Pulmonary Week 2:
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Pulmonary Week 2
1. Describe the both the conducting and respiratory components of the respiratory tree
including their histological appearance and explain the functional significance of each of
these components.

Conducting
o Nasal cavities and sinuses
 Mucous controls inhaled debris and microorganisms
 Cavities and sinuses warms and humidifies inhaled air
 Olfactory bulb provides sense of smell
o Nasopharynx
 Warms and humidifies inhaled air
o Oropharynx
 Junction at which the esophagus meets the laryngeal orifice
o Larynx
 Contains the vocal folds, an essential part of phonation
 Vocal folds (“vocal cords”) is the last barrier which prevents aspiration of
foreign objects down into the trachea
 Momentary closure of vocal folds is important in completing the val salva
maneuver
o Trachea
 Anterior and lateral—12 to 20 hyaline cartilage “horseshoe” rings
 Posterior—a smooth muscle called “trachealis” that bridges the horseshoe ring
gap, controls lumen size, and aids in coughing
 Lumen is lined by mucosa (respiratory epithelium, basement membrane, and
richly vascular lamina propria), then submucosa (loose CT and seromucous
glands that deliver secretions to mucosal surface), then finally adventitia
(protective CT, i.e. cartilaginous rings)
o Bronchi
 Right and left “mainstem”  lobar  segmental
 Walls of larger bronchi contain irregular rings of hyaline cartilage
 Walls of smaller bronchi contain plates and islands of cartilage
 Similar to the trachea, the lumen is lined by mucosa, then submucosa, and finally
adventitia
 There is a gradual reduction in goblet cell propensity in the mucosa as we move
away from the trachea, and an increase in Clara cells
 Lamina propria within the mucosa layer contains elastic fibers and lymphoid
nodules
 Seromucous glands in the submucosa still connect to surface
 Smooth muscle completely encircles lumen
o Bronchioles
 Diameter size ≤ 1 mm
 No cartilage or submucosal glands
 Cuboidal ciliated epithelium in place of simple columnar
 Goblet cells replaced by Clara cells (secretory & non-ciliated)
 Clara cells: dome-shaped, degrade toxins, reduce surface tension and
serve as mitotic stem cells
 Smooth muscle arranged helically and complete encircles lumen
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
Respiratory
o Respiratory bronchioles
 Bronchioles which contain alveolar protusions
 Otherwise similar to bronchioles
o Pulmonary alveoli (alveolar ducts, alveolar sacs, alveoli proper)
 Small air sacs (200 µm in diameter)
 Lined by simple epithelium called pneumocytes (two types)
 Inhabited by “Dust cells” of the immune system
 Thin walls separate a cluster of alveoli—they contain pulmonary capillaries and
elastic fibers and they are called “interalveolar septae”)
2. Describe the embryological development of both components of the respiratory tree.

4 week old embryo
o Tubular outgrowth emerge from primitive digestive tract
o Tubular outgrowth form laryngo-tracheal diverticulum and lung buds
o Foregut endoderm forms innermost layers of respiratory tree
o Splanchnic mesoderm forms stroma, smooth muscle, and cartilage
3. Describe the composition and histological appearance of the respiratory mucosa and
explain how it provides the muco-ciliary clearance mechanism.




30% Columnar Ciliated Cells
o Cilia projections contains 9+2 microtubules, beats rhythmically
o These structures move mucus and trapped matter towards nasopharynx
30% Goblet Cells
o Secretes mucus to trap debris and microbials, protect the cells below
30% Basal Cells
o Stel cells for renewal and regeneration
10% Other Cells
o Mostly hormone producing APUD cells
4. In microscopic sections, differentiate between the trachea, bronchi, bronchioles and
pulmonary alveoli.




Trachea—large, muscular, cartilaginous, respiratory epithelium
Bronchi—smaller, muscular, cartilaginous
Bronchiole—microscopic, muscular, not cartilaginous
Pulmonary alveoli—microscopic, not muscular or cartilaginous, RBCs
5. Describe the muco-ciliary clearance mechanism and factors that affect it in disease states.





Goblet cells in conducting airway secrete mucous
Mucus traps debris, toxins, and invading microorganisms
Cilia on ciliated cells beat towards the nasopharynx to continually expel mucus
Factoid! The debris tend to move upwards in a spiral pattern
Chronic insult (i.e. smoking) lead to the dysfunction of this mechanism
o Mucus no longer effectively moved up the respiratory tree
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6. Describe the structure and ultra structure of the two types of pneumocytes and the
alveolar macrophage cells and their roles in health and disease states.



Type 1 Pneumocytes
o Thin and flattened (80 nm wide)
o Line 95% of the alveolar surface
o Linked by tight junctions
o Minimal thickness at 0.5 µm facilitates rapid gas exchange
Type 2 Pneumocytes
o More numerous but line only 5% of alveolar surface
o Secrete surfactant to reduce surface tension and prevent alveolar collapse
o Surfactant reduce surface tension at the alveoli and thus prevent the alveoli from
completely collapsing on exhalation and allows them to be reopened with a lower
amount of force
o A lack of surfactant results in collapsed air spaces alongside hyperexpansion and
vascular congestion
Dust cells
o Resident macrophages that absorb debris, attack invading microorganisms, and release
inflammatory factors to initiate an immune response
o Loss of Dust cell population makes the lung more prone to infection
7. Describe the key features of the blood-air barrier and indicate the functional significance
of surfactant. <Histology Booklet p. 22, 53>
The Blood-Air Barrier is minimal in thickness (0.5 u) which provides rapid gaseous exchange
between pulmonary capillary and pulmonary alveoli
4 components:
(1) Type 1 Pneumocyte with tight junction – attenuated cytoplasm (i.e. appears think &
flattened), covering about 95% of surface area of a pulmonary alveoli
- Covered by a thin layer of surfactant secreted by Type II pneumocyte
(2) Basement membrane of Type 1 Pneumocyte
May be fused together
(3) Basement membrane of pulmonary capillary endothelial
cells
(4) Pulmonary capillary endothelial cell – enclosing capillary lumen
- The tight junction prevents indiscriminate fluid leakage
Type 2 Pneumocyte: produces surfactant that  surface tension  prevent alveolar
collapse during expiration when air is being squeezed out of the alveoli
8. Specify the main components of total resistance offered to flow of air in and out of the
lungs and describe the relationship between flow, driving pressure and resistance.
Keys Mechanical factor contributing to air flow in & out of lungs:
1) Elastic recoil of lungs
2) Elastic recoil of chest wall
3) Total resistance to airflow
 Air molecules require energy to move forward  to begin air flow, resistance (an opposing
energy) must be overcome
o Total resistance to airflow in & out of lungs have 3 components:
(1) Inertia of the respiratory system (negligibly)
(2) Tissue resistance of the lungs & chest wall (20%) Please see obj 10 for explanation
(3) Airways resistance (80% - can  tremendously in both health & disease
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


