Introduction to the respiratory system
pathophysiology
Structural and functionalpropertiesof airways and lungs
- defencemechanismsof airways and lungs
Respiration as a processensuringa gas exchange
- ventilation & diffusion & perfusion
Ventilation– pulmonary mechanics
- volumesand capacities
- static and dynamicairflow resistance
- dynamiccollapse
- obstruction vs. restriction
Diffusion – principlesand determinants
- alveolar-capillary membrane
- „oxygen cascade“
Lung circulation – principlesand determinants
Warming up questions
• (1) WHY do we breathe???
• (2) HOW do we breathe???
– principles of the quiet breathing
• (3) WHEN do we breathe???
– all the time/non-stop, the death = „until the last breath“
STRUCTURAL-FUNCTIONAL CONSIDERATIONS IMPORTANT
FOR PP OF RESPIRATION & PARTICULAR DISORDERS
Respiration and gas exchange in the lungs
• ventilation = mechanical process
– breathing in narrower meaning
• diffusion= chemical process
– through alveolo-cappilary barrier
• perfusion= circulatory process
– circulation of blood in lungs
4
deathfromlung disease is almost always due to an
inability to overcomethe altered mechanical
properties of the lung or chest wall,or both
The delicate structure-function coupling of lungs
• The main role of the respiratorysystem is GAS
EXCHANGE,i.e. extraction of oxygen from the
external environmentand disposal of wastegases,
principallycarbon dioxide
– at the end of deep breath 80% of lung volumeis air, 10%
blood and 10% tissue
• lung tissue spreads over an enormous area !
• The lungs have to provide
– a large surfacearea accessibleto the environment(tennis
courtarea) for gas exchange
– alveoli walls haveto presentminimalresistancetogas
diffusion
• Close contact with the external environment means
lungs can be damaged by dusts, gases and infective
agents
– host defenceis thereforea key priority for the lung and is
achieved by a combination of structural and immunological
means
Structure of airways
• There are about 23 (18-30) divisions(223 i.e. approx. 8
millions of sacs) between the trachea and the alveoli
– the firstseven divisions, the bronchi have:
• walls consisting of cartilage and smooth muscle
• epithelial lining with cilia and goblet cells
• submucosal mucus-secreting glands
• endocrine cells - Kulchitsky or APUD (amine precursor and uptake
decarboxylation) containing 5-hydroxytryptamine
– the next 16-18 divisions the bronchioles have:
• no cartilage
• muscular layer progressively becomes thinner
• a single layer of ciliated cells but very few goblet cells
• granulated Clara cells that produce a surfactant-like substance
Wall structure of conducting airways and respiratory region
Lung defense – multiple mechanisms (details later)
Mucocilliary escalator
Functional classification of airways
• Conducting airways (= anatomicaldead space) – g1-15
• nose (mouth)
• larynx
• trachea
• main bronchi& bronchioles
– gas conduction, humidification & warming, defense
• Acinar airways (=respiratoryspace) – g16-23
• respiratorybronchioles
• alveolarducts& sacs
• alveoli
– gas exchange
• The concept of acinus
– the functional3-D unit - part of parenchyma- in which all
airways havealveoli attached to their wall and thus
participating in gas exchange
Alveoli
• Thereare approximately 300-400 million
alveoli in each lung with the total surface
area is 40-80m2
• Cell types of the epithelial lining
– type I pneumocytes
• an extremely thin cytoplasm, and thus provide only
a thin barrier to gas exchange, derived from type II
pneumocytes
• connected to each other by tight junctions that
limit the fluid movements in and out of the alveoli
• easily damageable, but cannot divide!
– type II pneumocytes
• slightly more numerous than type I cells but cover
less of the epithelial lining
• the source of type I cells and surfactant
– macrophages
Alveolo - capillary barrier
• Alveolar epithelia
– type I
– type II
• Capillary endothelium
– non-fenestrated
• Interstitium
– cells (very few!)
