respiratory system Flashcards
what is inhalation
route of exposure
respiratory toxicology is _
Toxic responses of the cells of the respiratory tract, regardless of exposure route (may be inhalation or systemic, parent compound or metabolite)
what are the compound of interest in pheumotoxicology
occupational & environmental chemicals
therapuetic agents
what is the structure & function of the lungs
Nasopharangeal region = Nasal cavity, Pharynx and laynx
Trachea and Bronchi which is the conducting airway
Lower respiratory tract = trachea, primary bronchi and lungs
Respiratory bronchioles and alveoli = gas exchange regions
why os the respiratory tract susceptible to toxicty
- Highly perfused (Lung receives 100% of right side cardiac output, Exposed to systemic toxins and their metabolites)
- Exposed to air (Defence mechanisms)
- Highly complex tissues, numerous cell types
- Local xenobiotic metabolism
the air leaving the nasal cavity is
warm, moist, clean, turbulence free
the nasopharyngeal contains _ mucosa
olfactory
contains specialised epithelium which is responsible for the sense of smell
what is the structure of the olfactory mucosa
the olfactory mucosa is high in the nasal cavity and coverted in a mucus layer
- olfactory receptor cells are located in the olfactory epithelium.
- columnar epithelial cells, olfactory stem cells and the cribriform plate separates the olfactory bulb and the mucosa
- nerve fibre are within the bulb which linkeds to the olfactory tract
Can the olfactory mucosa be used for drug transport
- Recent research suggests that the olfactory mucosa is a realistic route for delivery of therapeutics
- Toxicological route = Some evidence in experimental animals that some metals (when inhaled) can translocate into CNS via the olfactory cells, but not others
how would the nasopharyngeal region be described
vascularised mucous epithelium
- large particles filtered out by nostril hairs
- water soluble molecules absorb
- nasal squamous cell carcinoma in long term inhalation studies in rats with HCHO
- perforated nasal septum with chromium (VI)
what is the pharynx
First recognisable tube of the respiratory system. Halfway down there is an opening in the wall of the pharynx which connects to the middle ear. This is called the Eustachian tube and serves to allow pressure changes to be communicated to the ear so that the eardrum can maintain the correct tension
What is formaldehyde and what is caused by inhalation
a common chemical, found primarily in adhesive or bonding agents for many materials found in households and offices, including carpets, upholstery, particle board, and plywood paneling.
The release of formaldehyde into the air may cause health problems, such as coughing; eye, nose, and throat irritation; skin rashes, headaches, and dizziness.
what is the trachea
10cm tube which extends from the larynx
lined with classical psuedo stratified ciliated colomnar epithelium which is risk in goblet cells
how does mucus work in the cilia
bathes the surface of the cilia which beat regularly and move the cilia up the trachea. Any particulate matter that has got through the upper defences will (hopefully) become trapped in this mucous and be moved upwards and expelled by coughing or swallowing. This defence mechanism is also known as the mucociliary escalator.
what is the lamina propria
made up of loose connective tissue; mucous and serous glands and some elastic fibres. It also maintains the characteristic C-shaped cartilage rings which are connected at the anterior of the tube by smooth muscle. These rings serve to maintain an open airway and the smooth muscle allows for control of lumenal diameter.
what is the entire trachea encased in
adventitia of connective tissue
what tissue and cells are located in the thracheobronchial region
(conducting airways)
- smooth muscle – allow lumenal diameter control (salbutamol)
- Ciliated epithelial cells
- Mucous (goblet) and serous epithelial cells
- Club cells (non ciliated)
- nerves
- mucociliary escalator
how does the smooth muscle work to change the dilation of the bronchiole
Parasympathetic nervous system: the vagal nerve releases acetylcholine which acts on the muscurinic receptors causing constriction of the bronchial smooth muscles.
what are club cells and what are they involved in
Cilia-free domed cells, abundant in the tertiary bronchioles. High content of xenobiotic metabolising enzymes. Progenitor cells for a variety of lung epithelial cells
Involved in: Protection (secretion of oxidases and anti-proteases and antimicrobials)
Surfactant secretion (processing of the liquid liner to the lung)
Origin of the most common form of lung cancer
what are the cells involved in the alveoli region
Alveolar type I cells (type 1 pneumocytes)
Alveolar type II cells ( type 2 pneumocytes)
Interstitial cells
Macrophages
how are the two types of pneumocytes different
Type I = squamous, 0.15um, constitutes 95% of area for gas exchange
Type II = cuboidal, granules (for storing surfactant), only 5% of area for gas exchange but 60% of total cells.
