Airway Host Defence Flashcards
What are the 3 broad defense mechanisms and some examples of each?
- PHYSICAL
Cough
Barrier function Mucociliary Clearance - CHEMICAL
Mucus composition and viscocity
Antimicrobial peptides - CELLULAR
Phagocytosis by macrophages Immune response
What are the 3 major atmospheric polutants?
- carbon monoxide
- Nitrogen oxides
- Sulphur oxides
What causes production of CO?
incomplete combustion of carbon in fuels
What is the danger of CO?
binds hemoglobin with 200x affinity of oxygen
can impair mental skills
What produces NO?
burning of fossil fuels at high temps in power stations and cars
What does NO cause?
inflammation of eyes and upper respiratory tract at low concentrations
High concentrations can cause acute trachetis, acute bronchitis, and pulmonary edema
What produces sulphur oxides?
burning of sulphur containing fossil fuels
What does exposure to sulphur oxides cause?
Inflammation of mucous membranes, eyes,
upper respiratory tract and bronchial mucosa
•Short term exposure to high concs can cause edema
What is the largest pollutant by weight?
CO
What in cigarettes is responsible for the high risk of bronchial carcinomas?
Tar and largely aromatic hydrocarbons
What are the 3 mechanisms of clearing inhaled materials?
- Impaction
- Sedimentation
- Diffusion
How does impaction work? What kind of particles does this get rid of?
largest particles fail to turn at the corners of the respiratory tract. Particle hits wet surface and sticks. 95% particles > 5 m filtered by nose
How does sedimentation work? where is this mechanism most important?
gradual settling of particles due to their weight. Mechanism dominates in small airways
How does diffusion work to clear particles?
random movement of particles as result of their continuous bombardment by gas molecules. Only
for smallest particles (<0.1 m)
What kind of protective process is coughing?
a very non-specific protective reflex
When does the cough reflex develop?
about one month after birth
What initiates coughing?
A variety of irritants triggering specialized cough receptors in/under the airway epithelium
What are the 4 phases of the cough?
- Deep and rapid respiratory effort
- Compression due to closing of the glottis, activation of the diaphagm, and chest wall muscles
- Sudden opening of glottis and high expiratory airflow
- Relaxation of muscles and reversal of pressures
What kind of epithelial cells are in bronchial epithelia?
Ciliated, pseudostratified, columnar epithelium
What are 3 functions of tight junctions?
- structural support
- barrier
- separate apical and basolateral domains
the mucous layer in the respiratory system is subdivided into two layers, what are they?
Gel layer: top, stickier layer
Sol layer: less viscous
What two factors need to be controlled in order to have effective movement of the mucous blanket?
the length of the cilia (between 5-7 µm in the trachea and become shorter) and the height of the sol layer
What is the end point for the mucous? which way does it travel?
Moves upwards from the lungs towards the epiglottis
End point is the pharynx where it is swallowed
Cilia are found down to about which bronchial division?
the 16th
Ciliated epithelia line which 8 structures of the respiratory and associated systems?
bronchi, bronchioles of lungs plus nasal cavity, paranasal sinuses, eustachian tubes, middle ear, pharynx, trachea
Whats the basic structure of cilia?
9+2 arrangement
- ATPase or dynein arms on subfibre (complete) A
- Nexin links connecting doublets
What is the recovery stroke for cilia movement? How much cycle time does this account for?
From rest position, cilia bend sideways and back
Takes place near cell surface and accounts for 3/4 of cycle time
What comes after the recovery stroke?
Effective stroke - cilia moving perpendicular to the cell surface
claws on the tip of cilia engage with overlying mucous and sweep it towards the head
- this is the only time the cilia engage with the mucous
What factor will inhibit ciliary beating frequency (CBF)? How?
neuropeptide Y
by reducing intracellular calcium
Increases in intracellular calcium will…
increase CBF
What do mechanoreceptors int he epithelium do with regards to cilia?
Increase CBF in response to mechanical stimulation
What 5 factors affect mucocillary host defense in healthy people?