In general, resistance  R = P/ Flow, where R = resistance, & P= the pressure
difference or driving pressure. ** R is only meaningful during airflow (unit = cm
H20/L/sec)
Total resistance is R = PA - PB / Flow, where PA is alveolar pressure, PB is barometric
pressure or atmospheric pressure at the airway opening (typically the mouth)
Resistance offered by healthy lungs during quiet inspiration (2 cm H20/L/sec) is very small
compared to that of smoking pipe (500 cm H2O/L/sec) for a given flow rate
o This small resistance is mainly due to the anatomic arrangement of the
tracheobronchial tree
o In a branched system of tubes (e.g. our airways), frictional resistance depends on:
 (a) individual resistance of each tube
 (b) the ways in which the tubes are connected
o A branching system can be connected in two ways:
1) In series: Rtotal= R1 + R2 + R3 etc…
(Total resistance of the system = the sum of each individual resistance).
2) In parallel: 1/Rtotal = 1/R1 + 1/R2 + 1/R3 etc...
(Total resistance of the system << any individual single resistance.
E.g. R1 = R2 = R3 = R4 = 2
 1/Rtotal = 1/R1 + 1/R2 + 1/R3 + 1/R4 = 1/2 + 1/2+ 1/2 + 1/2= 4(1/2) = 2
 Since 1/ Rtotal = 2  Rtotal = 1/2
*The general rule: if you have 4 identical R set up in parallel  R total of the system = ¼ of a single
R. Now, 20 identical R in parallel  R total = 1/20 of a single R and 100 identical R in parallel  R
total = 1/100 of a single R
9. Describe the relationship between total cross sectional area, airways resistance and
airflow velocity in the bronchial tree (A system of branching tubes)

Resistance in a single tube is inversely related to the radius of the tube to the 4th power
 (R α 1/r4)
o  radius, diameter, or cross sectional area of the tube   resistance.
o Consider how our airways branch from the trachea to the alveoli:
o At each new branch point, the daughter airways that arise from that same branch point
belong to the same generation.
o The airways of the same generation tend to be of the same size.
o # of branches  as we move from the trachea to the pulmonary alveoli
o Also, the radius, diameter & cross section of the individual airway gets
progressively smaller
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Pulmonary Week 2:
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A small diameter usually causes a higher resistance, but the large number of
parallel airways in that generation reduces the overall resistance.
o Because the branching airways are arranged in parallel   # of branches   overall
resistance
o Remember, if you have 100 branches arranged in parallel having identical
resistance (R)  R total of system = 1/100 of R
o As we move from trachea to alveoli, the total resistance become almost insignificant at
the alveoli
o Most of the overall airway resistance comes from the Upper Respiratory Tract &
generations 0 through 6 where total cross sectional area of the generation is relatively
small.
o Enormous expansion of the sum of the cross sectional area of parallel airways from
about 2.5 cm2 in the trachea to 180 cm2 at about generation 16, the end of the
conducting zone
o Affects airways resistance
o ALSO impact on airflow velocity
 Velocity of air thru a series of branching tubes in parallel is similar to
resistance
 Airflow velocity  1/total cross sectional area and R  1/total cross sectional
area
 Airflow velocity  & Resistance  as the total cross sectional area  as we
move from trachea to alveoli
 Why airflow velocity? Check out:
http://sprojects.mmi.mcgill.ca/resp/bernoulli_effect.htm
**Important:
As air moves from trachea to the
distal airways, airflow velocity .
In the respiratory zone of lung,
convective flow stops &
diffusion is the main mode of
gas movement
The parallel arrangement of
the tracheobronchial tree
optimizes the conflicting
demands of the lung by having:
1) A small volume of
airway that does NOT
contribute to gas
exchange (the
conducting zone)
2) A small resistance to
accommodate the
flow of large amounts
of air into respiratory
zone
 As air moves from alveoli to
trachea, airflow velocity 
allowing air to exit in reasonable time period through the relatively small airway volume of the
conducting zone.
o
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Pulmonary Week 2:
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10. Define tissue resistance of the lungs and explain why it is inversely related to lung
volume.
Lung tissue resistance = the resistance offered by lung tissue as it expands
 Lung tissue resistance varies w/ lung volume
 Lung tissue resistance  as lung volume , 2 reasons for that:
(1) The tethering effect of the alveoli
o At high lung volumes, the alveoli are more distended and the elastic recoil tension in their
walls is higher.
o In our lungs, airways are surrounded by and attached to alveoli  The airways are thus
pulled open by the high tension in the distended alveolar walls of their neighboring
airways
o As lung volume , the tension in the
alveolar attachments to the airways ,
pulling the airways open outwards
o This  airway diameter and  resistance
(R α 1/r4)
o At lower lung volumes approaching RV, the
elastic recoil tension in the alveolar wall is
less
o Thus, airways are narrower and
contribute more to airway resistance
o Some airways may even begin to close at
such low volumes especially at the
bottom of the lungs where the lungs are
less expanded
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Pulmonary Week 2:
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(2) The change in the parasympathetic tone
o Airways are surrounded by a smooth muscle layer innervated by the PSN system
o PSN  smooth muscles to actively contract  constricts the airways
o Stretch receptors (mechanoreceptors) within this smooth muscle layer detect changes in
lung volume
o During inspiration when lung volume  these mechanoreceptors  neural firing rate
 PSN signals to the smooth muscles   constriction of airways  airflow
resistance
o During expiration,  lung volume  PSN signals  smooth muscle constriction & air
flow resistance
11. Distinguish between airflow and airflow velocity and describe the key features of
laminar and turbulent airflow, where they typically appear in the airways and where they
change in disease.

