Respiratory System Toxicity Flashcards
Describe the anatomy of the respiratory tract
Upper: nosel, pharynx and larynx
Lower: trachea, bronchi, bronchioles, alveolar duct and alveoli
What is the role of the lower respiratory tract
Receive inhaled oxygen and transfer into blood
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
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
What conditions should the air be when entering the lower respiratory tract
Warm, clean, moist and free from large particles
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
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
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
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
What causes the constrictions of bronchial smooth muscles
Vagal nerve releasing AcH which acts on muscarinic receptors
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
What are club cells involved in
Protections: secret oxidases and anti-proteases and anti-microbials
Surfactant secretion: process liquid liner to lung
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
Describe type I alveolar cells
Squamous and constitute 95% of area for gas exchange
Flattened and very thin
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
What defence mechanism do the lungs have
Clearance of particles via mucociliary elevator and phagocytosis
Release chemical mediators as protectants
Specific defences
What is interception
Occurs when larger particles are being intercepted by upper airways
What is impaction
Inertia moves particle further down airway and enter bronchial region
What is sedimentation
Deposition of particles in the smaller bronchi, low velocity
Where does xenobiotic metabolism happen in the lungs
Nasal mucosa
Club cells
Type I and type II alveolar cells
What CYPs are most active in the lung
1A1 (only after induced by smoking)
2E1
2B6
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
- Rupture of lysosomal membrane in macrophage
- Lysosomal enzymes digest macrophage
- Release of particle from lyses macrophage
- 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