Type II cells can differentiate into Type I cells.
what are the defense mechanism of the lungs
- Clearance of particles: (mucociliary escalator, phagocytosis [alveolar macrophages to lymphatics –> dissolution])
- Release of chemical mediators as protectants eg glutathione, protein
- Specific defences - immune system
what are the particle sizes found in the lungs
Nano = Ultrafine = < 100 nm (Conventional)
Nano = <10 nm (suggested by unique quantum and surface-specific functions)
Fine = 100 nm - 3 m
Respirable (rat) = < 3 m (max = 5 m)
Respirable (human) = < 5 m (max = 10 m)
Inhalable (human) = ~ 10 - 50 m
Aerosol particle size influences site of deposition =
- Interception: occurs with the larger particles actually being intercepted by the upper airways
- Inpaction: inertia moves the particle further down the airway and enter the bronchial region
- Sedimentation: deposition in the smaller bronchi, velocity is low
- Diffusion: important in the deposition of particles in the sub-micrometer size
how are particles cleared from the airway
Nasal-mechanically removed
Tracheobronchial-mucociliary escalator
Pulmonary- macrophages, me, or penetrate the epithelial membrane and transported in the blood
what cells are involved in xenobiotic metabolsim
- Nasal (olfactory) mucosa
- Club cells (Highest activity)
- Type I and II alveolar cells
many toxicants are activated by these enzyme systems
What CYPs are active in human lungs
IAI (mRNA,protein and induced by smoking)
1A2 (+/- mRNA + protein)
1B1 (++ mRNA + protein, related catalytic activity)
2A6 (++ mRNA, +/- protein)
2B6 (+++ mRNA + protein, related catalytic activity)
2C (+/- mRNA + Protein)
2E1 (+++ mRNA + protein, related catalytic activity)
2FI, 2J2, 2S1, 3A4, 3A5, 3A7, 4B1
which phase II enzymes are expressed higher in the lung vs the liver
SULT1A1
SULT1A3/4
SULT1C2
SULT2B1/2
UGT2A1
desribe the specific toxicity of trichloroethylene to mouse club cells (how was it discovered)
- Mice given a single, 6h exposure to trichloroethylene showed dose dependent vaculoation of club cells
- Isolated Club cells produced a range of metabolites including chloral (major metabolite), trichloroethanol, and trichloroacetic acid, but no glucuronides
- In hepatocytes the major metabolite was trichloroethanol and its glucuronides
- UDP glucuronyl transferase activity was compared between cell types; hepatocytes could form glucuronides from tri-chloroethanol; Club cells could not
- However, only chloral could cause the specific lesion observed in Club cells; results in vivo from a failure to conjugate trichloroethanol
describe the pathogenesis of lung damage
- Local irritation
- Cancer
- Allergic response
- Cellular
- Fibrosis
what causes local irritation
- Ammonia and Chlorine are examples of Irritant gases = Cause bronchial restriction and oedema
(Chronic effects are rare) - Arsenicals = induce irritation on acute exposure, prolonged exposure may cause lung cancer
- Ground-level ozone (air pollution) = exacerbate chronic respiratory diseases, cause short-term reductions in lung function
Describe ammonia & chloride and how they are considered an irritant
The site of deposition of gases in the respiratory tract define the pattern of toxicity.Water solubility is critical in determining how deeply a gas penetrates.
Highly soluble gases dissolve in the naso-pharangeal region and are not transported further into the resp. tract.
They can cause LOCAL effects.
what is the most toxic form of arsenic
arsine gas
how is it thought that ozone and oxides of nitrogen cause here effects
peroxidation of cellular membranes = causes increased membrane permeability and results in fluid accumulation = Oedema
what happens when type II cells come into contact with ozone/oxide of nitrogen
Proliferate to form Type I cells.
