L2 and 3

What is cell stress?

changes that are nonlethal and disrupts homeostasis

What is cellular injury?

alteration in cell structure or biochemical functioning that overwhelms the cell’s ability to compensate and adapt

When does injury occur?

Cell can’t adapt to the changes and cannot maintain normal, critical functions

How does the cell respond to stressors/injurious stimuli?

Adapts or dies

What does cell response vary based on?

cell type, nature and intensity of injury, metabolic state at injury

What’s the difference between reversible vs. irreversible cell injury?

Reversible the cell can reestablish function

Irreversible the cell cannot reestablish function

What can lead to irreversible cellular injury?

longer duration or higher intensity injuries

Which occurs faster in the cell: morphological/histological changes or functional changes?

Functional

Microscopic lesions develop ___ hours after an ischemic event

4-12

In what type of tissue/cell is acute cell swelling is worse?

Neurons

What is the most common reversible cellular injury?

Acute Cellular Swelling

What causes cell to swell?

Na/K pump failure causing influx of Na and H2O

How does hypoxia cause acute cell swelling?

Lack of ATP production → Na/K pump failure

What can cause cell membrane injury?

Free radicals, lytic pores, bacterial cytolysins, NK Cells

How does acute cellular swelling show macroscopically?

Rounded margins, bulges at the surface, pale, heavy, wet

What is being shown

hydropic degeneration

What is being shown? Parenchymal organ.

Hydropic degeneration

What characterizes irreversible cell injury?

Inability to repair cell damage

Inability to restore cell or mitochondria function

What cells are most susceptible to hypoxia causing irreversible cell injury?

Neurons, cardiomyocytes, renal tubular epithelium

What is the most crucial in the transition from reversible to irreversible damage?

membrane damage and calcium homeostasis

What things cause cytoplasmic changes in irreversible cell damage?

Mitochondrial swelling and increased membrane permeability

What are characteristics of mitochondrial swelling?

loss of dense granules, formation of amorphous densities, calcium deposits

What are signs of increased membrane permeability?

myelin figure formation, leakage of enzymes, inflammation

What are the irreversible nuclear changes?

pyknosis, karyorrhexis, karolysis

What is pyknosis?

chromatin condensation, nuclear shrinking

What is karyorrhexis?

nuclear fragmentation

What is karyolysis?

nuclear dissolution

What are the 4 mechanisms of cellular injury

1. Hypoxia

2. Free radicals

3. Chemical/traumatic

4. Infectious

What is hypoxia due to?

ischemia usually

Where do free radicals do most damage?

cell membrane

What are the 2 pathways of ATP production?

oxidative phosphorylation and glycolytic pathway

How is ATP made in oxidative phosphorylation?

Oxygen is reduced to transition ADP to ATP

Oxidative phosphorylation is a major pathway in what species?

mammals

How does oxidative phosphorylation cause reduction of oxygen?

by electron transport chain in mitochondria

How is ATP made in glycolytic pathway?

Hydrolysis of glucose in absence of oxygen

What is produced as a by product in glycolytic pathway?

lactate

ATP depletion as little as _____ has widespread effects and is the fundamental cause of ____.

5-10%, necrotic cell death

What does a loss of ATP do?

• Na/K and Ca pumps malfunction

• No oxidative phosphorylation

• Structure disrupted

• Accumulation of misfolded proteins

What are the major causes of ATP depletion?

• reduced supply of oxygen and nutrients

• mitochondrial damage

• toxins

How can the mitochondria be damaged?

increased cytosolic Ca, free radicals, oxygen deprivation

What are the consequences of mitochondrial damage?

Membrane proteins, cytochrome C and apoptosis-inducing enzymes (Capases) are released into the cytosol and causes apoptosis.

What does mitochondrial permeability transition pore cause?

loss of membrane potential, stopping oxidative phosphorylation, loss of ATP then necrosis

What does cytochrome C in cytosol do?

causes apoptosis

Cytosolic Ca is maintained at ___ concentrations

very low

Where is most intracellular Ca sequestered?

in mitochondria and ER

How does increased intracellular Ca cause cell injury?