Flow rate = amount of fluid (ml) moving per sec
o [Flow rate = ml/sec].
 Flow velocity = distance fluid travels in 1 sec
o [Velocity = flow rate / cross-sectional area of the tube (cm2) =cm/sec].
 Air is a fluid  follows the principles of fluid dynamics as it moves in and out of the lungs.
 In the airways, flow will occur when a pressure difference exists between one point along the
airway and another (driving pressure), from higher pressure to a lower pressure.
 Flow can exist in three patterns: Laminar Flow, Tubulent Flow, Disturbed Laminar Flow
(1) Laminar Flow
o This type of flow occurs in smooth tubes and at LOW flow rates.
o Flow in small airways diameter < 2mm) is laminar, silent & slow
o The flow is streamlined and there is no turbulence. The flow occurs in parallel layers, with
minimal disruption between these layers.
o The flow rate is greatest at the centre and diminishes towards the periphery  laminar
flow is described as having a bullet shaped or parabolic "velocity profile"
o In Latin, laminae = layers
o Laminar flow = circular layers of fluid movement w/ the fastest being in the center to
the slowest at the walls of fluid movement
o During laminar flow the relationship between driving pressure and flow is linear, ΔP α ΔV
o  driving pressure, flow will  proportionally
(2) Turbulent Flow
o This type of flow occurs in rough tubes and at higher flow rates.
o Flow in the large airways such as the trachea is turbulent, fast and noisy
o The flow is not streamlined and there is lot of swirling (eddies) of the fluid.
o The flow is not greatest at the centre  "velocity profile" of turbulent flow is more flat
(or more blunt) than that caused by laminar flow.
o Fluid flow in both axial & radial direction
o Fluid velocity is on average the same everywhere in tube
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Pulmonary Week 2:
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o
o
The radial component of turbulent flow constantly impacts the walls of the tube and
consumes energy, therefore, a higher pressure difference is needed to maintain a given
flow rate.
The relationship between driving pressure and flow in turbulent flow is alinear: ΔP α V2
o To double the flow under turbulent conditions  the pressure difference must be > 2X.
** P  greater laminar flow compared to turbulent flow because some of the P in turbulent
flow is expended in generating radial flow
(3) Disturbed Laminar Flow
o A combination of laminar and localized turbulent
fluid movements referred to as eddies.
o Eddies occur where the tube either narrows,
branches, or where there are irregularities in
the tube surface.
o This type of flow represents a mix between
laminar and turbulent flow and is present in the
majority of airways.
12. Explain how indices obtained from the expiratory force vital capacity help determine
whether a patient has an obstructive ventilatory defect





During expiration, the more effort healthy individuals put into contracting their expiratory
muscles  can force air out of their lungs at greater flow rates
This efforts affects flow rate at high lung volumes
This efforts DOES NOT affect flow rate at low lung volumes
o Here flow rate is independent of effort due to air flow limitation
In the clinical setting, patients are routinely asked to perform a forced expiratory vital
capacity maneuver, emptying their lungs as rapidly and forcefully as possible from maximal
inspiration to maximal expiration to determine the degree of air flow limitation.
There are two important measurements obtained from the Pulmonary Function Test (PFT):
FEV1 & FVC
FEV1 = forced expiratory volume in 1 sec
FVC = forced vital capacity used to estimate Vital Capacity (VC)
FEV1/FVC ratio = % of VC is expired in 1st sec – used to differentiate between
abnormal patterns of ventilator defect
**Other measurements include FEF25-75%
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Pulmonary Function Test Results
Obstructive Lung Disease
 Disproportionate FEV1 
compared to FVC 
 Low FEV1
 Low FEV1/FVC ratio
Asthma
 Episodic
 FEV1/FVC ratio improves
with bronchodilator;
worsens with
bronchoprovocation
Restrictive Lung Disease
 Low lung volumes & capacities
 Low FEV1
 Normal or Above Normal
FEV1/FVC ratio
 Normal or low DLCO
COPD
Chronic Bronchitis
 Sputum production
 Normal DLCO
 High RV & FRC
9
Emphysema
 Lung compliance curve
shifted to left
 Low DLCO (alveoli wall
destruction
 High TLC, RV, FRC (lung
hyperinflation)
Pulmonary Week 2:
Airways Disease
13. Define dynamic compression of the airways using the equal pressure point hypothesis
and specify the factors that affect airflow limitation in health and disease.
Note: from www.sallyosborne.com “Airways Resistance and Airflow through the Tracheobronchial
Tree”
Equal Pressure Point Hypothesis:
=points along the airways at which the intrapleural P is equivalent to airway P
-as lungs empty, Equal Pressure Point moves from larger to smaller airways towards alveoli
-increases dynamic compression of the airways
->results in airway collapse or closure
Dynamic Compression of the airways:
-develop close to the equal pressure point where intrapleural P EXCEEDS airway P AND
-inadequate cartilaginous support or traction provided by neighbouring alveoli
Factors that affect airflow limitation in health and disease:
1) Inertia of the respiratory system
2) Tissue resistance of the lungs and chest walls/ Lung Compliance
20%
-↓ in elastic recoil of lungs ↓ its contribution to a greater P in the airway vs. intrapleural P
-> Greater dynamic compression
1) Airways Resistance
80%
-the greater the resistive drop in P along the airway from alveolus to Equal P Point
-the sooner the development of an Equal P Point
-the greater the dynamic compression
14. Compare and contrast the histological sections of the auditory tube, olfactory mucosa,
epiglottis, and larynx.
Auditory Tube
Olfactory Mucosa
Respiratory
Epithelium
1) tall columnar
cells w/ apical
cilia
2) goblet shaped
cells (palestaining)
3) small,
rounded basal
cells on bm
underlying
basement
membrane
Lamina Propria
-loose CT
-cellular + highly
vascular
modified, extra-thick
pseudostratified epithelium
1) olfactory receptor cells
-true bipolar neurons
-nuclei in centermost layer
-apical process w/ non-motile
cilia receptive to odoriferous stimuli
2) supportive cells
-mechanically support receptive
cells
3) small basal cells
-base of epithelium
-stem cells for olfactory receptor
cells
lamina propria
1) unmyelinated axons from
receptor cells
Epiglottis
lingual surface:
stratified
squamous nonkeratinizing
epithelium
undersurface:
from the above to
stratified
columnar to
pseudostratified
ciliated
columnar
epithelium
10
Larynx
False vocal cords True vocal cords
Respiratory
Stratified
Mucosa
Squamous NonKeratinizing
Epithelium
towards the
laryngeal ventricle,
epithelium changes
to
Pseudostratified
type
lamina propria
-cellular + highly
fibrous
Pulmonary Week 2:
Airways Disease
=axons of cranial nerve I
1) many small blood vessels
2) serous glands of Bowman
-watery surface secretion
bony tissue of nasal concha
sero-mucous
glands
central core of
elastic cartilage
sero-mucous
glands
central core of CT
-mostly elastic
fibers
-some skeletal
muscle (vocalis
muscle)
15. Describe the histological features of the trachea with special reference to mucosa,
submucosa and adventitia
Mucosa
epithelium
basement membrane
lamina propria (highly
vascular)
(30%) goblet cells: mucus
Submucosa
mostly loose CT
Adventitia
outer protective CT
seromucous glands: secretions
12-20 hyaline cartilage
horseshoe rings
smooth muscle (Trachealis)
-bridges gap
-controls lumen size
(30%) respiratory epithelium/
pseudostratified ciliated
columnar epithelial cells
(30%) basal cells - stem cells
(10%) others
-mostly hormone producing
APUD (amine precursor uptake
decarboxylation?) cells
16. Discuss the hilus of the lung with special reference to histological appearance of the main
bronchi.
Hilus of Lung
The site where major blood vessels, bronchi, nerves and lymphatics enter or emerge from the lung.
Main Bronchi: Structurally similar to the trachea with 2 exceptions:
1. the arrangement of cartilage into small plates
2. the circular arrangement of smooth muscle, which completely envelops the lumen and is
submucosal in location.
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17. Describe the essential histological features of the lung with special reference to
intrapulmonary bronchi and bronchioles.
18. Contrast the main cell types in the respiratory epithelium of the bronchus with those of
the bronchioles.
Lung
 spongy, honeycomb-like network
 contains tubular structures of different sizes and at different levels of histologic
organization
 consists of millions of alveoli
Bronchi
Bronchioles