• fibroblasts
• contractile cells
• immune cells (interstitial macrophages, mast
cells, …)
– ECM
• elastin and collagen fibrils
(1) PRINCIPLES OF VENTILATION AND ITS
ABNORMALITIES
Ventilation (breathing) as a mechanical process
• Inspiration
– an activeprocess that results from the descent of the
diaphragm and movement of the ribs upwards and outwards
under the influence ofthe external intercostal muscles
• in resting healthy individuals, contractionof the diaphragmis
responsible formost inspiration
– respiratorymuscles are similar to other skeletal muscles but are
less prone to fatigue
• weakness may play a part in respiratory failure resultingfrom
neurological andmuscle disorders andpossibly with severe chronic
airflow limitation
– inspirationagainst increased resistance mayrequire the use of
the accessory muscles of ventilation
• sternocleidomastoidandscalene muscles
• Expiration
– follows passively as a result of gradual lesseningofcontraction
of the intercostalmuscles,allowingthe lungs to collapse under
the influence oftheir own elasticforces (elastic recoil and
surface tension)
– forced expirationis also accomplished with the aid of accessory
muscles
• abdominal wall andinternal intercostal muscles
Muscles performing inspiration
Boyle-Mariotte law (for ideal gas)
Mechanics of ventilation – breathing cycle
• pressures and pressuregradients
– pressureon the body surface(Pbs),
• usuallyequalto atmospheric(Pao)
– alveolar pressure(Palv)
– „elastic“ pressure(Pel)
• generatedby lung parenchymaandsurface tension
– pressurein pleural cavity (Ppl)
– trans-pulmonarypressure(PL)
• pressure difference between alveolusandpleuralcavity
• PL = Palv - Ppl
– trans-thoracicpressure(Prs)
• pressure difference between alveolusandbody surface
• determinesactualphase of ventilation, i.e.inspiriumor
expirium
• Prs = Palv - Pbs
Mechanical properties of the chest wall vs. lungs
= opposing elastic recoil
lung has a tendencyto shrink
(surfacetension + lung elasticity)
chesthas a tendencyto expand
(anatomyof thoraciccavity and
muscles)
resultingbalance
Pneumothorax = the absence of neg. i-pleural P
Is negative value of i-pleural P homogenous?
situation at the end of quiet expirium
gravitation and lung own weight decrease
negativity at the bases (and vice versa on apexes)
Lung volumes and capacities (tj. ≥ 2 volumes)
• The ratio of RV to
TLC (RV/TLCratio) in
normal individualsis
usually less than
0.25
• abnormal =
increasedRV/TLC
ratio in different
types of pulmonary
disease
– obstructivediseases
•  RV
– restrictivediseases
•  TLC
Spirometry
• absolutely most common pulmonary functiontest (PFT)
• allows to classify ventilation disorders
– obstructive
– restrictive
– combined
• usefulfor provocationtests too
– COPD vs. asthma  bronchodilator (s-B2agonist)
– bronchial hyperreactivity (metacholine)
PEFR
The most important parameters
Spirometry limitation
• spirometry can measure almost all
volumes and capacities with
exception of RV
– RV, FRC and TLC
normally80%FVC
RV (normally
20%TLC)
TLC
Spirometry in diagnosis of main types of ventilation
disorders
cannot exhalenormally
cannot inhale normally
Ventilation
• pressurenecessary to distendlungs has
to overcome two kinds of resistances
– (1) STATIC = elastic recoil
• in the respiratorypart of airwaysand lung
parenchyma
– (2) DYNAMIC = airwayresistance
• in the convection partof airways
• energy requirementsfor respiratory
muscles to overcome these resistances
are normally quite low
– 2-5 % of a total O2 consumption
• but increases dramaticallywhen
resistanceincreases (up to 30%)
(ad 1) Elastic properties of the lung
27
• lungs have an inherentelastic
property that causes them to tend
to collapse generatinga negative
pressure within the pleural space
– the strengthof this retractiveforce
relates to the volume of the lung
• for example, at higherlung volumesthe
lung is stretched more,and a greater
negative intrapleural pressureis
generated
– at the end of a quiet expiration,the
retractiveforce exerted by the lungs is
balanced by the tendency of the
thoracic wall to spring outwards
• at this point, respiratory musclesare
restingand the volumeof the lung is
knownas the functionalresidualcapacity
(FRC)
the systemof airway
elastic fibres
The transmural pressure
across the respiratory
system at FRC is zero. At
TLC, both lung pressure
and chest wall pressure
are positive, and they
both require positive
transmural distending
pressure. The resting
volume of the chest wall
is the volume at which
the transmural pressure
for the chest wall is zero,
and it is approximately
60% of TLC. At volumes
greater than 60% of TLC,
the chest wall is
recoiling inward and
positive transmural
pressure is needed,
whereas at volumes
below 60% of TLC, the
chest wall tends to recoil
outward
Elastic recoil is determined by two kinds of forces
• lung compliance(“distensibility”)
– a measure of the relationship between this retractive
force and lung volume (pressure-volume relationship)
– defined as the change in lung volume brought about by
unit change in transpulmonary (intrapleural) pressure
(L/kPa)
• surfacetensionproduced by the layer of fluid that lines
the alveoli
– determined by the cohesive (binding together)
forces between molecules of the same type
• on the inner surface of the alveoli there is a fluid that can
resist lung expansion
• there would be a lot of surface tension because there is an airwater
interface in every alveolus
• if surface tension remained constant, decreasing r during
expiration would increase P and smaller alveolus would empty
into large one
– this collapsing tendency is offset by pulmonary
surfactant which significantlylowers surfacetension
Historical misconception
Pulmonary surfactant
• Complex mixture of lipids and proteins
at the alveolar cell surface (liquid – gas
interface) reducing surface tension
– superficiallayer made of phospholipids
(dipalmitoyl lecithin)
– deeper layer (hypophase)made of proteins
(SP-A, -B, -C, -D)
• Surfactantmaintains lung volume at the
end of expiration
• Continuallyand very rapidly recycles
– influenced by many hormonesincl.
