Adaptation injury and death

Adaptation: Discuss the pathogenesis of hypertrophy, hyperplasia, atrophy, and metaplasia at both the cellular and organ level and compare and contrast physiologic and pathologic causes.

Necrosis: Compare and contrast the morphologic differences in the different forms of necrosis with emphasis on causative mechanisms.

Ischemia: Compare and contrast ischemia and hypoxia and discuss the molecular events that occur at a cellular level in response to a lack of oxygen, emphasizing the events that distinguish reversible from irreversible injury. Discuss reperfusion injury.

Oxidative Stress: Define the term “free radical”. Discuss their formation, mechanisms for causing injury, and how they are removed.

 Cell Death: Compare and contrast the etiology, mechanisms, and morphology of apoptosis with those of necrosis. Discuss the circumstances that determine whether a cell will undergo apoptosis or necrosis.

Intracellular Accumulations: Describe the mechanisms of intracellular

accumulations and their morphologic and clinical consequences.

Calcification: Compare and contrast dystrophic and metastatic calcification in terms of pathogenesis, morphologic appearance, and clinical significance

What is the definition of Pathology

A bridging discipline involving both basic sciences and clinical practice

• Studies the structural and functional changes in cells, tissues, and organs that underlie disease states

Etiology definition

the cause

Pathogenesis definition

the mechanism of the development of the disease

•Morphology

structural alterations in cells and tissues due to the disease process

Clinical Signs and Symptoms

functional consequences of the morphologic changes

Causes of Cell Injury

• Sequence of Events in Cell Injury and Cell Death

• […]

• […]

• […]

  • Morphologic Patterns of Tissue Necrosis

• Apoptosis

• Autophagy

• Reversible Injury

• Irreversible Injury (Cell Death)

• Necrosis

• Apoptosis[…]

Cells tend to maintain their intracellular milieu in a narrow range of physiologic parameters. They react to adverse influences by:

• […]

• […]
• […]

• Adapting
• Sustaining reversible injury
• Suffering irreversible injury and dying

Causes of Cellular Injury

• […]
• […]
• […]

• […]
• […]
• […]
• […]

• Oxygen deprivation
• Physical agents
• Chemical agents and drugs

• Infectious agents
• Immunologic reactions
• Genetic derangements
• Nutritional imbalances

Reversible Cell Injury

• The stage of injury at which the deranged function and morphology of the injured cell can […] if the damaging stimulus is removed

• Morphology

• Cellular swelling

  • Commonly seen

  • Associated with increased permeability of the cell membrane

  • Can be seen in individual cells, if many cells are affected—can be seen in the organ

  • AKA: hydropic change or vacuolar degeneration

• Fatty change:

• Manifested by the appearance of triglyceride-containing lipid vacuoles in the cytoplasm

• Principally encountered in organs associated with lipid metabolism

return to normal

Reversible Cell Injury

• The stage of injury at which the deranged function and morphology of the injured cell can return to normal if the damaging stimulus is removed

• Morphology

• Cellular swelling

  • […]

  • Associated with increased permeability of the [part of the cell]

  • Can be seen in individual cells, if many cells are affected—can be seen in the […]

  • AKA: […]

• Fatty change:

• Manifested by the appearance of triglyceride-containing lipid vacuoles in the cytoplasm

• Principally encountered in organs associated with lipid metabolism

• Commonly seen

• Associated with increased permeability of the cell membrane

• Can be seen in individual cells, if many cells are affected—can be seen in the organ

• AKA: hydropic change or vacuolar degeneration

Reversible Cell Injury

• The stage of injury at which the deranged function and morphology of the injured cell can return to normal if the damaging stimulus is removed

• Morphology

• Cellular swelling

  • Commonly seen

  • Associated with increased permeability of the cell membrane

  • Can be seen in individual cells, if many cells are affected—can be seen in the organ

  • AKA: hydropic change or vacuolar degeneration

• Fatty change:

• Manifested by the appearance of […] in the [part of the cell]

• Principally encountered in organs associated with […]

• triglyceride-containing lipid vacuoles in the cytoplasm

• lipid metabolism

Reversible Cell Injury

• Morphology

• The cytoplasm of injured cells my become more [eosinophilic (redder) or basophillic (bluer)]

• Blebbing of cell membrane

• Blunting or distortion of [part of the cell]