respiratory epithelium reduced in height



gradual reduction in # of goblet cells
Elastic fibers and lymphoid nodules in
lamina propria
Seromucous glands connect to surface
Smooth muscle completely encircles
lumen
Irregular hyaline cartilage plates








Simple columnar to simple cuboidal
epithelium
Goblet cells replaced by Clara cells
Lamina propria rich in elastic fibers
No submucosal glands
Smooth muscle arranged helically and
completely encircles lumen
No cartilage
19. Discuss the causes and mechanisms of cough and chronic sputum production.
Cough
 Can be voluntary or reflexive
o afferent: stimulate irritant receptors in airway, travels up CN X (vagus)
o efferent: activate inspiratory muscles and diaphragm, via phrenic nerve
o activate expiratory muscles, larynx, CN X (vagus) – recurrent laryngeal nerve
 Phases of cough
1. Inhalation of gas (Not a critical component of cough) – inspire a LARGE volume of gas
2. Compressive - GLOTTIS is CLOSED; isometric contraction of the expiratory muscles
increases intrathoracic pressure up to 300 mm Hg; expiratory effort against a closed
glottis
3. Expiratory phase – GLOTTIS OPENED; high intrathoracic pressure causes a high
expiratory flow rate
 Receptor location: most sensitive sites are larynx and tracheobronchial tree, especially the
carina and sites of bronchial branching. Irritation on smaller airways and alveoli will not
induce cough.
 Stimuli: cig smoke, ammonia, ether vapour, acid/alkaline solution, mucus, dust, etc.
 ACEi induced cough likely due to accumulation in the lungs of bradykinin, substance P,
and/or prostaglandins. Stops within 4 days of d/c drug.
Chronic Sputum Production
 Mucus contains: mucus glycoproteins (mucins), water, and peptides
 Mucus moves from lower airways, trapping particles and travelling up mucociliary ladder,
coughed up and swallowed
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


Mucus is ↑ in chronic bronchitis due to ↑ production of mucins and ↑ secretion from goblet
cells.
Stimuli include neutrophil elastase, LPS, cigarette smoke, oxidative stress  leading to
goblet cell metaplasia and mucus hypersecretion (also caused by smoking)
Chronic inflammation can lead to formation of pus and contribute to purulent sputum
20. Discuss the pathogenesis (mechanism of which disease is caused) of COPD, asthma,
bronchiolitis obliterans, and bronchiectasis
COPD
 Is essentially due to the inhalation of noxious particles and gases, especially smoking and
occupational hazards
 Along with host factors (ie. Alpha 1 antitrypsin deficiency/genetic factors), lead to lung
inflammation  oxidative stress and proteinases affect the lung
 Squamous metaplasia results in response to smoke exposure
 Lung parenchymal damage decreases diffusive capacity (↓ DLco)
 Glandular enlargement and goblet cell hyperplasia  excess mucus production
Asthma
 Inflammatory condition associated with allergies, genetics, viral infections; often
precipitated by stress or exercise
 Exposure to an antigen/irritant results in the release of histamine/leukotrienes/growth
factors leading to airway smooth muscle constriction
 Can be accompanied with pulmonary vascular dilation and leakage, ↑ mucus secretion, and
airway remodelling if chronic
 Largely a reversible condition with drugs or spontaneously
 Lung parenchyma is often not affected
 Smooth muscle hypertrophy leads to hyperreactive airways
 Goblet cell hyperplasia  ↑ mucus production, may form plugs
Bronchiolitis Obliterans
 Chronic inflammation of bronchioles that can obstruct the lumen
 Caused by inhalation of noxious substances, infection, connective tissue disease, chronic
rejection, adverse drug reactions, or idiopathic
 Inflammation results in edema and movement of cell substances to obstruct airway lumen
 Smooth muscle hyperplasia, bronchiolectasis, fibrosis due to inflammation
Bronchiectasis
 Irreversible ilation of the bronchial tree
 Due to infection, obstruction, congenital defects, immunodeficiency, connective tissue and
immune disorders (common in cystic fibrosis)
 Neutrophils release mediators that cause inflammatory reactions and destroy the structure
of bronchial walls
 ↑ susceptibility of infection
 Often will find fluid filled dilated bronchi, ↑ sputum production, hemoptysis
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21. Correlate the patho-physiological process in the obstructive lung diseases with the
changes observed in physiological measurements

