Lecture 4

Two mechanisms of cell injury-toxins

1) direct interaction

2) conversion to reactive toxic metabolites (indirect action) -> they need to be metabolized first : not toxic at first and then metabolized then become toxic

toxic metabolites are usually produced by?

cytochrome P-450 in the SER of the liver

types of toxic metabolites?

can be free radicals or electrophiles forming adducts

which organ is the most susceptible to drug/toxic-induced injury

liver

Acetaminophen (found in tylenol) is detoxified in liver how?

detoxified to glucuronide and sulphate conjugates which makes them more water soluble and excreting in urine

What species is relatively deficient in glucuronyl transferase

cats

Why are cats particularly susceptible to acetaminophen toxicity?

cats are relatively deficient in glucuronyl transferase, so less acetaminophen undergoes glucuronidation (which are less reactive compounds)

What happens when cats cannot efficiently glucuronidate acetaminophen?

a larger proportion is metabolized to NAPQI, increasing toxicity

What happens when NAPQI accumulates in hepatocytes?

It forms cellular adducts → causes molecular damage → hepatocyte necrosis.

what is cellular adducts

A piece of a cellular macromolecule—such as DNA, RNA, or a protein—that is permanently and chemically bonded to a foreign substance or metabolite

What metabolite do cats and dogs produce relatively more of than humans after acetaminophen exposure?

para-aminophenol

what does para-aminophenol cause after being released from liver cells?

Oxidative damage to hemoglobin in RBCs

Why is methemoglobin dangerous?

MetHb cannot bind oxygen, impairing oxygen transport and damage to those organs that require high demand of oxygen

Carbon Tetrachloride Toxicity can be found in?

Found in environment and industrial chemicals

Does carbon tetrachloride have to be broken down or is it naturally toxic to the body?

Has to be broken down and metabolized by the liver

Carbon tetrachloride causes what type of damage to the lipids?

Causes oxidative damage to the lipids in the membrane

Carbon Tetrachloride mild conditions

Fat being stored (but is reversible)

Carbon tetrachloride long term exposure/ acute

Severe per-oxidation of lipids within the membrane and membrane permeability

Explain the process of the long term exposure/acute damage

Sodium and calcium will rush into the cell -> cell will swell and influx potassium -> irreversible damage

How to know if its irreversible damage?

If mitochondria is completely damaged / proteins are denatured

Profound disturbance of membrane function

Signs of the liver from tetrachloride damage

More pale areas of the liver of the central lobular region, enhanced reticular pattern and fat depositions within hepatocytes

When do grossly visible changes of cell injury usually become apparent?

After several hours of injury

What is an important early functional change in injured cardiac myocytes?

Loss of function can occur within seconds of complete oxygen deprivation, even before structural changes are visible (unable to contract).

What is the earliest morphological change in reversible cell injury?

Cellular swelling due to failure of energy-dependent ion pumps.

How quickly can reversible cell injury begin after an injurious stimulus?

Within minutes

For myocardial ischemia, approximately when does irreversible injury/cell death begin?

About 20-60 minutes after complete coronary artery occlusion.

What changes occur over the first several hours after irreversible cell injury?

Biochemical changes and protein leakage (e.g., creatine kinase and troponins), followed by electron microscopy changes

What is the key difference between functional and morphological evidence of cell injury?

Function can be lost very rapidly, while visible morphological changes take hours to develop.

What is the approximate timeline for morphological changes after myocardial injury?

Minutes: reversible injury/cell swelling

20-60 min: irreversible injury begins

A few hours: biochemical/protein leakage + EM changes

4-12 h: LM changes (light microscope)

12-24 h: gross changes

Reversible cell injury is also called what?

cell degeneration

morphological changes of reversible cell injury

1) Cellular swelling

2) Fatty Change

Irreversible cell injury morphology

1) necrosis

2) apoptosis

Why is there cellular swelling in reversible cell injury damage?

Changes in membrane permeability

Gross appearance of cellular swelling?

Organ swollen with rounded edges and tissue will buldge and be wet and heavy

Histological appearance of cellular swelling

Cells enlarged with pale cytoplasm and nucleus in normal position

If mild swelling its called:

Cloudy swelling

If cell swelling continues what can appear in the cytoplasm

poorly delineated vacuoles

*(small, bubble-like clear spaces within a cell's cytoplasm that do not have sharp, well-defined, or distinct borders)

Moderate cell swelling is called:

Hydropic degeneration

Severe cell swelling is called:

ballooning degeneration (mostly seen in virus infected cells)

Describe a renal tubular epithelium reversible injury

Surface blebbing

Slight swelling of mitochondria

Clumping of nuclear chromatin

Lipidosis / fatty degeneration of reversible injury are mainly seen where?

In the liver (mainly cells highly involved in fat metabolism) -> called hepatic lipidosis or fatty liver

What does liver normally do with free fatty acids

breaks them down and stores them

what are the 3 mechanisms that can occur to get fatty liver?

1) increase in uptake

2) altered metabolism due to hypoxia (decrease apo-protein synthesis)

3) decrease export (decrease apo-protein synthesis)

• without apoprotein, liver cannot package triglycerides into bloodstream

What is apo-protein synthesis

cells create the protein components that bind to lipids to form lipoproteins

What do you see with fatty liver

Swollen, rounded edges and is pale

can even float in formalin / water because of all the fat

what do you see under histology of fatty liver changes

- presence of well delineated, lipid filled vacuoles in the cytoplasm , displaced nucleus to the side (macro or micro vesicular: there is usually a mix)

- there may be a single, large vacuole or multiple small vacuoles

Histological appearance of fatty change can use what staining technique

can use the "oil red O" stain to confirm it is lipid (if its lipid it will stain red)