• Loosening of intercellular attachments

• Mitochondrial changes

  • Swelling

  • Appearance of phospholipid-rich amorphous densities

• Dilation of the ER with detachment and dissociation of ribosomes

• Nuclear alterations:

  • Chromatin clumping

• Collections of phospholipids called “myelin figures” derived from damaged cellular membrane

• eosinophilic (redder)

• microvilli

Reversible Cell Injury

• Morphology

• The cytoplasm of injured cells my become more eosinophilic (redder)

• Blebbing of cell membrane

• Blunting or distortion of microvilli

• Loosening of intercellular attachments

• Mitochondrial changes

  • […]

  •[…]

• Dilation of the ER with detachment and dissociation of ribosomes

• Nuclear alterations:

  • Chromatin clumping

• Collections of phospholipids called “myelin figures” derived from damaged cellular membrane

• Swelling

• Appearance of phospholipid-rich amorphous densities

Reversible Cell Injury

• Morphology

• The cytoplasm of injured cells my become more eosinophilic (redder)

• Blebbing of cell membrane

• Blunting or distortion of microvilli

• Loosening of intercellular attachments

• Mitochondrial changes

  • Swelling

  • Appearance of phospholipid-rich amorphous densities

• Dilation of the ER with detachment and dissociation of ribosomes

• Nuclear alterations:

  • […]

• Collections of phospholipids called “[…]” derived from damaged cellular membrane

• Chromatin clumping

• myelin figures

Irreversible Injury (Cell Death)

• With persistent or excessive exposure to […], the injured cell reaches a “point of no return” and undergoes cell death

• There are no definitive morphologic or biochemical correlates of irreversible injury but there are three phenomena that characterize it:

• Inability to restore mitochondrial function (oxidative phosphorylation and ATP generation)

• Loss of structure and function of the plasma membrane and intracellular membranes

• Loss of DNA and chromatin structural integrity

Cell Death

• Cell death occurs by different mechanisms, depending on the nature and severity of the insult

• Necrosis
• Severe disturbances such as loss of oxygen or nutrients, toxins,

others.
• Accidental

• Apoptosis
• Less severe injury or the need to eliminate cells during normal

processes

• noxious agents

Irreversible Injury (Cell Death)

• With persistent or excessive exposure to noxious agents, the injured cell reaches a “point of no return” and undergoes cell death

• There are no definitive morphologic or biochemical correlates of irreversible injury but there are three phenomena that characterize it:

• Inability to restore [what important function] (oxidative phosphorylation and ATP generation)

• Loss of structure and function of the [part of the cell] and [part of the cell]

• Loss of [DNA or RNA] and chromatin structural integrity

Cell Death

• Cell death occurs by different mechanisms, depending on the nature and severity of the insult

• Necrosis
• Severe disturbances such as loss of oxygen or nutrients, toxins,

others.
• Accidental

• Apoptosis
• Less severe injury or the need to eliminate cells during normal

processes

• Inability to restore mitochondrial function (oxidative phosphorylation and ATP generation)

• Loss of structure and function of the plasma membrane and intracellular membranes

• Loss of DNA and chromatin structural integrity

types of cell death

• necrosis

• apoptosis

Necrosis

• Severe disturbances such as loss of oxygen or nutrients, toxins,

others.
• Accidental

Apoptosis

• Less severe injury or the need to eliminate cells during normal

processes • Regulated

Necrosis

• Associated with loss of […]

• Leakage of […]
• Ultimately dissolution of the cell

• membrane integrity

• cellular contents

Necrosis

• The leaked cellular contents often elicit a local host reaction

Inflammation

• This process cleans up […] and starts the repair process
  • Enzymes responsible for digesting the cellular debris can come from the […], or from […]

• It is often the culmination of […] that cannot be corrected

• cellular debris

• dead cell itself

• inflammatory cells

• reversible injury

Necrosis

• The biochemical mechanisms of necrosis vary with different injurious stimuli

• Mechanisms can include:

• […]

• […]

• […]

• Failure of energy generation (ATP)

• Damage to cellular membranes

• Irreversible damage to cellular proteins, lipids, and nucleic acids

Necrosis: Morphology

• Cytoplasmic changes:

• Increased [eosinophilia or basophilia]

• May have a […] appearance

• Myelin figures are more prominent in […]