glucocorticoids
• lung maturationin pre-term newborns
Pulmonary surfactant adsorption to the interface and surface film formation. Processes that may contribute to transport of surface
active surfactant species to the interface include 1) direct cooperative transfer of surfactant from secreted lamellar body-like
particles touching the interface, 2) unravelling of secreted lamellar bodies to form intermediate structures such as tubular myelin
(TM) or large surfactant layers that have the potential to move and transfer large amounts of material to the interface, and 3) rapid
movement of surface active species through a continuous network of surfactant membranes, a so-called surface phase, connecting
secreting cells with the interface.
Perez-GilJ , Weaver T E Physiology 2010;25:132-141
©2010 by American Physiological Society
Newborn respiratory distress syndrome (nRDS)
• hyaline membrane syndrome
• surfactant substitution
– porcine or modified bovine
• sterilized
– synthetic
– next generation
• recombinant SPproteins
• indication: nRDS
– less convincing evidence for ARDS, aspiration, pneumonia, …
Abnormalities of elastic properties
• changeof lung compliance(TLC,FRC, RV)
–  pulmonary emphysema, aging (TLC, FRC, RV)
–  interstitial disease (TLC, FRC, RV)
• e.g. pulmonary fibrosis or bronchopneumonia
• lack of surfactant(TLC,FRC, RV)
– infant or adult respiratory distress syndromes
(IRDS or ARDS, resp.), i.e. tendency of lung to
collapse
– alveolar lung edema (damages/dilutes surfactant)
• diseases that affectthe movementof the thoracic
cage and diaphragm
– marked obesity
– diseases of the thoracic spine
• ankylosing spondylitis and kyphoscoliosis
– neuropathies
• e.g. the Guillain-Barre syndrome)
– injury to the phrenic nerves (spine C3-C5)
– myasthenia gravis
(ad 2) Airway (dynamic) resistance
• Poiseuille’s law for pressure states that the
pressure is
– directly proportional to flow, tube length, and
viscosity
– and it is inversely proportional to tube radius
• Overcoming increased resistance requires forced
expiration
Airflow velocity and pattern
Airflow – where is the highest resistance?
Airflow resistance
• From the trachea to the periphery, the airways become smaller in size
(although greater in number)
– the cross-sectional area available for airflow increases as the total number of
airways increases
– the flow of air is greatest in the trachea and slows progressively towards the
periphery (as the velocity of airflow depends on the ratio of flow to crosssectional
area)
• in the terminal airways,gas flow occurs solely by diffusion
• The resistance to airflow is very low (0.1-0.2 kPa/L in a normal
tracheobronchial tree), steadily increasing from the small to the large
airways
• Airway tone is under the control of the autonomic nervous system
– bronchomotor tone is maintained by vagal efferentnerves
– many adrenoceptors on the surface of bronchial muscles respond to circulating
catecholamines
• sympathetic nerves do not directly innervate them!
• Airway resistance is also relatedto
lung volumes
– because airways are ‘tethered’ by alveoli
(i.e. pulled open by radial traction)
– visible on bronchoscopy
– patients with obstruction benefit from
breathing in high lung volumes
Airway-Parenchymal Interdependence
Airflow resistance – effect of changed airway diameter
• theoreticalamplifying effectof luminal
mucuson airflowresistancein asthma
– (a) Accordingto Poiseuille’slaw,resistanceto
flow (R) is proportionaltothe reciprocalof the
radius(r) raised to the fourth power.
