Respiratory System Toxicity Flashcards by Diana Bespalova

Describe the anatomy of the respiratory tract

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

How well did you know this?

Not at all

Perfectly

What is the role of the lower respiratory tract

Receive inhaled oxygen and transfer into blood

How well did you know this?

Not at all

Perfectly

Describe the susceptibility of the respiratory tract

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

How well did you know this?

Not at all

Perfectly

Describe the nasopharyngeal region

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

How well did you know this?

Not at all

Perfectly

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

Warm, clean, moist and free from large particles

How well did you know this?

Not at all

Perfectly

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

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

How well did you know this?

Not at all

Perfectly

Describe the structure of the nasopharyngeal region

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

How well did you know this?

Not at all

Perfectly

Describe the structure of trachea

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

How well did you know this?

Not at all

Perfectly

Describe the mucocilliary escalator

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

How well did you know this?

Not at all

Perfectly

What causes the constrictions of bronchial smooth muscles

Vagal nerve releasing AcH which acts on muscarinic receptors

How well did you know this?

Not at all

Perfectly

Describe club cells

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

How well did you know this?

Not at all

Perfectly

What are club cells involved in

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

How well did you know this?

Not at all

Perfectly

Describe the alveolar region

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

How well did you know this?

Not at all

Perfectly

Describe type I alveolar cells

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

How well did you know this?

Not at all

Perfectly

Describe type II alveolar cells

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

How well did you know this?

Not at all

Perfectly

What defence mechanism do the lungs have

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

How well did you know this?

Not at all

Perfectly

What is interception

Occurs when larger particles are being intercepted by upper airways

How well did you know this?

Not at all

Perfectly

What is impaction

Inertia moves particle further down airway and enter bronchial region

How well did you know this?

Not at all

Perfectly

What is sedimentation

Deposition of particles in the smaller bronchi, low velocity

How well did you know this?

Not at all

Perfectly

Where does xenobiotic metabolism happen in the lungs

Nasal mucosa
Club cells
Type I and type II alveolar cells

How well did you know this?

Not at all

Perfectly

What CYPs are most active in the lung

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

How well did you know this?

Not at all

Perfectly

What is the relationship between CYP mRNA and related catalytic activity

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

Describe the expression of Phase I enzymes in lung vs liver

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

Describe the expression of phase II enzymes lung vs liver

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

What can occur from lung damage

Fibrosis Local irritation Cancer Allergic response

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

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

Name 2 examples of irritant gases

Ammonia and chlorine Cause bronchial restriction and oedema

What effect do arsenicals have on the lungs

Induce irritation on acute exposure Prolonged exposure may cause lung cancer

What effect does ground level ozone have on the lungs

Exacerbate chronic respiratory diseases Cause short term reductions in lung function

Name 3 things that can cause local irritation in the lungs

Irritant gases Arsenicals Ground level pollution

What toxin can cause cellular damage and oedema

4-Ipomeanol

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

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

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

Lower expression of CYP4B1 in humans than animals

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

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

What happens after prolonged exposure to ozone

Formation of fibrous tissues

What are biological effects from the oxidation of lipids

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

What affect does ozone have on ATP releases

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

Name 2 things that can cause pulmonary fibrosis

Silica Asbestos Coal Talc Aluminium Beryllium

What physiological changes happen to cause pulmonary fibrosis

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

What can induce an allergic response

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

What is a hapten

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

How does a hapten cause an immune response

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

Name a few causes of cancer

Cigarette smoke Arsenic Chromates Nickel

Name a systemic toxin

Paraquat: highly toxic Diquat: less toxic

Describe the mechanism of action for paraquat

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

How does paraquat enter alveolar cells

Enters alveolar cells via polyamine transporter Misidentified by transporter

Why does paraquat accumulate in the cell

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

Why is diquat less toxic than paraquat

Poorer substrate for the polyamine transporter

Describe the redox cycle that paraquat undergoes

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

What is bleomycin and describe its mechanism of action

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

Why does bleomycin induce pulmonary toxicity

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

What is the primary response in the lung

Inflammation Irritation Oedema Mild damage Reversible

What is the secondary response in the lung

Fibrosis Emphysema Tumours Irreversible

How can we study lung damage

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