• Vacuoles appear after digestion of organelles

• Discontinuities in plasma and organelle membranes

• eosinophilia

• glassy, homogenous appearance

• necrotic cells

Pyknosis

• Characterized by nuclear shrinkage and increased basophilia

• Nucleus becomes a dark, shrunken mass which can undergo fragmentation

Karyorrhexis

The nucleus fragments into visible fragments

Karyolysis

The basophilic nucleus fades away due to digestion of DNA by deoxyribonuclease

Fates of Necrotic Cells
• May persist for some time or be digested by enzymes and disappear

• They may be replaced by […], which are either […] by inflammatory cells or further degraded into fatty acids

• myelin figures

• phagocytosed

Necrosis
• Morphologic changes that occur after cell death in living tissue

• Types

• […]

• […]

• […]

• […]

• Coagulative

• Liquefactive

• Caseous

• Fat

Coagulative Necrosis

• A form of necrosis in which the underlying architecture of the tissue is preserved for at least [how many days] following cell death

• Characteristic of infarction in solid organs, except the [what organ]

• The injury denatures both structural proteins and enzymes, blocking […]

• Leukocytes are recruited to the area and ultimately digest the dead cells

• Cellular debris is removed by [what process] (neutrophils and macrophages)

• several days

• beain

• proteolysis

• phagocytosis

Liquefactive Necrosis

• Is seen in:

• […]

• […]

• In these cases, the infection results in a rapid accumulation of inflammatory cells—pus

• Enzymes from these cells digest (“liquify”) the tissue

• Hypoxic death of cells in the CNS also results in liquefactive necrosis

• Focal bacterial infections

• Occasionally in fungal infections

Liquefactive Necrosis

• Is seen in:

• Focal bacterial infections

• Occasionally in fungal infections

• In these cases, the infection results in a rapid accumulation of inflammatory cells—pus

• Enzymes from these cells digest (“liquify”) the tissue

• [NEED TO KNOW]

Hypoxic death of cells in the CNS also results in liquefactive necrosis

Gangrenous Necrosis

• […]

• Used in clinical practice

• Typically refers to the condition of a limb that has […] and undergoes coagulative necrosis involving multiple tissue layers

• Bacterial infection can occur on top of this, superimposing liquefactive necrosis on the coagulative necrosis (“wet gangrene”)

• Not a distinctive pattern of cell death

• lost its blood supply

Gangrenous Necrosis

• Not a distinctive pattern of cell death

• Used in clinical practice

• Typically refers to the condition of a limb that has lost its blood supply and undergoes coagulative necrosis involving multiple tissue layers

• […] can occur on top of this, superimposing liquefactive necrosis on the coagulative necrosis (“[other name]”)

• Bacterial infection

• wet gangrene

Caseous Necrosis

• Caseous means “[…]”

• Most often encountered in [what disease]

• Obliteration of the tissue architecture

• Microscopic appearance—collection of fragmented or lysed cells with a granular pink appearance, often surrounded by macrophages and lymphocytes

• cheese like

• TB

Caseous Necrosis

• Caseous means “cheese like”

• Most often encountered in TB

• Obliteration of the tissue architecture

• Microscopic appearance—collection of […] with a […], often surrounded by macrophages and lymphocytes

• fragmented or lysed cells

• granular pink appearance

Fat Necrosis

• Refers to focal areas of […]
• Can occur in the setting of release of activated […] into the substance of the pancreas and peritoneal cavity
• Can occur with […] to areas with adipose tissue

• fat destruction

• pancreatic lipases

• trauma

Fibrinoid Necrosis

• A special form of necrosis occurring in [what type of reactions] in which complexes of antigens and antibodies are deposited in blood vessel walls

• May also occur with [type of disease] (severe hypertension)

• Deposited immune complexes and plasma proteins leak into the vessel wall, producing a bright pink amorphous appearance on H&E

• immune reactions

• malignant hypertension

Fibrinoid Necrosis

• A special form of necrosis occurring in immune reactions in which complexes of antigens and antibodies are deposited in blood vessel walls

• May also occur with malignant hypertension (severe hypertension)

• Deposited immune complexes and plasma proteins leak into the […], producing a […] appearance on H&E

• vessel wall

• bright pink amorphous

Apoptosis

• A distinctive form of cell death designed to eliminate unwanted host cells

• Occurs physiologically

• […]

• […]

• […]

• […]

• […]

• During embryogenesis

• Hormone-dependent physiologic involution

• Cell deletion in proliferating populations

• Deletion of autoreactive T cells in the thymus

• After a variety of mild injurious stimuli

Apoptosis

• In pathologic conditions

• Eliminates cells damaged beyond repair

  • […]