- Age: CBF is higher in neonates and teens, lower in adults
- Sex: Clearance slower in males than females
- Sleep: Clearance is decreased during sleep
- Exercise: Strenuous exercise increases MCC (no effect of gentle exercise)
- Gravity: No effect on heathy individuals really, but postural drainage may assist in CF
What are 3 diseases that affect mucociliary clearance?
- Primary ciliary dyskinesia
- aka immotile cilia syndrome - Bronchiectasis
- Cystic Fibrosis
What is Primary Ciliary Dyskinesia?
Impaired ciliary action usually due to absence of dynein arms or radial spokes (sometimes) in cilia
Ciliary motion is abnormal and not coordinated
What are the results of having primary ciliary dyskinesia?
Incidence of resp. infection high.
- Bronchitis, rhinitis, sinusitis, otitis media (middle ear infection), obstructive lung disease.
Males usually sterile due to sperm immobility.
What is bronchiectasis?
abnormal widening of the bronchi
What is thought to cause defective MCC in bronchiectasis?
local damage to the respiratory tract epithelium due to infection
How are particles cleared in the alveoli?
No mucous or cilia
Particles engulfed by macrophages
How do macrophages kill and remove foreign bacteria/particles?
Phagocytose foreign particles: migrate to small airways to load on mucociliary escalator OR
leave via lymphatics
Contain lysozyme so can directly kill bacteria
What can impair macrophage activity ?
Cigarette smoke,
alcohol, alveolar hypoxia, ozone, radiation
the principal mononuclear phagocyte of the alveolar surface is…
the alveolar macrophage!
Where are alveolar macrophages derived from?
circulating blood monocytes
What is the composition of respiratory mucous?
Water with high molecular mass + cross-linked glycoproteins + serum and cellular proteins
What two elements of respiratory mucous give it the viscoelastic properties?
Glycoproteins and water
What are mucins and what is their role in mucous?
gigantic biopolymers of glycoproteins characterized by presence of one or more large region rich in serine and threonine.
Amino acids covalently attached via linkage sugar NAG
Role:
- provide structural framework of defense barrier,
- prevent barrier dehydration,
- present carbohydrate sites which pathogens attach to
Human resp mucous is a mixture of what two kinds of mucous?
MUC5AC (goblet cells)
- main one
MUC5B (mucous cells in submucosa)
Airway mucous is a mixture of products from which 4 places?
- Alveolar liquid
- Secretory products from cells lining the surface epithelium
- Submucosal gland products
- Serum transudate
What type of cells can transform into goblet cells in disease?
clara cells
How much larger volume wise are submucosal glands compared to goblet cells?
about 40 times
What happens when a secretory granule docks with the plasma membrane of a SMG? What happens to the mucin polymers
a secretory pore forms.
The pore has a high ionic conductance and Ca2+ inside the granule is exchanged for extracellular Na+. This Na+/ Ca2+ exchange triggers a polymer-gel phase transition, when the mucin polymer matrix undergoes extensive swelling and switched from condensed to hydrated state
What kind of material is mucous? What kind of flow properties does it have?
Viscoelastic material characterized by nonlinear (non Newtonian viscosity) and time-dependent flow (thixotropic) properties
What are viscosity and elasticity? In terms of rheology?
Viscosity = resistance to flow and is the capacity of a material to absorb energy when moving
- extent to which it resists the tendency to flow
Elasticity = capacity of a material to store energy used to move or deform it
- tendency to recover its original shape
What happens to the viscosity of mucous as the applied force increases?
the viscosity decreases
What is rheology?
the characterization of the physical properties of mucous
What is phelgm? What does it contain?
purulent secretion that is a product of airway inflammation, Containing breakdown products of inflammatory and epithelial cells; including DNA and actin fragments, bacteria, cell debris and mucins
What is sputum?
Phlegm that has been expectorated
What is the sol layer or pericilliary liquid layer like?
low viscosity medium
about 7 µm deep
What factors are contained in the sol layer? What does this acheive?
Antibacterial factors
- lysozyme, lactoferrin…
Broad antibacterial spectrum against S. aureus and P. aeruginosa
What is responsible for the hydration of mucous and the depth of the sol layer?
