Pathophysiology of the
respiratory system I
Structural properties of airways and lungs
Respiration and gas exchange
- ventilation & diffusion & perfusion
Pulmonary mechanics
Ventilation – perfusion (in)equality
The delicate structure-function coupling
of lungs
• The main role of the respiratory system
is to extract oxygen from the external
environment and dispose of waste
gases, principally carbon dioxide
– at the end of deep breath 80% of lung
volume is air, 10% blood and 10% tissue
• lung tissue spreads over an enormous area !
• The lungs have to provide
– a large surface area accessible to the
environment (tennis court area) for gas
exchange
– alveoli walls have to present minimal
resistance to gas diffusion
• Close contact with the external
environment means lungs can be
damaged by dusts, gases and infective
agents
– host defense is therefore a key priority for
the lung and is achieved by a combination
of structural and immunological means
3
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 first seven 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
4
Wall structure of conducting conducting
airways and alveolar region
5
Alveoli
• There are 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 6
Alveolo - capillary barrier
• Alveolar epithelia
– type I and II cells
• Capillary
endothelium
– non-fenestrated
• Intersticium
– cells (very few!)
• fibroblasts
• contractile cells
• immune cells
(intersticial
macrophages,
mast cells, …)
– ECM
• elastin and
collagen fibrils
7
Pulmonary vasculature and lymphatics
8
• Lungs are the only organ through which all the blood (CO) has to pass!!!
• Lungs have a dual blood supply
– deoxygenated blood from the right ventricle via the pulmonary artery
– systemic (nutritional) supply throughout the bronchial circulation
• arises from the descending aorta
• bronchial arteries supply tissues
down to the level of the
respiratory bronchiole
• bronchial veins drain into the
pulmonary vein, forming part of
the physiological shunt observed
in normal individuals
• Drainage is provided by the four
main pulmonary veins (into the
left atrium)
• Lymphatics start in the interstitial
space between the alveolar cells
and the capillary endothelium of
the pulmonary arterioles
– the tracheobronchial lymph nodes are
arranged in five main groups:
• paratracheal, superior
tracheobronchial,
subcarinal, bronchopulmonary and
pulmonary
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
9
(1) VENTILATION & PULMONARY
MECHANICS
10
11
set by opposing recoil forces of the chest and lungs and the effort of respiratory muscles
Mechanika dýchání
• tlaky a tlakové gradienty
– tlak na povrchu těla (Pbs), většinou
totožný s atmosferickým (Pao)
– tlak v alveolu (Palv)
– „elastický“ tlak vyvíjený
parenchymem plic a povrchovým
napětím (Pel)
– tlak v pleurální dutině (Ppl)
– transpulmonální tlak = tlakový
rozdíl mezi alveolem a pleurální
dutinou (PL)
• PL = Palv - Ppl
– transtorakální tlak = rozdíl mezi
alveoly a tělesným povrchem (Prs),
určuje zda probíhá inspirium nebo
expirium
• Prs = Palv - Pbs
12
Ventilation
• pressure necessary to
distend lungs has to
overcome two kinds of
resistances
– DYNAMIC = airway resistance
(in the convection part of
airways)
– STATIC = elastic recoil (in the
respiratory part of airways
and lung parenchyma)
• energy requirements for
respiratory muscles to
overcome these two
resistances is normally quite
low (2-5% of a total O2
consumption)
• but increases dramatically
when resistance increases
(up to 30%)  subjective
perception as a dyspnea
13
Ventilation (breathing) as a mechanical process
14
• Inspiration
– an active process that results from the descent of
the diaphragm and movement of the ribs upwards
and outwards under the influence of the
intercostal muscles
• in resting healthy individuals, contraction of the
diaphragm is responsible for most inspiration
– respiratory muscles are similar to other skeletal
muscles but are less prone to fatigue
• weakness may play a part in respiratory failure
resulting from neurological and muscle disorders and
possibly with severe chronic airflow limitation
– inspiration against increased resistance may require
the use of the accessory muscles of ventilation
• sternocleidomastoid and scalene muscles
• Expiration
– follows passively as a result of gradual lessening of
contraction of the intercostal muscles, allowing the
lungs to collapse under the influence of their own
elastic forces (elastic recoil)
– forced expiration is also accomplished with the aid
of accessory muscles
• abdominal wall
Airflow
• Movement of air through the airways results
from a difference between the pressure in the
alveoli and the atmospheric pressure