  • […]

  • […]

• Severe DNA damage

• Accumulation of misfolded proteins

• Certain infectious agents

Apoptosis

• Induced by a tightly regulated intracellular program

• Cells activate enzymes which degrade the cells own DNA and nuclear and cytoplasmic proteins

• The cellular membrane remains intact

• The debris is rapidly cleared—[reaponse]

• no inflammatory response

Apoptosis: MolecularMechanisms

• The fundamental event is the activation of capiases

• These activated enzymes cleave numerous targets

• End result is the release of nucleases which degrade DNA.

• Two distinctive pathways cause caspase activation

• Mitochondrial ([Intrinsic or extrinsic]) Pathway
• Death Receptor ([Intrinsic orExtrinsic]) Pathway

• Mitochondrial (Intrinsic) Pathway
• Death Receptor (Extrinsic) Pathway

Mitochondrial Pathway of Apoptosis

• The choice between whether or not apoptosis will occur is determined by the permeability of the mitochondria.

  • When cells are deprived of […] and […], or exposed to agents which damage DNA, or cause the accumulation of misfolded proteins; sensors are activated.

• Other related sensors inhibit the anti-apoptotic molecules Bcl-2 and Bcl-xL.

• [what component] activates caspases

• growth factors

• tropic hormones

• Cytochrome c

Mitochondrial Pathway of Apoptosis

• Some of these sensors (BH3-only proteins) activate pro-apoptotic molecules ([…])

• These dimerize and insert themselves into the mitochondrial channel, forming channels through which mitochondrial proteins escape into the cytosol

Bax and Bak

Permeability of Mitochondrial Membrane • Controlled by more than 20 proteins

• Prototype is BCL-2

• In healthy cells

  • […] and […] keep cells viable

  • Are produced in response to growth factors

  • Function by holding two pro-apoptotic members of the family (BAX and BAK) in check

  • With cessation of growth signals, damage to DNA, or accumulation of misfolded protein, sensors ( BH3-only protein) become activated

  • Shift balance to favor BAX and BAK

• BCL-2

• BCL-XL

Death Receptor Pathway of Apoptosis

• A large number of cells express surface molecules, called death receptors.

• Trigger apoptosis

• Most belong to the […] receptor family

• Contain a “[…]” in their cytoplasmic regions

• Mediates interactions with other proteins

• TNF (tumor necrosis factor)

• death domain

Death Receptor Pathway of Apoptosis

• Prototypic death receptors

• […]

• […]

• Activation of these receptors causes:

• Binding and aggregation of […] leading to its activation

• Caspase-8 may activate pro-apoptotic members of the Bcl-2 family--feeding into the […]

• Type 1 TNF

• Fas (CD95)

• caspase-8

• mitochondrial pathway

Clearance of Apoptotic Cells

• Induce phagocytosis by producing a number of “eat me” signals • Macrophages clear the apoptotic bodies
• […]

No acute inflammatory response

Apoptosis: Morphology

• […]
• […]
• […]

• […]

• macrophages

• Cell shrinkage
• Chromatin condensation
• Formation of cytoplasmic blebs and apoptotic bodies

• Phagocytosis of apoptotic cells or cell bodies

• macrophages

Autophagy

• Refers to lysosomal digestion of the cell’s own components

• “Self-eating

• Survival mechanism

• Allows starved cell to live by eating its own contents and recycling them to provide nutrients and energy

• Intracellular organelles are sequestered in an […]

• The vacuole fuses with lysosomes to form an […]

• Contained cellular components are digested

• May be associated with […]

• ER-derived double membrane phagosome

• autophogolysosome

• atrophy

Atrophy: Morphology

• Loss of cellular constituents

• […]

• […]

• Degradation of cellular proteins

• Ubiquitin-proteosome pathway

• Ubiquitin ligases are activated in nutrient deficiency and disuse

• Ubiquitin is attached to cellular proteins, targeting them for degradation in the proteosome

Autophagy

• Increased number of autophagic vacuoles • Residual bodies

• Lipofuscin granules

• May progress to cell injury and death

• Decreased protein synthesis

• Increased protein degradation

Atrophy: Morphology

• Loss of cellular constituents

• Decreased protein synthesis

• Increased protein degradation

• Degradation of cellular proteins

• […]