– (b) Withoutluminalmucus,
bronchoconstriction toreducethe airway
radiusby half increasesairflow resistance16-
fold.
– (c) A small increasein mucusthickness(tM),
which reduces the radiusof the airwayby only
one-tenth,hasa negligibleeffect on airflow in
the unconstricted airway (comparewithpanel
a).
– (d) With bronchoconstriction,the same
amountof luminalmucusmarkedly amplifies
the airflowresistanceof this airway
The difference between quiet and forced expiration
for the most part of expiration,the flow rateis
effort-independent
Flow-volume loop: peak inspiratory and initial expiratory flow rates are dependent
on effort, whereas expiratory flow rates later in expiration are independent of effort
• In forced expiration, the driving pressure raises both the
PALV and the PPL
– between the alveolus and the mouth, a point will occur (C) where
the airwaypressure will equal the intrapleural pressure, and
airway compression will occur
• equal pressure point
– however, this equal pressure point and event. compression of the
airway is not fixed during the entire expiration (as the lung volume
decreases)
– initially, it does not existsince in the absence of lung disease, the
equal pressure point occurs in airways that contain cartilage, and
thus they resist collapse
– later, the equal pressure point moves closer to the alveoli causing
transient occlusion of the airway
• this, however, results in an increase in pressure behind it (i.e. upstream)
and this raises the intra-airway pressure so that the airways open and
flow is restored
– the airways thus tend to vibrate at this point of 'dynamic airway
compression'
Why is expiratory flow limited?
Mechanism of dynamic compression in forced expiration
Pressures,incm H2O, are shown at differentpointsinthe breathing cycle,atmospheric pressure is zero,and valuesforalveolarand
intrapleural pressure are giveninthe appropriate spaces. The yellow arrows show the directionand magnitude of the transmural
pressure across the lungs. By convention, transmural pressure is calculated as alveolar pressure minus intrapleural pressure. If
transmural pressure is positive, it is an expanding pressure on the lung and the yellow arrow points outward.
During inspiration,the diaphragmcontracts,
causingthe volume of the thorax to increase. As
lung volume increases,the pressure in the lungs
must decrease. (Boyle’s law)Halfway through
inspiration(B), alveolarpressure falls below
atmospheric pressure (−1 cmH2O). The
pressure gradient betweenthe atmosphere and
the alveoli drives airflow into the lung. Air flows
into the lungs until, at the end of inspiration (C),
alveolarpressure is once againequal to
atmospheric pressure; the pressure gradient
betweenthe atmosphere andthe alveoli has
dissipated, andairflow into the lungs ceases.
During inspiration,intrapleural pressure
becomes evenmore negative thanat rest.
There are two explanations forthis effect: (1)As
lung volume increases,the elastic recoil of the
lungs also increases andpulls more forcefully
against the intrapleural space,and (2) airway
and alveolar pressures become negative.
Together, these two effects cause the
intrapleural pressure to become more negative,
orapproximately −8 cmH2O at the end of
inspiration. The extent to which intrapleural
pressure changes during inspirationcanbe used
to estimate the dynamic compliance of the
lungs.
Normally,expiration is a
passive process. Alveolar
pressure becomes
positive (higher than
atmospheric pressure)because
the elastic forces ofthe lungs
compress the greatervolume
of air in the alveoli. When
alveolar pressure increases
above atmospheric pressure
(D), air flows out of the lungs
and the volume in the lungs
returns to FRC. The volume
expiredis the tidal volume. At
the end of expiration (A),all
volumes and pressures return
to their values at rest and the
systemis ready to begin the
next breathing cycle.
EPP and dynamic compression/collapse of airways
EPP and dynamic
compression/collapse of
airways
Dynamic compression in various situations
• The respiratory system is represented as
a piston with a single alveolus and the
collapsible part of the airways within the
piston
• C, compression point; PALV, alveolar pressure; PEL,
elastic recoil pressure; PPL, pleural pressure.