– alveolar pressure (PALV) is equal to the elastic recoil
pressure (PEL) of the lung plus the pleural pressure
(PPL)
– positive PALV occurs in expiration and a negative
pressure occurs in inspiration
• During quiet breathing the sub-atmospheric
pleural pressure throughout the breathing cycle
slightly distends the airways
– during vigorous expiratory efforts (e.g. cough) the
central airways are compressed by positive pleural
pressures exceeding 10 kPa
– the airways do not close completely because the
driving pressure for expiratory flow (alveolar
pressure) is also increased
• When there is no airflow (i.e. during a pause in
breathing) the tendency of the lungs to collapse
(the positive PEL) is exactly balanced by an
equivalent negative PPL
15
The relationship between
maximal flow rates on
expiration and inspiration is
demonstrated by the maximal
flow-volume (MFV) loops
Elastic properties of the lung
16
• lungs have an inherent elastic property
that causes them to tend to collapse
generating a negative pressure within
the pleural space
– the strength of this retractive force relates
to the volume of the lung; for example, at
higher lung volumes the lung is stretched
more, and a greater negative intrapleural
pressure is generated
– at the end of a quiet
expiration, the retractive
force exerted by the lungs
is balanced by the
tendency of the thoracic
wall to spring outwards
• at this point, respiratory
muscles are resting and
the volume of the lung is
known as the functional
residual capacity (FRC)
the system of airway
elastic fibres
Anatomical – functional considerations explain
alveolar stability (due to alveolar interdependence
and collateral ventilation)
17
18
Elastic recoil is determined by two kinds of forces
• lung compliance (“distensibility”) = connective tissue
– a measure of the relationship between this retractive
force and lung volume
– defined as the change in lung volume brought about by
unit change in transpulmonary (intrapleural) pressure
(L/kPa)
• surface tension produced 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
is fluid that can resist lung expansion
• there would be a lot of surface
tension because there is an air-water
interface in every alveolus
• if surface tension remained
constant, decreasing r during
expiration would increase P and
smaller alveolus would empty into large one (A)
– this collapsing tendency is offset by pulmonary surfactant
which significantly lowers surface tension (B)
19
Pulmonary surfactant
• Complex mixture of lipids
and proteins at the alveolar
cell surface (liquid – gas
interface) reducing surface
tension
– superficial layer made of
phospholipids (dipalmitoyl
lecithin)
– deeper layer (hypophase)
made of proteins (SP-A, -B, C,
-D)
• Surfactant maintains lung
volume at the end of
expiration
• Continually recycles
– influenced by many
hormones incl.
glucocorticoids
• lung maturation in pre-term
newborns
20
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 (LB) touching the interface, 2) unravelling of secreted LB 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 (so-called surface phase) connecting secreting cells with the
interface.
Perez-Gil J , Weaver T E Physiology 2010;25:132-141©2010 by American Physiological Society
Abnormalities of elastic properties
• change of lung compliance
–  in pulmonary emphysema, aging ( TLC, 
FRC,  RV)
–  in interstital 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. lung collapse
– lung edema (damages surfactant)
• diseases that affect the movement of the
thoracic cage and diaphragm
– marked obesity
– diseases of the thoracic spine
• ankylosing spondylitis and kyphoscoliosis
– neuropathies
• e.g. the Guillain-Barré syndrome)
– injury to the phrenic nerves
– myasthenia gravis
22
Forced expiration - dynamic compression
• 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 airway pressure will
equal the intrapleural pressure,
and airway compression will occur
– however, this compression of the
airway is temporary, as the
transient occlusion of the airway
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 compression'
23
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
25
Airflow pattern as a result of change in
airway diameter  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 cross-sectional
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 decreasing
from the medium size to small airways
• Airway tone is under the control of the autonomic
nervous system
– bronchomotor tone is maintained by vagal efferent nerves
– many adrenoceptors on the surface of bronchial muscles
respond to circulating catecholamines
• sympathetic nerves do not directly innervate them!