• Opening of mitochondrial transmission pore

• Activation of phospholipases, proteases, endonucleases and ATPase

• Induction of apoptosis by caspases

What is a free radical?

any molecule with an unpaired electron

What do free radicals do?

react with substances to damage cells or create abnormal cells

What are reactive oxygen species (ROS)?

an oxygen free radical

What are the most important reactive oxygen species?

hydrogen peroxide, hydroxyl, nitric oxide

Where are hydrogen peroxide, hydroxyl, nitric oxide produced?

in mitochondrial respiration in cell

What is oxidative stress?

increased production or decreased scavenging of ROS leading to excess damage

What are the pathologic effects of free radicals?

• Lipid peroxidation in membranes

• Oxidative modification of proteins

• DNA fragmentation

When there is free radical accumulation what things work to minimize injury?

• Antioxidants (Vit A, C, E)

• Binding of iron and copper to storage/transport proteins

• Scavenging enzymes

What are important antioxidants?

Vitamin A, C, E and glutathione

What are examples of scavenging enzymes?

glutathione peroxidase, superoxide dismutase, Catalase

What does glutathione peroxidase do?

Decomposes H2O2 into water

What does superoxide dismutase do?

converts O2 to hydrogen peroxide (H2O2)

What is a consistent feature of most forms of cell injury?

Loss of selective membrane permeability

How does indirect membrane damage occur?

• ATP depletion

• Ca-mediated activation of phospholipases

How does direct membrane damage occur?

Bacteria, viruses, lytic complement components

How do reactive oxygen species (ROS) injure the cell membrane?

via lipid peroxidation

How does decreased phospholipid synthesis injure the cell membrane?

via defective mitochondria function or hypoxia

How does increased phospholipid breakdown injure the cell membrane?

increased degradation of membrane phospholipids

What are the most important sites of membrane damage?

mitochondrial, plasma, lysosomal membranes

If damage is too severe to DNA what happens?

apoptosis

Why is the brain more susceptible to irreversible cell injury than muscle?

Brain does almost no glycolysis

Muscle does abundant glycolysis for oxygen support

How does acute cellular swelling appear microscopically?

Expanded, rounded, pale eosinophilic or vacuolated cytoplasm

What is the nucleus composed of

chromatin surrounded by a bi-layered nuclear membrane with pores

Describe euchromatic nuclei

loosely coiled, active transcription to mRNA

Describe heterochromatic nuclei

tightly coiled, inactive

What is shown

euchromatic nuclei where you can clearly see nuclei

What is being shown?

heterochromatic nuclei where cells are dense

Where is the nucleolus found

within the nucleus

The nucleolus ____ membrane bound

IS NOT

What is the function of the nucleolus

rRNA synthesis

What measures the cells synthetic activity?

prominence of nucleoli

What are examples of cells that have more prominence of nucleoli

mitotically active and cancer cells

What lines the rough ER

ribosomes

What is the rough ER continuous with

nuclear membrane

What is the rough ER responsible for

protein synthesis and basophilia of cells cytoplasm

What is the function of the smooth ER

metabolizing drugs, lipids, steroids, carbohydrates, glycogen

Describe cells with abundant smooth ER

pink, finely vacuolated cytoplasm (like endocrine)

What cells have abundant smooth ER

endocrine

What does the golgi apparatus do

synthesis and packaging center for proteins to be exported out of cell

What is this showing

cells with granulated golgi

What does the mitochondria do?

produces ATP through oxidative phosphorlation

The mitochondria is involved in

apoptosis

How does the mitochondria make ATP

through oxidative phosphorylation

What cell activities is the mitochondria part of

cell signaling, differentiation, growth

Lysosomes contain

hydrolytic enzymes

Enzymes in lysosomes are synthesized by

the rough ER

Enzymes in lysosomes are processed and packaged in the

golgi

Enzymes in the lysosomes are released into

cytosol

Lysosomes aid in

intracellular digestion

What do membrane bound structures interact with

cytoskeleton

What is the cytoskeleton

structural network that helps in movement, cell division, and biochemical pathways

What are the types of filaments found in the cytoplasm?

microfilaments, intermediate filaments, microtubules

Describe microfilaments

in microvilli that facilitate in cell motility

Describe intermediate filaments

provide physical strength to cells often via junctional complexes near base of cell