[PL2.2] CELL INJURY, CELL DEATH,& ADAPTATIONS

MECHANISMS OF CELL INJURY

Cellular response to injury depends on the nature, duration, and severity of the stimulus

mechanism of cell injury

Consequences of injury depend on the type, state, and adaptability of the cell

mechanism of cell injury

Any injurious stimulus may trigger multiple interconnected mechanisms that do what?

damage cells

Cell injury results from abnormalities in what?

essential cellular components

One major mechanism of cell injury involving energy metabolism and apoptosis

mitochondrial damage

Causes of mitochondrial damage include increased cytosolic Ca2+, toxins, and what?

oxygen deprivation

Three major consequences of mitochondrial damage

atp depletion, ROS formation, leakage of mitochondrial proteins

Mitochondrial damage results in decreased energy due to what?

atp depletion

Mitochondrial damage promotes oxidative stress through what?

formation of reactive oxygen species

Mitochondrial damage triggers apoptosis through what?

leakage of mitochondrial proteins

ATP depletion is frequently associated with what types of injury?

hypoxic and chemical injury

ATP depletion leads to decreased activity of what membrane pump?

sodium pump

Sodium pump failure due to ATP depletion causes what?

cell swelling and ER dilation

ATP depletion alters what aspect of the cell?

energy metabolism

ATP depletion causes detachment of ribosomes and dissociation of polysomes, resulting in what?

decreased protein synthesis

Early loss of selective membrane permeability leads to what?

overt membrane damage

Membrane damage can be caused by ATP depletion and what ion-mediated activation?

calcium-mediated activation of phospholipases

Bacterial toxins and viral proteins can cause what type of injury?

membrane damage

Immune system component that can contribute to membrane damage

lytic complement components

External harmful factors that can cause membrane damage

physical and chemical agents

Highly reactive molecules that contribute to membrane damage

reactive oxygen species (ROS)

Membrane damage mechanism: decreased production of structural lipids

↓ phospholipid synthesis

Membrane damage mechanism: increased degradation of structural lipids

↑ phospholipid breakdown

Structural cell support disruption that contributes to membrane damage

cytoskeletal abnormalities

ROS and lipid changes can cause damage to what organelle membrane?

mitochondrial membrane

Effect of membrane damage on cell's outer boundary

plasma membrane damage

Membrane damage to which organelle causes release of enzymes and further cell injury

lysosomal membrane

DNA damage activates sensors that trigger what pathway?

p53-dependent pathway

What cellular process is triggered by severe DNA damage?

apoptosis

Examples of causes of DNA damage include

radiation, anticancer drugs, ROS, aging

Accumulation of oxygen-derived free radicals in cells is called

oxidative stress

Highly reactive molecule with a single unpaired electron in its outer orbit

free radical

Reactive species commonly derived from oxygen to form ROS and other radicals

oxygen

Examples of reactive oxygen species (ROS)

superoxide, hydroxyl radicals, hydrogen peroxide

Source of ROS normally produced in cells

mitochondrial respiration and energy generation

What removes ROS to prevent cellular damage?

intracellular ROS scavengers

Oxidative stress occurs when there is what imbalance?

increased ROS production or decreased scavenging

Normal cytosolic free calcium concentration in cells

~0.1 μmol

Normal extracellular calcium concentration

1.3 mmol

What happens when intracellular calcium levels increase?

cell injury

Increased mitochondrial calcium causes opening of what?

mitochondrial permeability pore

Opening of mitochondrial pore leads to what consequence?

failure of ATP generation

Increased cytosolic calcium activates enzymes that cause what?

cell damage

Where are newly synthesized proteins folded in healthy cells?

endoplasmic reticulum

What helps fold proteins in the ER?

chaperones

What happens to misfolded proteins in the ER?

shuttled into the cytoplasm

Accumulation of misfolded proteins in the ER can lead to what?

ER stress

Prolonged ER stress triggers what response?

unfolded protein response

Severe or unresolved ER stress can lead to what?

apoptosis

Type of cell injury that is correctable if the damaging stimulus is removed

reversible cell injury

Two key features of reversible cell injury

cellular swelling and fatty change

Plasma membrane changes in reversible injury include

blebbing, blunting, loss of microvilli

Mitochondrial changes in reversible injury include

swelling and amorphous densities

Cytoplasmic inclusions composed of phospholipids from damaged membranes

myelin figures

Endoplasmic reticulum change in reversible injury

ER dilation with detachment of polysomes

Nuclear change in reversible injury

disaggregation of granular and fibrillar elements

Another term for cellular swelling

hydropic change or vacuolar degeneration

What accumulates inside the cell during cellular swelling?

water

Cellular swelling is due to failure in maintaining what?

ionic and fluid homeostasis

Earliest manifestation of almost all forms of cell injury

cellular swelling

Cellular swelling is usually caused by failure of which membrane pump?

sodium-potassium (Na⁺/K⁺) pump

Failure of the Na⁺/K⁺ pump is often due to what?

ATP depletion from oxygen deficiency

Type of reversible injury seen in lipid-metabolizing organs like the liver

fatty change

Fatty change is characterized by accumulation of what in the cytoplasm?

lipid vacuoles

Cause of fatty change in cells

toxic injury that disrupts metabolic pathways

Organ commonly affected by fatty change

liver

Point at which cell injury can no longer be reversed

point of no return

Hallmark morphologic change of irreversible cell injury

cell death

Two principal types of cell death

necrosis and apoptosis

Type of cell injury that occurs with continuing and severe damage

irreversible cell injury

Ultrastructural changes of irreversible injury with disruption and discontinuous

Plasma and organelle membranes

Ultrastructural changes of irreversible injury with severe swelling (+) Electron-dense deposits

Mitochondria

Ultrastructural changes of irreversible injury with disaggregation

Endoplasmic Reticulum

Ultrastructural changes of irreversible injury with loss and disappearance

Nuclei

Ultrastructural changes of irreversible injury with myelin figures and amorphous debris

others

Type of cell death caused by severe injury and always pathological

necrosis

Key characteristic of necrosis: structural protein alteration

denaturation of cellular proteins

Necrosis results in the leakage of what?

cell contents through damaged membranes

Local response triggered by necrotic cell contents

inflammation

Necrosis involves enzymatic digestion of what?

lethally injured cell

Common cause of necrosis due to lack of oxygen

ischemia

Cause of necrosis due to infection

microbial toxins

Type of injury that can cause necrosis

burns, chemical, and physical injury

Internal cellular cause of necrosis

leakage of active proteases

Staining feature of necrotic cells on H&E due to RNA loss and protein accumulation

eosinophilia

Glassy homogeneous appearance in necrotic cells is due to

loss of glycogen

Cytoplasmic texture of necrotic cells

vacuolated and moth-eaten

What replaces dead cells in necrosis?

myelin figures

Aggregates of what are seen in necrotic cells?

denatured proteins (fluffy material)

All nuclear changes in necrosis are due to

breakdown of DNA

Type of nuclear change characterized by nuclear fading due to enzymatic degradation

karyolysis

Type of nuclear change characterized by shrinkage and increased basophilia

pyknosis

Type of nuclear change characterized by fragmentation of the nucleus

karyorrhexis

Three nuclear patterns in necrosis

karyolysis, pyknosis, karyorrhexis