26
Airway resistance
• Ohm´s law:
– flow is inversely
proportional to
resistance
• Poiseuille’s law:
– determinants od resistance
• This means that the most
important variable here is the
radius
• Overcoming increased resistance
requires forced expiration
27
Airflow resistance - bronchoconstriction
• theoretical amplifying effect of
luminal mucus on airflow
resistance in asthma. (a)
According to Poiseuille’s law,
resistance to flow (R) is
proportional to the reciprocal of
the radius (r) raised to the fourth
power. (b) Without luminal
mucus, bronchoconstriction to
reduce the airway radius by half
increases airflow resistance 16fold.
(c) A small increase in mucus
thickness (tM), which reduces the
radius of the airway by only onetenth,
has a negligible effect on
airflow in the unconstricted
airway (compare with panel a). (d)
With bronchoconstriction, the
same amount of luminal mucus
markedly amplifies the airflow
resistance of this airway
28
Airflow obstruction
• In patients with severe
COPD, limitation of
expiratory flow occurs even
during tidal breathing at rest
• To increase ventilation these
patients have to breathe at
higher lung volumes and
also allow more time for
expiration by increasing flow
rates during inspiration,
where there is relatively less
flow limitation
• Thus patients with severe
airflow limitation have a
prolonged expiratory phase
to their respiration
29
VÝMĚNA PLYNŮ V PLICÍCH & POMĚR
VENTILACE-PERFÚZE
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Functional classification of airways
• Conducting airways (=
anatomical dead space)
• nose (mouth)
• larynx
• trachea
• main bronchi & bronchioles
– gas conduction, warming
• Acinar airways (= respiratory
space)
• respiratory bronchioles
• alv. ducts & sacs
• alveoli
– gas exchange
• Pulmonary acinus
– the functional 3-D unit – a part
of the parenchyma in which all
airways have alveoli attached to
their wall and thus participating
in gas exchange
31
Koncept acinu
• 3-D struktura následující po terminálním bronchiolu
– 3 úrovně větvení resp. bronchiolu a násl. cca 8 větvení alveolárních duktů,
– každý plicní lalůček (anatomický pojem) tak vyplňuje 10 - 30 acinů
– vzhledem k tomu, že kyslík (pouze) difunduje (neproudí) a tedy mění svůj
koncentrační gradient směrem k periferii acinu, je tento koncept důležitý
pro pochopení ventilačně – perfúzní nerovnováhy
Výměna plynů v plicích
• hlavní funkce dýchacího systému –
výměna plynů mezi okolím a krví – je
podřízena časově variabilním nárokům
organismu na O2
– udržovány v optimálním rozmezí zejm.
regulací intenzity ventilace
• nároky jsou určeny spotřebou ATP a jeho
nahrazováním mitochondriemi (ox.
fosforylací)
• alveolo-kapilární výměna plynů probíhá z
alv. prostoru do krve prostou difuzí přes
stěnu alveolu, plicní intersticium a stěnu
kapilár
• hnací silou dodávky O2 (a recipročně CO2)
je postupný pokles jeho parciálního tlaku,
tj. koncentrační gradient mezi
vdechovaným vzduchem, krví a tkáněmi:
– parciální tlak = tlak, který by plyn měl
pokud by byl ve směsi sám
Výměna plynů v plicích
34
• důvody poklesu PO2:
– difuze v acinárních cestách a
postupný pokles gradientu
– kompetice s CO2 v alveolu (do
výše atm. tlaku)
• alveolární rovnice plynů
– rozpustnost =  100% difuze
přes alveolo-kapilární
membránu
– fyziologický pravo-levý zkrat
• míchání okysličené a
neokysličené krve (aa.
bronchiales a vv. coronarie)
– fyziologicky malá část Hb jako
Met-Hb a COHb
– postupné spotřebovávání v
průběhu acinu
Kvantitativně
• (1) vdechovaný atmosférický vzduch
– 21% O2, 0.03% CO2, 78% N2, vodní páry 0.6% a zbytek tvoří
další plyny (argon, helium, ..)
