Pathological basis of disease exam 1 -- Cell injury

Cell membranes are damaged by 4 things:

1. ROS/free radicals

2. Decreased phospholipid synthesis (ATP, hypoxia)

3. Phospholipid breakdown

4. Cytoskeletal abnormalities

Decreased ATP —> _______ —> ________ (for membrane-bound organelles)

Ribosomes detach, decreased protein synthesis

Mitochondrial damage results in:

Leakage of pro-apoptotic proteins and decreased energy production. Loss of membrane potential. Can generate both necrosis and apoptosis

Cells respond to stress/injury in 3 ways:

1. Adapt

2. Degenerate

3. Die

Necrosis is always _____, apoptosis can be _____

Pathogenic, programmed

4 targets of cell injury

1. Integrity of cell membranes

2. Aerobic respirations via mitochondrial oxidative phosphorylation for ATP production

3. Protein synthesis

4. Integrity of nucleus

Hypoxia

Oxygen is insufficient at the tissue level to maintain adequate homeostasis

5 cell types that are sensitive to hypoxia and cell swelling

1. Neurons

2. Cardiac myocytes

3. Renal proximal tubular epithelium

4. Hepatocytes (liver)

5. Endothelium

Why is the renal proximal tubular epithelium sensitive to hypoxia and swelling

High concentration of sodium potassium ATPases pumped against the gradient so it needs a lot of oxygen and ATP

Why is endothelium sensitive to hypoxia and swelling

It does not recieve oxygen from the blood that passes by (gets it from vasculature instead), very sensitive to low oxygen

Reversible cell injuries

• Mild swelling of cells and organelles

• Membrane alterations (blebbing, loss of microvilli)

• Ribosomes detach from rough ER

• Chromatin clumping

• Fatty change

• Mitochondrial changes

• Nuclear alterations

  CELL MEMBRANE STILL INTACT

Irreversible cell injuries

• Marked swelling

• Lysosome disruption

• Amorphous deposit in mitochondria

• Membrane disruption (causes necrosis)

• Nuclearr changes (pyknosis)

• More myelin figures

4 characteristics of acute cell swelling

1. Mild damage to cell membranes

2. Hypoxia

3. Decreased energy production

4. Injury to enzymes regulating membrane ion channels

3 causes of ATP depletion

1. Reduced supply of oxygen and nutrients

2. Mitochondrial damage

3. Some toxins

Decreased ATP leads to:

• Failure of Na/K and Ca pump

• Detachment of ribosomes, fewer proteins

• Failure of glycolysis, lowe pH

• Accumulation of misfolded proteins

4 causes of mitochondrial damage

1. Increased intracellular Ca+

2. Free radicals/ROS

3. Hypoxia

4. Toxins

Consequences of calcium increase

• Activation of phospholipases, proteases, endonucleases, ATPase

• Leads to necrotic and apoptotic pathways

Origins of ROS

• Inflammation

• Decreased removal/scavenging

• Radiation

• Drugs

• Generated in normal cellular processes and in response to ^ stressors

Antioxidant mechanisms in the mitochondria

Removes free radicals

Effects of ROS in cell injury/death

• Disruption of plasma membrane, organelles

• Loss of enzymatic activity, abnormal folding

• Mutations, breaks

White muscle disease is caused by:

ROS (Lack of vitamin E and selenium —> can’t perform reducatase cycle)

4 causes of membrane damage

1. Free radicals

2. ATP depletion

3. Bacterial toxins

4. Viruses

Consequences of membrane damage in mitochondria

Mitochondrial membrane becomes more permeable —> decreased ATP and apoptotic triggering proteins

Consequences of membrane damage in plasma membrane

Influx of Na+, water, and Ca++, loss of K+ and other cellular subsstrates

Consequences of membrane damage in Lysosomal membrane

Leakage of enzymes that digest protein, DNA, RNA, and glycogen

When does reversible damage become irreversible?

When there is lysosome disruption, mitochondrial dysfunction, and severe membrane imbalance

Necrosis

Inflammatory cell death

Karyorhexis

Type of nuclear change where pyknotic nucleus undergoes fragmentation

Pyknosis

Type of nuclear change characterized by nuclear shrinkage and increased basophilla. DNA condenses into a shrunken, solid basophilic mass

Karyolysis

Basophilia of the chromatin may fade, a change that presumably reflects DNAase activity

Coagulative necrosis

Type of necrosis

• Architecture is preserved

• Enzyme damage

• Caused by ischemia, bacterial exotoxins, chemical toxins

• Classic necrosis of the kidney

• Lack of blood supply causing lesions = infarction

Liquefaction necrosis

Type of necrosis

• Digestion of dead cells

• Bacterial infections and WBCs

• Central nervous system ischemia

• Often happens in the brain

Caseous necrosis

Type of necrosis

• Loss of architecture

• Tuberculosis/myobacteria/corynebacteria

• Birds and reptiles develope this die to low levels of myeloperoxidase in their heterophils. Can’t digest many bacteria

Fat necrosis

Type of necrosis

• Release of activated pancreatic lipase into fat

• Diets high in fatty acids and low in antioxidants

• Chalky-white

• Classically pancreatitis

Gangrene

Condition resulting from the decay of body tissue, often due to a lack of blood flow or bacterial infection. Initial lesion is coagulation necrosis

Dry gangrene

Coagulation necrosis due to infarction followed by mummification. Tissue dries out and bacteria can’t grow. Includes frostbite

Infarction

Obstruction of the blood supply to an organ or region of tissue leading to tissue death

Moist/wet gangrene

Necrotic tissue with further degradation by bacteria, causing it to rot

Gas gangrene

Similar to moist gangrene, populated by anaerobic bacteria like clostridium. Penetrating wounds and necrotic tissue are good environments for anaerobes

Capsases

Enzymes that degrade cellular components. Important in apoptosis

Physiological apoptosis

Type of apoptosis characterized by

• Embryogenesis (“programmed cell death”

• Hormonal

• Self-reactive lymphoctes

• Inflammatory cells

Pathological apoptosis

Type of apoptosis characterized by

• DNA damage

• Accumulation of misfolded proteins

• Virus infections (such as adenovirus and HIV)

Intrinsic pathway to apoptosis

Extrinsic pathway to apoptosis

Apaf-1

Pro-apoptotic factor in intrinsic pathway. Activates caspase 9

FLIP

Anti-apoptotic factor in extrinsic pathway. Binds to and neutralizes procaspase 8

Bcl-2 and Bcl-x

Anti-apoptotic factors in intrinsic pathway. Control membrane permeability (more permeability = release of pro-apoptotic factors)

Smac/DIABLO

Pro-apoptotic factor. Binds to + neutralizes IAPs in intrinsic pathway

Cytochrome C

Pro-apoptotic factor, binds to and activates caspase 9 in intrinsic pathway

Bax and Bak

Pro apoptotic factor, creates channel in mitochondria, binds/blocks function in Bcl-2 family in intrinsic pathway

IAPs (inhibitors of apoptosis)

Anti-apoptotic factors. Block activation of caspases in intrinsic pathway

Bid, Bim, Bad

Pro-apoptotic factor, activates Bax and Bak

Mcl-1

Anti-apoptotic factor in intrinsic pathway