells. These include granular leukocytes (basophils; eosinophils; and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). White Myeloid Cells: Histology 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 Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage mechanism used by hypoxic central nervous system Central nervous system The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. Nervous System: Anatomy, Structure, and Classification cells
• Coagulative and liquefactive necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage: not mutually exclusive
• Damaged cardiac myocytes Myocytes Mature contractile cells, commonly known as myocytes, that form one of three kinds of muscle. The three types of muscle cells are skeletal, cardiac, and smooth. They are derived from embryonic (precursor) muscle cells called myoblasts. Muscle Tissue: Histology undergo coagulative necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage; as leukocytes Leukocytes White blood cells. These include granular leukocytes (basophils; eosinophils; and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). White Myeloid Cells: Histology 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 Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage occurs.

Caseous necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage :

• 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 Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
• Mycolic acid Mycolic acid Long fatty acids found in the cell walls of some actinobacteria, including Mycobacterium tuberculosis. Tuberculosis from the mycobacterial cell wall Cell wall The outermost layer of a cell in most plants; bacteria; fungi; and algae. The cell wall is usually a rigid structure that lies external to the cell membrane, and provides a protective barrier against physical or chemical agents. Cell Types: Eukaryotic versus Prokaryotic induces granuloma formation.

Fat necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage:

• 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: Histology due to trauma or enzymatic release
• Release of pancreatic lipases Lipases An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. Lipid Metabolism 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: Anatomy → destruction of adipocytes Adipocytes Cells in the body that store fats, usually in the form of triglycerides. White adipocytes are the predominant type and found mostly in the abdominal cavity and subcutaneous tissue. Brown adipocytes are thermogenic cells that can be found in newborns of some species and hibernating mammals. Adipose Tissue: Histology 
• Liberated fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance combine with calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes, producing chalky-white areas (fat saponification Saponification Fat Necrosis of the Breast).
• Seen in acute pancreatitis Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute Pancreatitis, fat necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage of the breast

Fibrinoid necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage:

• Microscopic change
• Deposition of immune complexes Immune complexes The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. C3 Deficiency in the walls of vessels
• Fibrinoid: fibrin Fibrin A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. Rapidly Progressive Glomerulonephritis combined with immune complexes Immune complexes The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. C3 Deficiency deposited in the vessel walls (homogeneously pink in hematoxylin and eosin stains)

Gangrenous necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage:

• Not a pattern of necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage; a clinical description used when a limb becomes necrotic due to ischemia Ischemia A hypoperfusion of the blood through an organ or tissue caused by a pathologic constriction or obstruction of its blood vessels, or an absence of blood circulation. Ischemic Cell Damage 
• Indicates coagulative necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage of multiple layers of tissue (dry gangrene Gangrene Death and putrefaction of tissue usually due to a loss of blood supply. Small Bowel Obstruction)
• With superimposed bacterial infection, liquefaction necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage 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 and leukocytes Leukocytes White blood cells. These include granular leukocytes (basophils; eosinophils; and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). White Myeloid Cells: Histology (wet gangrene Gangrene Death and putrefaction of tissue usually due to a loss of blood supply. Small Bowel Obstruction).

Dystrophic calcification Dystrophic Calcification Cellular Accumulations:

• Necrotic cells: eliminated by enzymatic digestion Digestion Digestion refers to the process of the mechanical and chemical breakdown of food into smaller particles, which can then be absorbed and utilized by the body. Digestion and Absorption and phagocytosis Phagocytosis The engulfing and degradation of microorganisms; other cells that are dead, dying, or pathogenic; and foreign particles by phagocytic cells (phagocytes). Innate Immunity: Phagocytes and Antigen Presentation
• Inadequately reabsorbed necrotic cells become a nidus of calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes and mineral deposition.

Other Cellular Mechanisms

Necroptossis

• Programmed necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage
• Caspase-independent cell death
• Similar to necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage in morphology, with apoptotic type of cell death 
• Clinical correlation Correlation Determination of whether or not two variables are correlated. This means to study whether an increase or decrease in one variable corresponds to an increase or decrease in the other variable. Causality, Validity, and Reliability:
  • Physiologic: mammalian growth plate
  • Pathologic: steatohepatitis Steatohepatitis Drug-Induced Liver Injury, Parkinson’s disease

Pyroptosis

• Apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage accompanied by cytokine IL-1 ( interleukin-1 Interleukin-1 A soluble factor produced by monocytes; macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. Interleukin-1 is a general term refers to either of the two distinct proteins, interleukin-1alpha and interleukin-1beta. The biological effects of il-1 include the ability to replace macrophage requirements for t-cell activation. Interleukins: fever-inducing cytokine)
• Pathway of apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage releases inflammatory mediators.
• Clinical correlation Correlation Determination of whether or not two variables are correlated. This means to study whether an increase or decrease in one variable corresponds to an increase or decrease in the other variable. Causality, Validity, and Reliability: death of cells infected by microbes 

Ferroptosis

• Iron-dependent pathway of cell death, characterized by lipid peroxidation Lipid peroxidation Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. Drug-Induced Liver Injury
• Results in the loss of membrane permeability (ruptured mitochondrial membrane)
• Occurs with excessive iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements or ROS, which glutathione-dependent defenses cannot handle
• Clinical correlation Correlation Determination of whether or not two variables are correlated. This means to study whether an increase or decrease in one variable corresponds to an increase or decrease in the other variable. Causality, Validity, and Reliability: cancer, neurodegenerative diseases, and stroke

Autophagy Autophagy The segregation and degradation of various cytoplasmic constituents via engulfment by multivesicular bodies; vacuoles; or autophagosomes and their digestion by lysosomes. It plays an important role in biological metamorphosis and in the removal of bone by osteoclasts. Defective autophagy is associated with various diseases, including neurodegenerative diseases and cancer. Cellular Adaptation

• “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 Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive ribosomes, transfer RNAs; amino Acyl tRNA synthetases; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs. Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. The Cell: Organelles or plasma membrane Plasma 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
  • 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 Vesicle Primary Skin Lesions, autophagosome, forms.
  • Mature autophagosome fuses with a lysosome (autophagolysosome), resulting in the degradation of contents.
• Clinical correlation Correlation Determination of whether or not two variables are correlated. This means to study whether an increase or decrease in one variable corresponds to an increase or decrease in the other variable. Causality, Validity, and Reliability:
  • Cancer
  • Neurodegenerative disorders (e.g., Alzheimer’s disease)
  • Infectious disease
  • Inflammatory bowel disease