• […]

• […]

Autophagy

• Increased number of autophagic vacuoles • Residual bodies

• Lipofuscin granules

• May progress to cell injury and death

• Ubiquitin-proteosome pathway

• Ubiquitin ligases are activated in nutrient deficiency and disuse

• Ubiquitin is attached to cellular proteins, targeting them for degradation in the proteosome

Atrophy: Morphology

• Loss of cellular constituents

• Decreased protein synthesis

• Increased protein degradation

• Degradation of cellular proteins

• Ubiquitin-proteosome pathway

• Ubiquitin ligases are activated in nutrient deficiency and disuse

• Ubiquitin is attached to cellular proteins, targeting them for degradation in the proteosome

Autophagy

• […]

• […]

• […]

• Increased number of autophagic vacuoles • Residual bodies

• Lipofuscin granules

• May progress to cell injury and death

Cellular Injury, Death, and Adaptation Mechanisms of Cell Injury and Death

• Mitochondrial Dysfunction and Damage

• Oxidative Stress

• […]

• […]

• Membrane Damage
• Disturbance in […]
• Endoplasmic Reticulum Stress
• DNA Damage
• Clinicopathologic Examples of Cell Injury and Necrosis

• Reactive Oxygen Species

• Cell Injury Caused by Reactive Oxygen Species

• Calcium Homeostasis

Cell Injury: Mechanisms

• The cellular response to injurious stimuli depends on the […] and it duration and severity

• Cell injury usually results from functional and biochemical abnormalities in one or more of a limited number of essential cell components

  • Cell membrane integrity
  • Aerobic respiration
  • Protein synthesis
  • Integrity of genetic apparatus

• *Consequences depend on the […]

• type of injury

• type of cell being injured and its status and adaptability

Cell Injury: Mechanisms

• The cellular response to injurious stimuli depends on the type of injury and it duration and severity

• Cell injury usually results from functional and biochemical abnormalities in one or more of a limited number of essential cell components

  • […]
  • […]
  • […]
  • […]

• *Consequences depend on the type of cell being injured and its status and adaptability

• • Cell membrane integrity
  • Aerobic respiration
  • Protein synthesis
  • Integrity of genetic apparatus

Reversible and Irreversible Cell Injury

• Within limits, cells can compensate for the biochemical mechanisms of injury

• Persistent or severe injury can cause [reversible or irreversible] • Inability to reverse mitochondrial dysfunction
• Development of profound disturbances in membrane function

irreversible injury

Mitochondrial Damage and Dysfunction

• Are sensitive to many types of injurious stimuli and damage to them may result in several biochemical abnormalities

• Failure of [what process] leads to decreased ATP generation and depletion of ATP in the cell

• Reduced activity of plasma membrane ATP-dependent sodium pumps

• Compensatory increase in anaerobic glycolysis leading to lactic acid

  accumulation and decreased intracellular pH

• Prolonged or worsening of ATP depletion causes structural disruption of the protein synthetic apparatus

oxidative phosphorylation

Mitochondrial Damage and Dysfunction

• Are sensitive to many types of injurious stimuli and damage to them may result in several biochemical abnormalities

• Failure of oxidative phosphorylation leads to decreased ATP generation and depletion of ATP in the cell

• […]

• […]

• […]

• Reduced activity of plasma membrane ATP-dependent sodium pumps

• Compensatory increase in anaerobic glycolysis leading to lactic acid

  accumulation and decreased intracellular pH

• Prolonged or worsening of ATP depletion causes structural disruption of the protein synthetic apparatus

Mitochondrial Damage and Dysfunction

• Ultimately there is irreversible damage to mitochondrial and lysosomal membranes

  • Cell undergoes […]

• Abnormal oxidative phosphorylation

  • Formation of […]

• Damage is associated with the formation of a high-conductance channel in the mitochondrial membrane
  • Loss of mitochondrial membrane potential compromises [what process]

  • Mitochondria contain several proteins that, when released into the cytoplasm, activate apoptosis

• necrosis

• reactive oxygen species

• oxidative phosphorylation

Oxidative Stress

• Refers to cellular abnormalities that are induced by […], which belong to a group of molecules known as […]

• ROS

• free radicals

Oxygen-Derived Free Radicals

• Reactive oxygen species (ROS)
• There are different types which are produced by two major pathways

• […]

• […]

• […]

• Reduction-oxidation (redox) reactions which occur during mitochondrial respiration and energy generation

• Produced in phagocytic leukocytes as weapons for destroying microbes and other substances

• Nitric oxide

Oxygen-Derived Free Radicals

• Damage caused free radicals is determined by their […]

• The condition where there are increased amounts of free radicals: […]

• Conditions increasing the generation of free radicals, their inactivation, and the methods by which they cause cell injury will be discussed later in the lecture

• rates of production and removal

• oxidative stress

What are Free Radicals?