The transepithelial movement of ions and water
How is the periciliary liquid layer (PCL) controlled ?
- When excess PCL is present, Na+ absorption via epithelial Na channels (ENaC) is dominant. Cl- is absorbed passively via the paracellular pathway
- When PCL volume if low, ENaC is inhibited which makes the apical membrane potential more negative, so generating a driving force for Cl- secretion.
What do epithelial cells lining the airways express as part of innate host defence mechanisms?
Antimicrobial peptides
AMPs are generally… which allows them to bind to prokaryotic cell membranes
cationic
high levels of what 2 things can inhibits the functioning of AMPs?
salt or serum proteins
What 2 small AMPs are found in the human airway?
- Defensins
2. Cathellcidins
What are 2 examples of large AMPs? What do they do?
- Lysozyme
- induces lysis of gram positive bacteria - Lactoferrin
- sequesters iron from bacteria
What does Coal Workers Pneumoconisis + Silicosis (CWP) refer to?
Interstitial disease of the lung resulting from chronic exposure to coal dust
Silicosis is due to the inhalation of dust containing silica (quartz)
What is the latency period for CWP and Silicosis?
long, like 20 years
What occurs to the lung tissue in CWP?
formation of lesions called coal dust macules
coal-dust laden macrophages within the walls of the respiratory bronchioles and adjacent alveoli. Often emphysema surrounding macule. In advanced disease, condensed masses of black fibrous tissue seen called nodules
What occurs in the lung tissue in Siliciosis?
- Infiltration of the alveolar walls with plasma cells, lymphocytes and fibroblasts, with some collagen deposition.
- Alveoli fill with eosinophils.
- Widening of alveolar walls with collagen and clusters of type II cells.
- Nodules rare
What are 3 asbestos related diseases ?
- Asbestosis
- Bronchial carcinoma
- Pleural disease
What causes asbestosis?
Asbestos fibres depositing at branch points in the airways.
Cascade of inflammatory activation which results in a fibroblast proliferation and extracellular matrix deposition in interstitial space
Pleural disease may occur after even….
trivial exposure to asbestos
What is pleural disease?
formation of pleural plaques or thickening which results in restriction and reduced compliance?
What is a severe complication that may develop from pleural disease?
Malignant mesothelioma
What is occupational asthma?
Variable airflow obstruction or bronchial hyper-responsiveness from conditions in a particular working environment
What are the two forms of occupational asthma?
- Immunologically mediated
2. Non-immunologically mediated
What is characteristic of immunologically mediated OA compared to the N-I mediated?
Latency period necessary to acquire sensitization
What is thought to be the cause of Non-immunologically mediated OA?
maybe extensive denudation of epithelium results in airway inflammation and hyper-responsiveness due to loss of epithelium-derived relaxing factors, exposure of nerve endings to neurogenic inflammation and non-specific activation of mast cells, with release of mediators and cytokines
Epithelial cells of the lungs are exposed to oxidants in which two ways?
- Internally from normal metabolic processes
2. Externally from environmental pollutants
What are examples of enzymatic and non-enzymatic antioxidant defenses against oxidants?
- non enzymatic: glutathione, vitamins C+D…
2. Enzymatic: superoxide dismutases, catalases, and peroxidases
Oxidative stress has been implicated in the pathogenesis and progression of many pulmonary diseases including….
asthma, cystic fibrosis, idiopathic pulmonary fibrosis and COPD, plus effects of environmental
pollutants
What is a free radical?
Any species that contains one or more unpaired electrons
What are 5 important ROS?
- Superoxide anion
- Nitric oxide
- Peroxynitrite
- Hydroxyl radical
- Hydrogen peroxide
What are the 2 primary ROS produced in vivo?
O2- and H2O2
What is the most harmful ROS?
OH-
What is the pathophysiology of oxidant stress in asthma?
there are more inflammatory cells than controls which results in more ROS being produced
airway antigen challenge + asthma attack = immediate formation of O2
deficiency in superoxide dismutases in asthma results in…
lower levels of epithelial lining fluid
Exposure to ROS results in apoptosis of epithelial cells
What is responsible for keeping the alveoli sterile?
alveolar macrophages