ALL obstructive disease have a) low FEV1/FVC1 b) low PEF
o This is because there is an object/buildup/remodeling that decreases the ability of
the lungs to expire air rapidly
i) Asthma
○ Why Low FEV1/FVC1? Asthma is condition involving airways – chronic inflammation,
remodeling (including a) increased smooth muscle around bronchioles which spasm, b)
increased ECM/basement membrane) – ultimately leading to airway wall thickening
ii) COPD
a) Chronic Bronchitis
○ Why normal DLCO? Parenchyma not affected
○ Why high RV, FRC? Excess mucous (hypertrophy of mucous glands & goblet cell
metaplasia), airway inflammation  difficulty expiring air  lung
hyperinflation with air trapped at end of expiration
b) Emphysema
○ Why low DLCO? Parenchyma affected
○ Why high TLC, RV, FRC? Inflammation  proteinases (e.g., elastase)  mucous
plugging, narrowing, decreased elasticity/increased compliance, damage
parenchyma  decreased “tethering” to keep airways open  when
intrapulmonary pressure increases to expire, airways collapse
22. Describe the role of smoking on the pathogenesis of COPD.
Smoking
 Tobacco smoke in airway  hypertrophy of mucous glands & goblet cell metaplasia (to
remove irritant)  excessive mucus in bronchial tree + cough  chronic bronchitis
 ↑ [free radicals] in tobacco smoke  oxidative stress and damage to lungs
 Tobacco smoke (irritant particles) in airway  body response = cytokine release + chronic
airway inflammation  remodelling + thickening  small airway disease (chronic
bronchiolitis)
 Tobacco smoke & free radicals  ↓ activity of antiprotease enzymes (i.e. alpha 1antitrypsin)  protease damage lung  destruction to alveolar wall  ↓ lung recoil 
emphysema
 Emphysema & small airway disease  ↓ expiratory flow; hyperinflation; gas exchange
abnormalities  cough, sputum, dyspnea, wheeze
23. Understand the importance of the immune system in the pathogenesis of asthma