• […]

• […]
• […]
• […]

• Chemical species with a single unpaired electron in an outer orbital

• Highly reactive
• Unstable
• Can initiate autocatalytic reactions which produce more free radicals

Free Radicals

• Seem to be a final common pathway for cell injury in varied processes

• […]

• […]

• […]

• […]

• Chemical

• Radiation

• Cellular aging

• Inflammation

How are free radicals formed formed?

• […]
• […]
• […]
• […]
• […]

• Radiation
• Endogenous reduction-oxidation reactions
• Metabolism of exogenous chemicals or drugs • Transition metals (iron, copper)
• Inflammation
• Reperfusion injury

Effects of Free Radicals

Peroxidation of membrane lipids

Oxidative modification of proteins

• […]

• […]

DNA damage

• Mutations

• DNA breaks

• Cross-linking

• Polypeptide fragmentation

Effects of Free Radicals

Peroxidation of membrane lipids

Oxidative modification of proteins

• Cross-linking

• Polypeptide fragmentation

DNA damage

• […]

• […]

• Mutations

• DNA breaks

Protective Mechanisms

• Antioxidants

• Endogenous

• Exogenous

• Spontaneous Decay

• Binding transition metals to proteins

• Free radical scavenging enzymes

• […]

• […]

• […]

• Catalase

• Superoxide dismutases

• Glutathione peroxidase

Membrane Damage

• Increased membrane permeability leading to overt membrane damage is common in most forms of cell injury that lead to necrosis

• The most important sites of membrane damage during cell injury are:

• Mitochondrial membrane damage: results in decreased production of ATP

• Plasma membrane damage: results in a loss of osmotic balance, an influx of

  fluids and ions, and a loss of cellular contents

• Injury to lysosomal membranes: results in leakage of their enzymes into the cytoplasm and resultant enzymatic digestion of cell components

Disturbances in Calcium Homeostasis

• Calcium ions normally serve as second messengers in several signaling pathways

• In excessive amounts in the cell cytoplasm • Can cause cell injury

• Cytosolic free Ca2+ is normally found in lower concentrations than extracellular Ca2+

  • Mostly found in mitochondria and ER

Disturbances in Calcium Homeostasis

• Ischemia and certain toxins increase cytosolic Ca2+
• Initially due to release from intracellular stores
• Later form increased influx across the dysfunctional plasma

membrane

• Excessive intracellular Ca2+ • Can activate various enzymes

Endoplasmic Reticulum Stress

• Accumulation of misfolded protein in a cell can stress the compensatory pathways in the ER and lead to cell death by […]

  • Unfolded protein response

• Intracellular accumulation of […] may be caused by abnormalities that increase their production or reduce the cell’s ability to eliminate them

• Protein misfolding within cells may cause disease by creating a deficiency of an essential protein or by inducing apoptosis

• apoptosis

• misfolded proteins

DNA Damage

• Exposure of cells to radiation or chemotherapeutic agents, intracellular generation of ROS, and acquisition of mutations may all induce […]

  • If severe, may trigger apoptotic death

• DNA damage is sensed by […]

• Lead to the accumulation of [what protein]

• The p53 protein

  • First arrests the cell cycle at the [what phase]

• • Allows for DNA repair
  • If repair is unsuccessful, triggers apoptosis

• DNA damage

• intracellular sentinel proteins

• p53 protein

• G1 phase

Ischemic and Hypoxic Injury

• [Common or uncommon]

• Useful model—complete occlusion of artery to an organ

• [Reversible or irreversible]

• May become irreversible

• Ischemic/reperfusion injury

• Common

• Reversible

Hypoxia and Ischemia

• Hypoxia is a condition in which a body or region of a body is […] at the tissue level. May be generalized or local

• Ischemia is a […] to tissues causing a decrease in oxygen. Typically caused by problems with blood vessels

• deprived of adequate oxygen

• restriction in blood flow

General Biochemical Mechanisms of Cell Injury

• […]
• […]
• […]
• […]
• […]

