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PED3011 Toxicology > Respiratory System Toxicity > Flashcards

Respiratory System Toxicity Flashcards

1
Q

Describe the anatomy of the respiratory tract

A

Upper: nosel, pharynx and larynx
Lower: trachea, bronchi, bronchioles, alveolar duct and alveoli

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2
Q

What is the role of the lower respiratory tract

A

Receive inhaled oxygen and transfer into blood

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3
Q

Describe the susceptibility of the respiratory tract

A

Highly perfused organ
Exposed to systemic toxins and their metabolites
Exposed to air
Highly complex tissues w numerous cell types

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4
Q

Describe the nasopharyngeal region

A

First part of upper respiratory tract
Conditions the incoming air before it enters the lower respiratory tract
Contains olfactory mucosa responsible for smell

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5
Q

What conditions should the air be when entering the lower respiratory tract

A

Warm, clean, moist and free from large particles

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6
Q

Is it possible for drugs to be transported to the CNS via the olfactory mucosa

A

Some evidence in animals that some inhaled metals can translocate into CNS but others not

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7
Q

Describe the structure of the nasopharyngeal region

A

Vascularised mucous epithelium
Nostril hairs to filter out large particles - not very efficient and allow small particles through
Can absorb water soluble molecules

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8
Q

Describe the structure of trachea

A

Stretches from larynx to bronchi
Has a mucous membrane released by goblet cells
Contains cilia
Soft tissue makes up most of trachea
Cartilage provides extra support

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9
Q

Describe the mucocilliary escalator

A

Particulate matter in trachea is trapped in the mucous layer
Cilia expel the matter by moving it up and out of trachea

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10
Q

What causes the constrictions of bronchial smooth muscles

A

Vagal nerve releasing AcH which acts on muscarinic receptors

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11
Q

Describe club cells

A

Cilia free domed cells abundant in tertiary bronchioles
Progenitor for variety of lung epithelial cells - origin of the most common form of lung cancer
High content of xenobiotic metabolising enzymes

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12
Q

What are club cells involved in

A

Protections: secret oxidases and anti-proteases and anti-microbials
Surfactant secretion: process liquid liner to lung

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13
Q

Describe the alveolar region

A

Gaseous exchange occurs
Contains type I and type II alveolar cells
Have interstitial cells to provide support
Have free-floating macrophages to engulf unknown bodies

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14
Q

Describe type I alveolar cells

A

Squamous and constitute 95% of area for gas exchange
Flattened and very thin

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15
Q

Describe type II alveolar cells

A

Cuboidal and g have granules fro storing surfactant
Only 5% of gas exchange area
Can differentiate into type I cells

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16
Q

What defence mechanism do the lungs have

A

Clearance of particles via mucociliary elevator and phagocytosis
Release chemical mediators as protectants
Specific defences

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17
Q

What is interception

A

Occurs when larger particles are being intercepted by upper airways

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18
Q

What is impaction

A

Inertia moves particle further down airway and enter bronchial region

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19
Q

What is sedimentation

A

Deposition of particles in the smaller bronchi, low velocity

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20
Q

Where does xenobiotic metabolism happen in the lungs

A

Nasal mucosa
Club cells
Type I and type II alveolar cells

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21
Q

What CYPs are most active in the lung

A

1A1 (only after induced by smoking)
2E1
2B6

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22
Q

What is the relationship between CYP mRNA and related catalytic activity

A

mRNA does not mean there will be catalytic activity in the lung

23
Q

Describe the expression of Phase I enzymes in lung vs liver

A

All CYPs show significantly lowered expression in lung
Exceptions: CYP2D6, CYP2J2 and CYP3A5 (50% or over)

Epoxy hydrolases and HCE1/CES1 have similar gene expression liver vs lung

24
Q

Describe the expression of phase II enzymes lung vs liver

A

Overall lower in lung than liver but have distinct isoforms
SULTs comparable apart from 2A1 and 2B1/2 that are substantially higher in lung
Most UGTs expressed at a much lower level

25
Q

What can occur from lung damage

A

Fibrosis
Local irritation
Cancer
Allergic response

26
Q

What is critical in determining how deeply a gas penetrates the lung

A

Water solubility
Highly soluble gases dissolve in naso-pharyngeal region and not transported into respiratory tract
= local effects