“Allergic asthma”: type I hypersensitivity reactions  cytokines from Th2 Cd4+ cells such
as IL-4, IL-5, IL-3  IgE created  stick to inflammatory cells (e.g., mast cells) 
histamines, and leukotrienes etc released w/ exposure to allergen  airway narrowing
o (Smooth muscle contraction, airway wall edema, increased mucus, recruitment of
additional inflammatory cells).
14
Pulmonary Week 2:
Airways Disease
24. List the major drug classes used in the management of asthma/COPD
Class –
Prototype
SABA (Short
acting β2
agonist) salbutamol
MOA
SE/safety
Pharmacokinetics
Binds β2 receptor,
activates adenylate
cyclise to ↑ cAMP
↑
bronchodilation
- Well tolerated
- tachycardia
- palpitations
(↓ β2 selectivity-↑ dose)
- tremor
Onset in ≤5 minutes,
used acutely
LABA (Long
acting β2
agonist) –
salmeterol,
formoterol
Same as SABA,
with ↑ β2
selectivity
- same as SABA
Inhaled
corticosteroids –
budesonide,
fluticasone
@ nucleus to
inhibit expression
of proinflammatory
cytokines (COX2)
- oral thrush
(candidiasis)
- dysphonia
(hoarseness)
- long term SE,
osteoporosis
Diskus, DPI
salmeterol is
slow acting
formoterol is
fast acting, can
use as rescue tx
MDI, DPI, diskus
Systemic
corticosteroids –
prednisone
Same as ICS
Anticholinergics
– iptratropium,
tiotropium
Antagonizes
muscarinic
receptors
M1 
bronchodilation
M3  ↓ bronchial
secretions
Phosphodiesterase
(PDE) Inhibitor,
slows breakdown
of cAMP  ↑
bronchodilation
- osteoporosis
- fat redistribution
“moon face”
- obesity “buffalo hump”
- hyperglycemia
- and many more!
- dry mouth
Slower onset of action
Dissociates from
receptor more slowly
than SABA
lasts 12 hours
not for rescue/acute
- Treats inflammatory
component of asthma,
needs to be used
regularly (twice a day
dosing)
- Immunosuppressant
- significant metabolic
effects
- less bronchodilation,
more SE, slower onset
of action compared to
ICS
- slower onset of
action than SABA
- tiotropium is longer
acting (once a day
dosing)
MDI, DPI,
nebules
Methylxanthines
- theophylline
- narrow therapeutic
range
- nausea, vomiting
- stimulatory; insomnia,
tremor, restlessness
- cardiac arrhythmias
- lots of drug
interactions!
15
Mode of
Delivery/Other
MDI, diskus,
nebules, DPI
If used >3
times/week,
need ICS therapy
oral
oral
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Airways Disease
Leukotriene
receptor
antagonists
(LTRA) –
montelukast
Monoclonal
antibodies –
omalizumab
Blocks
lipoxygenase
pathway, leading
to ↑
bronchodilation
Binds to
allergen/antigen to
stop interaction
with IgE = no
allergic response
- headache
oral
- possible
immune/injection site
reactions (45%)
- viral infections (24%)
- URTI (19%)
- headache (15)
- subcutaneous
injection every
2-4 weeks
- expensive
Combination therapy
ICS + LABA – chronic B2 agonist use can lead to receptor downregulation, so use ICS to upregulate β2
receptors in the lung; also, β2 agonist dilates airways, ↑ ICS deposition
fluticasone + salmeterol (Advair)
budesonide + formoterol (Symbicort)
MDI- Metered dose
DPI – dry powder
Diskus
Nebulizer
inhaler
inhaler
- ≤10% of dose reaches
alveoli
(depends on particle size;
smaller = ↑ drug to target)
- needs coordination
- can use aerochamber for
young or elderly
- patient controlled
- coordination not as
demanding
- fine powder; not
obvious the dose
has been delivered
- patient controlled
- coordination not as
demanding
- fine powder; not obvious
the dose has been delivered
- inconvenient
- not portable
- used for young patients
25. Describe mechanism of action of drug classes used in asthma/COPD
26. Describe major side effects and safety issues with these agents
27. Describe pharmacokinetic issues, modes of delivery
MOA
Bronchodilator:
β agonists  activate
- epi: α&β agonist
adenylate cyclase 
- isoproterenol: β1&β2 increase cAMP 
agonist
bronchodilation
- salbutamol
Pharmacokinetics
salbutamol: short
acting (SABA)
- onset minutes
- acute use
16
Side Effects
- Well-tolerated
- Tachycardia/
palpitation with high
dose
- tremor
Pulmonary Week 2:
Airways Disease
-
salmeterol
-
ipratropium
tiotropium
- theophylline
Corticosteroids
- not anabolic
-
prednisone
budesonide
fluticasone
ciclesonide
salmeterol: long acting
(LABA), 12h
- high selectivity for β2
- not for acute use, slow
onset
Ipratropium (Atrovent) Local: dry mouth due to
- minimize systemic
decreased Ach
absorption, nonselective for muscarinic
receptor
- M1 & M3 R:
bronchoconstriction
- M2 R: autoreceptor,
feedback inhibition of
Ach release
Anticholinergic
Tiotropium:
- selective to M1&M3 R
- long-lasting, better
acting
Theophylline:
- strong coffee
- Phosphodiesterase
inhibitor: inhibit
breaking down of cAMP
Methylxanthine:
Systemic (oral):
- Prednisone
- Act in nucleus
- inhibit expression of
pro-inflammatory
cytokines & COX2
- immunosuppressant
(beneficial)
Inhaled:
- budesonide,
fluticasone
(localized delivery,
minimize systemic side
effects
- ciclesonide: prodrug
activated by esterase in
airway, minimize
systemic&local side
effects
17
- narrow margin of
safety
- nausea, vomiting,
“stimulatory” (tremor,
insomnia, restlessness)
- cardiac arrhythmia
- common & frequent
drug interaction
Prednisone:
- Metabolic effects
- osteoporosis
- fat redistribution
(moon face)
- obesity
- hyperglycemia
Budesonide
- oral thrush (candida)
- dysphonia (hoarse
voice)
- systemic effects can
still occur with long
term use, osteoporosis
Pulmonary Week 2:
Airways Disease
Leukotriene
antagonists
Leukotriene receptor
allow oral dosing
not as efficacious
antagonist: Montelukast
LT2 (leukotriene)
- montelukast
receptor :
- mediates airway smooth
muscle proliferation 
asthma
Monoclonal Ab
Omalizumab
- subcutaneous injection - immune reaction
- omalizumab
- prevents interaction of every few weeks
- high cost
allergen with IgE
Combination Therapy: Bronchodilator “opens up” - oral, injection,
Chronic use of β2
- corticosteroid
airways, facilitating
inhalation (local effect) agonists may lead to
(inhaled) + long-acting inhaled corticosteroid
- size of particle
receptor
beta agonist:
deposition (which
matters: increase size, downregulation
- Advair: fluticasone + increased β2 receptor)
decrease ability to reach
salmeterol
target
- Symbicort: budesonide
- Nebulizer: vaporized
+ formoterol
liquid, mask inhaled
- Pressurized metered
dose inhaler:
aerosolized particles,
needs coordination drug
ends up at back of throat
- Dry powder inhaler:
not obvious that the
dose has delivered
Targets: bronchoconstriction, airway inflammation, mucous plugs, remodeling
28. COPD, asthma, bronchiectasis, bronchiolitis obliterans:
definition, etiology, pathology, pathogenesis (risk factors), natural history
29. Compare and contrast asthma and COPD in adults
30. Clinical presentation, pulmonary function test, radiological finding
Asthma
Definition
- Reversible airflow
obstruction
- bronchial hyperresponsiveness
- chronic airway
inflammation
- airway remodeling
COPD
Chronic Bronchitis
emphysema
- largely caused by
smoking, progressive,
partially reversible
airway obstruction &
lung hyperinflation
- Chronic Bronchitis:
cough productive of
18
Bronchiectasis
- Permanent dilation
of bronchi with inflam
changes in their walls
and lung parenchyma
- chronic airflow
limitation
Bronchiolitis
obliterans
- bronchiolitis
obliterans: not COPD,
occlusion of airway
lumen by polyps rich in
ECM
- small airway
(<2mm) disease (a
Pulmonary Week 2:
Airways Disease
- airway, spare
parenchyma
sputum
form of COPD)
- emphysema:
permanent
enlargement of alveoli
with wall destruction
Etiology
- 1-15% of pop.
- smoking (pulmonary - infection
- toxic inhalation
- hygiene hypothesis
inflammation) only 15- - bronchial obstruction - connective tissue
(CD4+ T cell-medicated 20% heavy smoker
- immune deficiency
disease
Th1/Th2 cytokine
develop COPD
- CF
- chronic rejection
balance shift to Th2
- occupation
-Non-obstructive
(allergic-type) response - α1-antitrypsin
(infection or
- familial extrinsic/
deficiency
congenital): CF,
allergic asthma onset - chronic infection by Kartageners’s (ciliary
before age 30: allergy, virus or atypical
dysfunction), immune
increased IgE, + skin
bacteria
deficiency, necrotizing
test
pneumonia (TB, staph)
- non-allergic/ intrinsic
- obstructive: foreign
asthma onset middle
body, neoplasm, mucus
age: environmental
irritants (smoke,
exercise, T)
- viral exacerbation
pathology
- Fragile epithelium
- squamous metaplasia - transmural
-Cellular infiltrate
- thickened basement - parenchymal
inflammation
- smooth muscle
membrane
damage
- permanent dilatation hyperplasia
- goblet cell hyperplasia - glandular enlargement - neo-vascularization - bronchiolectasis
- smooth muscle
- goblet cell
- mucopurulent
- fibrosis
hypertrophy
hyperplasia
material
- obliterative scarring
- mucus cast
- lymphoid follicle
- airway smooth muscle
- eosinophil, mast cell
hypertrophy
Pathogenesis - acute narrowing of
- imbalance of
- Recurrent
- chronic fibrosis/
airway  cough,
proteolytic and antiinflammation of
inflammation
dyspnea, wheezing
proteolytics
bronchial walls &
(neutrophil,
- reverse spontaneously - neutrophils (release fibrosis of surrounding macrophage)
with anti-inflam/
elastase) & macrophage parenchyma
bronchodilator
damage lung
- weakened walls 
- inflam cytokine
parenchyma during
irreversible dilation
secreted by Th2 
inflammation
airway smooth muscle - α1-antitrypsin (AAT)
contraction, airway wall synthesized in liver,
edema, increased
bind irreversibly to
mucus production,
proteolytic enzyme and
19
Pulmonary Week 2:
Airways Disease
recruitment of inflam inactivate them
cell to airway
- Emphysema
- stimulation of
classification:
parasympathetics
centriacinar (smoking,
- damaged airway epi  upper lobes), panacinar
decrease production of (AAT deficiency, lower
bronchial relaxing
lobes), paraseptal
factors
(distal acinar, tall thin
young adults, bullae
rupture  spontaneous
pneumothorax),
paracicatricial
(irregular, most
common)
Natural
Cough, wheeze, dyspnea -progressive dyspnea - progressive dyspnea
history
- Paroxysmal
- chronic bronchitis
- daily mucopurulent
- provoked
- increasing frequency sputum
- worse at night
of exacerbation
- infective exacerbation
- weight loss
- recurrent pleurisy
- hemoptysis
Clinical
- wheeze
- hyperinflation
- often related to
Presentation - hyperinflation during - wheezes
infection: productive
attacks
- R heart failure
cough, fever,
- allergy
- weight loss
hemoptysis (erosion
- hyper-resonance
- CB (chronic
through weakened
- use accessory muscle bronchitis): daily cough bronchial walls into
- sputum production
productive of sputum vessels)
- tachypnea
for several months over - clubbing
- tachycardia
min 2 consecutive yrs - localized coarse
- acute distress/
crackles
confusion
- wheezes
Pulmonary - reversible airflow
- partially reversible
- Airflow obstruction
Function
obstruction
airflow obstruction
- restrictive
Test
- hyperresponsive
- reduced diffusing
- normal or reduced
- normal DLCO
capacity
DLCO
- increase TLC, FRC, RV - decrease elastic recoil
- decrease VC
 decreased FEV1,
- decrease FEV1,
FEV1:FVC ratio, increase
FEV1:FVC ratio
TLC, FRC, RV
- decrease flow rate
Radiological - Normal CXR
- hyperinflation
- dilated bronchi
Finding
- bronchial thickening - emphysema bullae
- fluid filled bronchi
20
- progressive dyspnea
- unproductive cough
- symptoms develop
rapidly over months
- wheezes
- inspiratory squeaks
- hyperinflation
- fine crackles
- irreversible airflow
obstruction
- reduced DLCO
- gas trapping
- mosaic perfusion
Pulmonary Week 2:
Airways Disease
- mucoid impaction
Treatment
- incidental carcinoma - regional volume loss
- corticosteroid (main - bronchodilator
- bronchial hygiene
Tx, takes time)
- inhaled corticosteroid - Antibiotics
- β2 agonist
- Anti-inflammatories
- methylxanthine
- anticholinergic/
sympathomimetics
- leukotriene antagonist
- mAb
- centrilobular nodules
- bronchiectasis
- bronchodilator
- erythromycin
- corticosteroids
31. Describe and explain how it is possible that the distinct clinical and pathological features
of these conditions may overlap, and share features in common, particularly chronic airflow
obstruction and chronic inflammation.
These 4 clinical conditions overlap in terms of airflow obstruction and inflammation.
INFLAMMATION
 COPD includes a chronic inflammation of the lung parenchyma, and can present as
emphysema or obstructive bronchitis or bronchioitis
 Asthma is inflammation of the airways as well, leading to remodeling
 B ronchiectasis is chronic inflammation and/or infection resulting in permanent dilation
and destruction of the bronchi
 Bronchiolitis, as described by its name, is the recurrent inflammation of the respiratory and
membranous bronchioles
OBSTRUCTION
 COPD presents with progressive and/or partially reversible airflow limitation, presenting as
persistent dyspnea and exercise limitation
 Asthma presents as variable airflow limitation but with bronchodilator reversibility, with
exacerbations triggered by the environment
 Bronchiectasis can present as either obstructive or restrictive airflow limitation, along with
cough, sputum and/or hemoptysis
 Bronchiolitis, which can present together with bronchiectasis, involves irreversible airflow
obstruction and presents similar to COPD
32. Compare and contrast the rationale for the differing approaches to treating asthma and
COPD.
COPD
 Involves a number of non-pharmacological and pharmacological approaches
o Because it is well-known that there are many different triggers for COPD exacerbations.
 Vaccination (for both influenza and pneumococcal) for COPD  infections may play role in
causing exacerbations
 Pharmacological treatment is also common in COPD to reduce the frequency of
exacerbations.
ASTHMA:
 Goal of asthma management is to maintain control symptoms using the lowest dose of
medication
 Need to identify and eliminate environmental triggers for asthma
 Come up with an action plan to dictate how the patient should deal with exacerbations
21
Pulmonary Week 2:
Airways Disease
33. Explain why both pharmacological and non-pharmacological treatments are important
in the management of patients with obstructive lung disease.