• atmosferický tlak je 760 mmHg (101 kPa)
• parc. tlak O2 (PO2): 0.21 x 760 = 160 mmHg
• analogicky PCO2 = 0.3mmHg
• (2) alveolární vzduch (směs vdechovaného a
vydechovaného vzduchu)
– PAO2 = 100mmHg (13.3kPa), PACO2 = 40 mmHg (5.3kPa)
• parc. tlak O2 v alveolu je o něco nižší něž v atmosféře kvůli
většímu zastoupení CO2 v alveolu (vydechovaný vzduch)
• (3) arteriální krev
– PaO2 = 90mmHg (12kPa), PaCO2 = 45 mmHg
• difuze kyslíku není 100% a navíc existuje fyziologický zkrat
• (4) venózní krev
– PvO2 = 30 - 50mmHg
35
vzduch (P) alveolární (PA) arteriální (Pa) venózní (Pv)
O2 21kPa/150mmHg 13.3 kPa/100mmHg 12kPa/90mmHg 5.3kPa/40mmHg
CO2 0.03kPa/0.3mmHg 5.3kPa/40mmHg 5.3kPa/40mmHg 6.0kPa/45mmHg
Transport plynů krví
• krví je kyslík (97-98 ve vazbě na
Hb a 2-3 jako fyzikálně
rozpuštěný) dodáván do všech
částí těla, kde difunduje do tkání
– při fyziologickém PaO2
(90mmHg/12kPa) a fyziologickém
hemoglobinu je téměř 100%
saturace
• a do poklesu PaO2 na 12kPa
saturace významně neklesá
– saturace měřena pulzní oxymetrií
• rozhodující je množství v
mitochondriích
– pro dostatečnou produkci ATP je
nutné pO2 v tkáních > 0.13kPa
(1mmHg) = kritická tenze kyslíku
• organizmus potřebuje kyslík:
– cca 250ml/min  350l/den v klidu
– při zátěži mnohem více
Význam kyslíku v organizmu
• v těle neexistují větší zásoby kyslíku
• stačí cca na 5min
– dýchání a dodávka kyslíku tkáním je proto
nepřetržitý děj
– jeho úplné přerušení znamená
• ohrožení života (<5min)
– reverzibilní ztráta zraku za cca 7s, bezvědomí
za cca 10s
• klinickou smrt (~5-7min), event. smrt mozku
• smrt organizmu (>10min)
• 85-90% využito v aerobním metabolizmu
při výrobě ATP na
– udržení iontových gradientů
– svalová kontrakce
– syntézy
• pro zbytek procesů je pokles pO2 méně
kritický
– hydroxylace steroidů
– detoxikace (hydroxylace) cizorodých látek
v játrech
– syntéza oxidu dusnatého ( vazodilatace)
– degradace hemu hemoxygenázou
Sumárně: plíce jako součást „O2 dráhy“
Ventilace a perfúze plic
• vztah mezi ventilací a perfuzí plic je
variabilní
– do jisté míry i u zdravých lidí
• rozdíly mezi apexem a bazí plíce
– apex: ventilace alveolů s redukovanou
perfuzí (tzv. fyziologický mrtvý prostor,
VA/Q = 3.3)
– báze: perfuze alveolů s redukovanou
ventilací (fyziologický zkrat, VA/Q = 0.7)
• ventilačně perfuzní (VA/Q) nepoměr se
významně zvyšuje u některých plicních
nemocí a zodpovídá za jejich projevy
–  VA/Q poměru (tj.  mrtvého
prostoru)
• např. plicní embolie
–  VA/Q poměru (tj.  plicního zkratu)
• obstrukční nemoci plic
• kolaps plíce
• optimalizace  VA/Q - vazokonstrikční
reflex
– cévy okolo méně ventilované části plíce
se kontrahují
– ale!!! viz důsledky obstr. nemocí
39
Ventilation-perfusion inequality
40