– (a) at rest at functional residual capacity
– (b) forced expiration in normal subjects
– (c) forced expiration in a patient with COPD
Eupnoea vs. abnormal breathing pattern
• eupnoea
– f  VT = 12-18/min  500 mL
• pathology according to fervency,
volume and preferred position of
the subjects
– tachypnea  hypopnea
– orthopnea  platypnea  trepopnea,
– dyspnea
– apnea
Both types of airway resistance influence work of breathing
• the pressurenecessary for lunginflation (generated by
respiratory muscles)has to overcome two typesof resistances
• energy needed for respiratory musclesto deal with resistances
is normally very low
– 2 – 5% of a totalO2 consumption
– but the energy demanddramaticallyincreaseswith the rise of any
kind of ressistance(up to 30%)
• componentsof work of breathing
– non-elasticwork
• viscosity= 7 %
• airwayresistance = 28 %
– increases innarrowingof the airway lumenmay be due to:
» a) mucus,cells orother material withinthe lumen
» b) thickening of the airway wall that encroaches onthe lumen(hypertrophy)
» c) shorteningof smoothmuscle aroundthe lumen (bronchoconstriction)
» d) collapse of the airway wall into the lumen(emphysema)
– elasticwork = 65 %
• work of breathingcorrelateswith dyspnea
– it is a subjective symptom of many respiratorydiseases/conditions
– it is describedas a feeling of a lack of air or heavychest or difficult
breathing
Work of breathing
Thanks for your attention!
Quantitatively
• (1) inhaled atmospheric air
– 21% O2, 0.03%CO2, 78% N2, watergases 0.6% and the rest
other gases (argon, helium, ..)
• atm. pressure760 mmHg (101 kPa)
• PO2: 0.21 x760 = 160 mmHg
• analogically PCO2 = 0.3mmHg
• (2) alveolar air (mixture of inhaled and exhaled air)
– PAO2 = 100mmHg(13.3kPa),PACO2 = 40 mmHg (5.3kPa), Pwater
vapour = 47 mmHg
• PAO2 in alveolus slightly lower than atmospheric due to higher CO2
content in alveolus (diffusion fromblood)
• (3) arterial blood
– PaO2 = 90mmHg (12kPa),PaCO2 = 45 mmHg
• diffusion of oxygen not 100% and there is also physiologicalshunt
• (4) venous blood
– PvO2 = 30 - 50mmHg
air (P) alveolar(PA) arterial(Pa) venous (Pv)
O2 21kPa/150mmHg 13.3kPa/100mmHg 12kPa/90mmHg 5.3kPa/40mmHg
CO2 0.03kPa/0.3mmHg 5.3kPa/40mmHg 5.3kPa/40mmHg 6.0kPa/45mmHg
Hypoxia and its consequences
• HIF-1α regulation by proline hydroxylation
– (a) In normoxia, hypoxia-induciblefactor(HIF)-1αis
hydroxylatedby proline hydroxylases(PHD1,2 and
3) in the presence of O2, Fe2+, 2-oxoglutarate(2-OG)
and ascorbate.
• Hydroxylated HIF-1α (OH)is recognised by pVHL (the
productof the von Hippel-Lindau tumour suppressor
gene), which, together with a multisubunit ubiquitin
ligase complex, tags HIF-1α with polyubiquitin; this
allows recognition by the proteasomeand subsequent
degradation.
• Acetylation of HIF-1α (OAc) also promotes pVHL binding.
– (b) In response to hypoxia,proline hydroxylationis
inhibited and VHL is no longer able to bind and
targetHIF-1αfor proteasomaldegradation,which
leads to HIF-1α accumulationand translocationto
the nucleus.
• There, HIF-1α dimerises with HIF-1β, binds to hypoxiaresponseelements
(HREs) within the promoters of target
genes and recruits transcriptionalco-activators such as
p300/CBP for full transcriptionalactivity.
• A rangeof cell functions areregulated by the target
genes, as indicated.
– Abbreviation: CBP, CREBbinding protein; Ub,
ubiquitin.
Summary
• The physiological structure of the lungs
and airways ensures that
– the work consumed for mechanical breathing is
minimal
– the airways and the lungs are able to effectively
defend themselves against inhaled pathogens
and particles
– the area available to a gas exchange is huge,
and the diffusion barrier minimal
– in order to get enough O2 into peripheral
tissues, the exchange of gases in the lungs has
to be as effective as possible
– maintaining the concentration gradients
necessary to keep the passive diffusion going is
the principal driving force of ventilation
– pulmonary circulation is adapted to maximize
gas diffusion through the alveolar-capillary
membrane