Often, pharmacological treatments are not sufficient in the management of patients with
obstructive lung disease  because there are a lot of environmental factors can exacerbate
COPD
Therefore non-pharmacological treatments such as smoking cessation and vaccinations are
important in the management of patients with obstructive lung disease
Pharmacological treatments are also important as well primarily for the symptomatic
treatment of COPD, and are also useful in the management of exarcerbations.
34. Compare and contrast the pathophysiology and response to therapy for persons with
asthma and COPD.
COPD
 Pharmacological treatment in COPD: short acting bronchodilators or long acting
bronchodilators
o β 2-agonists and anticholinergics
o Evidence : combination of β2-agonists together with anti-cholinergics are more effective.
o Inhaled corticosteroids can be used by COPD patients to reduce the frequency of
exacerbations, but oral corticosteroids and antibiotics are primarily used only in the
case of exacerbations
o Oxygen is also used only when COPD patients become hypoxemic
ASTHMA:
 Primarily: inhaled corticosteroids as an anti-inflammatory + fast acting bronchodilator
(short acting β2-agonist) for the acute relief of symptoms
 Evidence for combined inhaled corticosteroids + long acting β2-agonists for long-term
treatment
35. Describe the indications, contraindications, benefits and side-effects of influenza and
pneumococcal vaccine in COPD