• ATP depletion
• Accumulation of oxygen-derived free radicals • Loss of calcium homeostasis
• Defects in membrane permeability
• Mitochondrial damage and dysfunction
• Damage to DNA and proteins

Hypoxia and Ischemia
• Cells subjected to hypoxic stress may not die immediately

• Activate compensatory mechanisms

• Induced by transcription factors of the [what factor]

  family

• Stimulates the synthesis of proteins that help the cell to survive in the face of low oxygen

• Some factors like [what factor]

  • Stimulate the growth of new blood vessels

• Other proteins cause adaptive changes in cellular metabolism

  • Glycolysis

• hypoxia inducible factor 1 (HIF-1)

• VEGF (vascular endothelial growth factor)

Hypoxia and Ischemia

• Persistent or severe hypoxia and ischemia ultimately lead to failure of […] generation and depletion of […] in cells

• This has serious effects on many critical cellular systems

ATP

ATP Depletion

• Reduced activity of plasma membrane [what pumps]

• Increased [type] glycolysis

• Disruption of the protein synthesis apparatus

• Increased […]

• Ultimately, irreversible damage to mitochondrial and lysosomal membranes resulting in necrosis

• ATP-dependent sodium pumps

• anaerobic

• reactive oxygen species (ROS)

Ischemia-Reperfusion Injury
• Some cells will proceed to die after blood flow has resumed

• Clinically important:

• […]

• […]

• […]

• Myocardial infarction

• Stroke

• Organ transplantation

Mechanisms of Reperfusion Injury

• Several mechanisms account for this
• Increased ROS production may occur during […], exacerbating damage
• Some generated by injured cells • Some by infiltrating leukocytes

• Influx of […]

• Inflammation induced by ischemic injury increases following reperfusion

• Activation of [what system] may cause injury

• reoxygenation

• calcium

• complement system

Cell Injury Caused by Toxins

• Toxins can be:

• […]

• […]

• Can produce cell injury that results in cell injury and leads primarily to necrotic cell death

• Direct-acting

• Latent toxins

  • Nor intrinsically active, but must first be converted to reactive metabolites which then act on target cells

• Environmental chemicals

• Substances produced by infectious pathogens

Cell Injury Caused by Toxins

• Toxins can be:

• Environmental chemicals

• Substances produced by infectious pathogens

• Can produce cell injury that results in cell injury and leads primarily to necrotic cell death

• […]

• […]

  • Nor intrinsically active, but must first be converted to reactive metabolites which then act on target cells

• Direct-acting

• Latent toxins

Cellular Adaptations to Stress

• Adaptations are reversible changes in the number, size, phenotype, metabolic activity, or functions of cells in response to changes in the environment

• […]: responses of cells to normal stimulation

• […]: responses to stress that allow cells to modulate their structure and function to escape injury

• Physiologic adaptations

• Pathologic adaptations

Physiologic adaptations

responses of cells to normal stimulation

Pathologic adaptations

responses to stress that allow cells to modulate their structure and function to escape injury

Hypertrophy

• An increase in the size of cell with a resulting increase in the size of the organ

• Occurs when cells have a […]

limited capacity to divide

Hypertrophy: Causes

• Increased functional demand or by growth factor or endocrine stimulation

• Physiologic

• […]

• Pathologic

• […]

• Uterus in pregnancy

• Left ventricular hypertrophy of the heart

Hypertrophy Mechanisms: Cardiac

• Involve at least two types of signals

• […]: stretch

• […]: soluble mediators which stimulate cell growth.

• These turn on signal transduction pathways, leading to the induction of a number of genes, which in turn stimulate cellular protein synthesis

• Mechanical triggers

• Trophic triggers

Hypertrophy Mechanisms: Cardiac

• May be a switch from […] forms or neonatal forms of a protein

• In cardiac hypertrophy, a switch from adult to fetal contractile proteins occurs

• Re-expression of genes normally active only in early development

adult to fetal

Hypertrophy: Morphology

• A limit is reached beyond which increased muscle mass no longer compensates for increased burden.

• Degenerative changes occur
• Fragmentation and loss of […]

myofibrillar contractile elements

Hyperplasia

• An increase in the[…] leading to an increase in the […]

• Occurs in tissues containing cell populations capable of replication

• May occur concurrently with […]

number of cells

size of the organ or tissue

hypertrophy