More extensive exposure can lead to the formation of fibrous tissues.
what is Ipomeanol
toxin produced by the mould Fusarium solani
how does 4-Ipomeanol effect the lungs
Selective necrosis of Club cells in experimental animals and cattle
Club cells bioactivate 4IP. Metabolites high affinity for macromolecules cause necrosis
=Oedema and hemorrhage
Activated intermediate (? Epoxide) covalent protein binding
5 times greater concentration than liver
why is 4-Ipomeanol not an issue in humans
lower expression of enzyme (CYP4B1?)
how does ozone effect the lungs
Exerts effects on lungs through endogenous reactions with lipids in epithelial surfactant lining (phopholipids and sterols)
Oxidation of lipids results in numerous biological effects including:
- interleukin-8 release
- loss of mitochondrial dehydrogenase activity
- enhanced cytotoxicity in lung macrophages as well as epithelial cells
how do oxides of nitrogen through to cause their effects
= Peroxidation of cellular membranes.
Cause increased membrane permeability and results in fluid accumulation. More extensive exposure can lead to the formation of fibrous tissues
ozone exposure causes _ from respiratory epithelial cells
ATP release
- believed to be a protective mechanism
what does ATP release cause in the lung
stimulates activates important cell survival
signals like ERK1/2 and Akt.
what is pulmonary fibrosis
chronic response to silica, Asbestos, Quarts
which can lead to a serious debilitating disease
silica, asbestos and quarts causes pulmonary fibrosis by what toxic effects
1 - rupture of lysosomal membrane in macrophages
2 - lysosomal enzymes digest macrophages
3 - release of particle from lysed macrophages
4 - fibrotic changes
what are allergic response
induced by direct allergens (pollen, spores, bacterial contaminants, cotton dust) & small molecules (Haptens) plus protein given allergens
- e.g Toluene diisocyanate
what is Toluene diisocyanate
used in the plastic industry, a small molecule which is an allergy
How do allergens causes pulmonary fibrosis
= Produces a hypersensitive response
Reacts with proteins in the blood or lung, protein becomes recognised as “foreign” by immune system. Form antigens and stimulate antibody production
Immune response on second or subsequent exposure
what has been linked to lung cancer
Cigarette smoke = leading cause
Arsenic
Chromates
Nickel
Uranium
Coke oven emissions
Asbestos, silica,
Welding fumes
Potentially many others
why is the cause of lung cancer sometimes hard to identify
latency period up to 20-30 years, may even be longer for mesothelioma
what is the key mechanism for lung cancer
Damage to DNA. May be oxidative DNA damage or DNA adducts from e.g. PAHs
how does asbestos cause DNA damage
- absorption of carcinogens and endogenious molecules
- chronic inflammation can be caused
- Asbestos can cause mesothelium
- Deletion translocation in chromosomes during mitosis can occur
- mesothelioma can be produced
Given an example of a systemic toxin
Paraquat
- non selective herbicide = highly toxic following ingestion
How is paraquat toxic in the lungs
Enters alveolar cells via polyamine transporter
- once inside cells results in redox cycling accumulates in alveolar cells and elsewhere
- wide spread damage to both Type I and II pneumocytes
- Oedema leading to a massive inflammaotry response
What is a less toxic substitute for paraquat
Diquat = poorer substrate for transporter
what is the cellular mechanism of paraquat
- entires via the receptors
-PQ2+ -> PQ+- (radical) = reduced by NADPH
(NADP+ is oxidised via Hexose monophosphate shunt to regenerate NADPH) - produces oxygen radical which causes fentons reaction
- causes lipid peroxidation and cell death
-depletes GSH levels
what is Bleomycin
antibiotic with anti-tumour properties
- administered IV, IM, subQ, IP or intrapleurally
- mainly (605) excreted unchanged, deactivated by bleomycin hydrolyase mainly in the liver
how does bleomycin induce pulmonary toxicty
Forms complex with Fe (II), oxidised to Fe (III), releasing free radical release, causing DNA strand breaks
why is bleomycin dangerous in lung
- no hydrolase in lung (or skin)
- Pneumonitis which may progress into fibrosis
- Damage to endothelium (mechanism as yet unknown but free radicals and cytokine induction involved)
- Influx of inflammatory cells (e.g. alveolar macrophages)
- Induction of apoptosis
=Activation of fibroblasts - fibrosis
Primary response of lungs to toxicity
Inflammation, Irritant, Oedema, Mild damage
Reversible
secondary response of lungs to toxicity
Fibrosis, Emphysema, Tumours
Irreversible
what are the study methods to look at lung toxicity
- Pulmonary Function Studies
- Morphology (biopsy)
- Broncho alveolar Lavage (saline) =pulmonary macrophages
- In vitro studies = Isolated perfused lung, Isolated lung cells (cultured at air-liquid interface or submersed), Precision cut lung slices