27
Q

Name 2 examples of irritant gases

A

Ammonia and chlorine
Cause bronchial restriction and oedema

28
Q

What effect do arsenicals have on the lungs

A

Induce irritation on acute exposure
Prolonged exposure may cause lung cancer

29
Q

What effect does ground level ozone have on the lungs

A

Exacerbate chronic respiratory diseases
Cause short term reductions in lung function

30
Q

Name 3 things that can cause local irritation in the lungs

A

Irritant gases
Arsenicals
Ground level pollution

31
Q

What toxin can cause cellular damage and oedema

A

4-Ipomeanol

32
Q

Why is there more damage to club cells than the liver when exposed to 4IP

A

Club cells bio activate 4IP
Metabolites have a high affinity for macromolecules = necrosis

33
Q

Why is 4IP not as damaging in humans as in animals

A

Lower expression of CYP4B1 in humans than animals

34
Q

How can ozone and oxides of nitrogen cause cellular damage and oedema

A

Endogenous reactions w lipids in epithelial surfactant lining = peroxidation of cell membrane
-> increased membrane permeability = fluid accumulation

35
Q

What happens after prolonged exposure to ozone

A

Formation of fibrous tissues

36
Q

What are biological effects from the oxidation of lipids

A

Interleukin-8 release
Loss of mitochondrial dehydrogenase activity
Enhanced cytotoxicity in lung macrophages and epithelial cells

37
Q

What affect does ozone have on ATP releases

A

Increases release
Believed to be protective mechanism by stimulating important cell survival signals like ERK1/2 and AKT

38
Q

Name 2 things that can cause pulmonary fibrosis

A

Silica
Asbestos
Coal
Talc
Aluminium
Beryllium

39
Q

What physiological changes happen to cause pulmonary fibrosis

A
  1. Rupture of lysosomal membrane in macrophage
  2. Lysosomal enzymes digest macrophage
  3. Release of particle from lyses macrophage
  4. Fibrotic changes
40
Q

What can induce an allergic response

A

Direct allergens i.e pollen, spores, dust etc
Haptens + proteins e.g toluene and TDI

41
Q

What is a hapten

A

Small molecules that elicit and immune response only when attached to a large carrier e.g proteins

42
Q

How does a hapten cause an immune response

A

Reacts with proteins in blood or lungs
Proteins is recognised as foreign by immune system
From antigen and stimulate antibody production
Immune response on second or subsequent exposure

43
Q

Name a few causes of cancer

A

Cigarette smoke
Arsenic
Chromates
Nickel

44
Q

Name a systemic toxin

A

Paraquat: highly toxic
Diquat: less toxic

45
Q

Describe the mechanism of action for paraquat

A

Ingested not inhaled
Accumulates in alveolar cells and undergoes redox cycling
Widespread damage to type I and II pneumocytes
= oedema and inflammatory response

46
Q

How does paraquat enter alveolar cells

A

Enters alveolar cells via polyamine transporter
Misidentified by transporter

47
Q

Why does paraquat accumulate in the cell

A

Has 2 big charges that cause the toxin to remain stuck in the cell

48
Q

Why is diquat less toxic than paraquat

A

Poorer substrate for the polyamine transporter

49
Q

Describe the redox cycle that paraquat undergoes

A

Forms a paraquat radical
Reduced by NADPH
Forms a superoxide w O2
Recycled and trapped in cell

50
Q

What is bleomycin and describe its mechanism of action

A

Antibiotic with anti-tumour properties
Forms complex with Fe2+ oxidises to Fe3+ = free radical release causing DNA strand breaks

51
Q

Why does bleomycin induce pulmonary toxicity

A

Deactivated by hydrolyse enzyme but lung has none of this enzyme
= pneumonitis which can progress into fibrosis

Damage to endothelium via free radicals and cytokine induction

52
Q

What is the primary response in the lung

A

Inflammation
Irritation
Oedema
Mild damage
Reversible

53
Q

What is the secondary response in the lung

A

Fibrosis
Emphysema
Tumours
Irreversible

54
Q

How can we study lung damage

A

Pulmonary function studies
Morphology via biopsy
Bronchi alveolar lavage
In vitro studies

PED3011 Toxicology (11 decks)

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