Target organ toxicity - Lung damage

Question 1

What makes the lungs susceptible to damage by toxic compounds?

Answer 1

High exposure
- Receives total cardiac output of blood
- Exposed to air
- Exposed to high oxygen

Question 2

What defence mechanism does the lungs have?

Answer 2

Defense:
- Mechanical: Cillia, mucus
- Phase 1 reactions: CYP enzymes (Clara cells)
- Phase 2 reactions: gluconidation

Enzymes:
Superoxide dismutase, glutathione synthetase, nicotinamide adenine dehydrogenase

Question 3

What type of lung cell have the highest amount of CYP?

Answer 3

Clara cells

Question 4

What toxic effects arise in the lungs and which compounds induce them?

Answer 4

• Irritants – SO2, NO, NH3, Cl2, HCl:
  –> Reduces permeability i.e lining-cell damage and obstruction due to oedema
  –> NO2, O3, phosgene, methyl isocyanate
• Inflammation bronchial constriction and swelling
• Allergic response – spores, microorganisms, cotton dust
• Fibrosis – silicosis, asbestos
• Cancer – smoking, nickel carbonyl, arsenic, nitroamine

Question 5

How does 4-Ipomeanol induce lung damage?

Answer 5

Is food toxin produced by mold Fusarium solani

Target: Non-ciliated bronchiolar cells (Clare cells)

Symptoms: Lung edema and hemorrhage

Mechanism:
Metabolized by CYP 4B1 to reactive epoxide controlled by glutathione

Question 6

How does paraquat induce damage to the lungs?

Answer 6

Paraquat is a bipyridylium herbicide

Mechanism:
Paraquat reacts with NADPH and forms a cation radical reacting with oxygen –> superoxide

Not enough superoxide dismutase to detoxify

Due to the high presence of oxygen in the redox cycle, NAPDH is depleted

The toxic effect is dose-related:
Larger doses can cause alveolar edema –> pulmonary fibrosis (up to six weeks after)

Within 24h of intake of toxic dosage –> renal tubular function is affected –> reduced excretion –> exacerbate toxicity