Influenza vaccines should be given annually to COPD patients
o Reduce exacerbations
o No evidence for reduced mortality or hospitalizations.
Pneumococcal vaccinations should be given every 5 to 10 years  no RCT evidence of
benefit
Contraindications: hypersensitivity to any component, acute febrile or neurological illness
36. Differentiate the gross and microscopic findings in COPD, asthma, bronchiolitis and
bronchiectasis.



COPD – chronic inflammation of airways and lung parenchyma, leading to progressive
airflow limitation and loss of elastic recoil, and hyperinflation during exertion
o Microscopically: squamous metaplasia, parenchymal damage, glandular
enlargement, goblet cell hyperplasia, lymphoid follicles
ASTHMA – inflammation in airways leading remodeling, variable airflow limitation and
hyperresponsiveness
o Microscopically: fragile epithelium, thickened basement membrane, goblet cell
hyperplasia, smooth muscle hypertrophy
BRONCHIOLITIS– inflammation to small airways (respiratory and membranous bronchioles)
resulting in irreversible airflow obstruction and reduced diffusing capacity
22
Pulmonary Week 2:
Airways Disease
Microscopically: cellular infiltrates, smooth muscle hyperplasia, bronchiolectasis,
fibrosis, obliterative scarring
BRONCHIECTASIS – permanent abnormal dilation and destruction of bronchi and
bronchioles due to chronic inflammation and recurrent infection, can be obstructive or
restrictive
o Microscopically: transmural inflammation, permanent dilation, neovascularization
o

37. Correlate the pathological findings with the physiological findings in patients with
chronic airflow obstruction.
Chronic airflow obstruction
Pathological
Hyperplasia and hypertrophy of both
goblet cells and bronchial mucus gland
Airway smooth muscle contraction, luminal
occlusion, thickening wall, decreased lung
elasticity, obliteration
Inflammatory cells recruited to airway 
inflammation
Loss of elastic recoil  hyperinflation
Hyperinflation  flattened diaphragm
Damaged airway epithelium
Bullae (air sacs with thin wall)
Physiological
Increased mucus production, sputum, cough
Increased resistance in airways  dyspnea
Narrowed airway  wheezing; ventilation-perfusion
abnormalities  hypoxemia  dyspnea
↑ residual volume; ↑ functional residual capacity; ↑
total lung capacity; ↓ vital capacity
↓ inspiratory capacity  dyspnea
↓ bronchial relaxing factors; ↓ neutral endopeptidase
(inactivates inflammatory mediators)
Obstruct function of host lung; put pressure on other
lung and interfere with its proper function; reduce
efficiency of surrounding tissues
38. Discuss the rationale for the use of oxygen therapy in patients with chronic hypoxia,
including mechanisms of delivery and the outcomes of therapy. (Case)
Long term O2 therapy can:
 Prevent tissue hypoxia
 Reverse secondary polycythemia
 Improve body weight
 Ameliorate cor pulmonale
 Enhance neuropsychiatric function, exercise tolerance and activities of daily living
 Stabilize pulmonary hemodynamics  survival benefit
* Supplemental oxygen does not greatly improve shortness of breath
 O2 most frequently delivered through a nasal cannula or oxygen mask at rates of 2-5 L/min.
 Transtracheal administration (requires humidifier) provides O2 sparing benefits
(scrupulous attention to catheter maintenance and hygiene – not suitable for all patients)
23
Pulmonary Week 2:
Airways Disease
39. Describe the modalities available for chest imaging, and the advantages and
disadvantages of each
(All answers from radiology lectures and powerpoints)
Chest X-Ray
Pros
o fast/available, cost-effective, good for confirmation of line placement, post surgical
imaging, low radiation, bone detail
Cons
o only 2D, not as good resolution as other techniques (e.g., CT)
Fluoroscopy
Pros
o real time, bone detail, inexpensive, available
Cons
o often require contrast media (has risks), poor tissue contrast, many layers are
superimposed, continuous low-dose radiation (radiation exposure)
Angiography/Catheterization
Pros
o good for arteries, easy to access blood for O2 saturation, intracardiac pressures,
cardiac/valcular abnormalities
Cons
o invasive, <1% risk of MI, dysrhythmia, CHF, renal failure, pseudoaneurysm from groin
puncture
Computed Tomography
Pros
o high resolution, fast, non-invasive, excellent for detecting Ca2+, 3D images, excellent
for bone and lung parenchyma
Cons
o high radiation exposure
Magnetic Resonance Imaging
Pros
o soft-tissue contrast (e.g., b/w vessels and cardiac chambers), great for cardiac motion
studies, not invasive, no radiation
Cons
o availability/cost, procedure time/claustrophobia, bone detail, weight<450lb (200kg),
no metal (e.g., pacemaker), rare serious contrast reactions
Ultrasound
Pros
o low cost, availability, portability, real-time imaging (e.g., useful for guiding a needle),
sensitivity to flow, lack of ionizing radiation
Cons
o confined to processes in contact with chest wall (e.g., pleural effusions & superficial
soft tissue lesions), not good for deep structures, obstructed by air in lungs, bone, high
calcified materials
Nuclear Medicine
Pros
o PHYSIOLOGICAL imaging (vs anatomical), good for ventilation-perfusion scanning
(e.g., in pulmonary embolism), simpler than echocardiography, non-invasive, used for
“myocardial perfusion scintigraphy (MIBI) to see coronary artery disease, risk post
MI, angina, and preoperatively, used for “radionuclide angiocardiography”which
labels RBCs with technetium-99m to image the blood pool (to calc ejection fraction,
wall motion analysis)
Cons
o radiation
24