Pathophysiology of the respiratory system I
Structural properties of airways and lungs
Respiration and gas exchange
- ventilation & diffusion & perfusion
Pulmonary mechanics
Airflow resistance and dynamic collapse
Obstructive lung diseases(COPD and bronchial asthma)
Warming up questions
• (1) WHY do we breathe???
– gas exchange
• (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“
(1) 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
5
death from lung disease is almost always due to an
inability to overcome the altered mechanical
properties of the lung or chest wall, or both
The delicate structure-function coupling of lungs
• The main role of the respiratory system is GAS
EXCHANGE, i.e. extraction of oxygen from the
external environment and disposal 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
Wall structure of conducting airways and respiratory region
Lung defense – multiple mechanisms (details later)
Mucocilliary escalator
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
Functional classification of airways
• Conducting airways (= anatomical dead space) – g1-15
• nose (mouth)
• larynx
• trachea
• main bronchi & bronchioles
– gas conduction, humidification & warming, defense
• Acinar airways (= respiratory space) – g16-23
• respiratory bronchioles
• alveolar ducts & sacs
• alveoli
– gas exchange
• The concept of acinus
– the functional 3-D unit - part of parenchyma - in which all
airways have alveoli attached to their wall and thus
participating in gas exchange
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
Alveolo - capillary barrier
• Alveolar epithelia
– type I
– type II
• Capillary endothelium
– non-fenestrated
• Intersticium
– cells (very few!)
• fibroblasts
• contractile cells
• immune cells (intersticial macrophages,
mast cells, …)
– ECM
• elastin and collagen fibrils
(2) PRINCIPLES OF VENTILATION AND ITS
ABNORMALITIES
Ventilation (breathing) as a mechanical process
• 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 external 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 and
surface tension)
– forced expiration is also accomplished with the aid of accessory
muscles
• abdominal wall and internal intercostal muscles
Muscles performing ventilation
Boyle-Mariotte law (for ideal gas)
Mechanics of ventilation – breathing cycle
• pressures and pressure gradients
– pressure on the body surface(Pbs),
• usually equal to atmospheric (Pao)
– alveolar pressure (Palv)
– „elastic“ pressure (Pel)
• generated by lung parenchyma and surface tension
– pressure in pleural cavity (Ppl)
– trans-pulmonary pressure (PL)
• pressure difference between alveolus and pleural cavity
• PL = Palv - Ppl
– trans-thoracic pressure (Prs)
• pressure difference between alveolus and body surface
• determines actual phase of ventilation, i.e. inspirium or
expirium
• Prs = Palv - Pbs
Mechanical properties of the chest wall vs. lungs
= opposing elastic recoil
lung has a tendency to shrink
(surface tension + lung elasticity)
chest has a tendency to expand
(anatomy of thoracic cavity and
muscles)
resulting balance
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/TLC ratio) in
normal individuals is
usually less than
0.25
• abnormal =
increased RV/TLC
ratio in different
types of pulmonary
disease
– obstructive diseases
•  RV
– restrictive diseases
•  TLC
Spirometry
• absolutely most common pulmonary function test (PFT)
• allows to classify ventilation disorders
– obstructive
– restrictive
– combined
• useful for provocation tests 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
normally 80% FVC
RV (normally
20% TLC)
TLC
Spirometry in diagnosis of main types of ventilation
disorders
cannot exhale normally
cannot inhale normally
(3) DISTENTION OF LUNGS COSTS ENERGY – IN
ORDER TO OVERCOME RESISTANCE
Lung mechanics has to deal with two types of resistance
• the pressure necessary to distend lungs
has to overcome two kinds of resistance
– (1) STATIC = elastic recoil
• 60-70% of the work of breathing
• in the respiratory part of airways and lung
parenchyma
– (2) DYNAMIC = airway resistance
• 30% of the work of breathing
• in the convection part of airways
• energy requirements for respiratory
muscles to overcome these resistances
are normally quite low
– 2-5 % of a total O2 consumption
• but increases dramatically when
resistance increases (up to 30%)
• Relationship between transpulmonary pressure (PL) and the pleural (Ppl),
alveolar (PA), and elastic recoil (Pel) pressures of the lung
• Alveolar pressure is the sum of pleural pressure and elastic recoil pressure
• Transpulmonary pressure is the difference between pleural pressure and alveolar
pressure
(ad 1) Elastic properties of the lung
(determining pressure – volume behavior of the lungs)
28
• 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)
– opening of the small airways is a result of the
radial traction generated by elastic fibres in the
parenchyma
the system of airway
elastic fibres
Situation in reaching FRV
• elastic recoil of lungs has a
tendency to reduce lung volume
(inwards), on the contrary, elastic
recoil of chest wall has a
tendency to expand the volume
(outwards) = FRC represents the
equilibrium and muscles are
relaxed
• thorax surgery or trauma causes
pneumothorax, lungs shrink to
volume when transpulmonary
pressure equals zero
– chest expands
– lung collapses, however, there is
still air in – approx. 10% TLC
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)
• 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 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 significantly lowers surface tension
Historical misconception
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 and very rapidly recycles
– influenced by many hormones incl.
glucocorticoids
• lung maturation in 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-Gil J , 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 SP proteins
• indication: nRDS
– less convincing evidence for ARDS, aspiration, pneumonia, …
Abnormalities of elastic properties
• change of 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 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-Barre syndrome)
– injury to the phrenic nerves (spine C3-C5)
– myasthenia gravis
(ad 2) Airway (dynamic) resistance
• Poiseuille’s law for pressure states that 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,
however, 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 efferent nerves
– many adrenoceptors on the surface of bronchial muscles respond to circulating
catecholamines
• sympathetic nerves do not directly innervate them!
• Airway resistance is also related to
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
• 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 16-
fold.
– (c) A small increase in mucus thickness (tM),
which reduces the radius of the airway by only
one-tenth, 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
Work of breathing – to overcome resistance
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
(4) DYNAMIC COMPRESSION OF THE AIRWAYS (DURING
FORCED EXPIRATION SUCH AS IN MANY PULMONARY DISEASES)
Airflow pattern
• 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
The relationship between maximal
flow rates on expiration and
inspiration is demonstrated by the
maximal flow-volume (MFV) loops
Flow-volume loop: peak inspiratory and expiratory flow rates are dependent on
effort, whereas expiratory flow rates later in expiration are independent of effort.
Why is expiratory flow limited?
• 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
• 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 exists in the absence of lung disease, since 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 (due to airway
obstruction or loss of radial traction in lung emphysema) 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/collapse'
Dynamic airway compression/collapse
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
(5) MOST COMMON OBSTRUCTIVE DISEASES
Various mechanisms of airway obstruction
• Narrowing of the airway lumen may be due to:
– a) mucus, cells or other material within the lumen
– b) thickening of the airway wall that encroaches on the lumen (hypertrophy)
– c) shortening of smooth muscle around the lumen (bronchoconstriction)
– d) collapse of the airway wall into the lumen (emphysema)
Ventilation disorders due to bronchial obstruction – basic
pathophysiological characteristics
• obstruction in airways massively increases their
resistance (dynamic resistance)
– Hagen-Poiseuille law
• since inspirium is an active process (muscles
and negative alv. and transthoracic pressure
overcome resistances) but expirium passive
one, obstruction leads to an impairment of
expiration
• participation of auxiliary respiratory muscles
leads to
– dynamic compression, air trapping and
hyperinflation of the lungs
• ↑ residual volume (FRC, RV, TLC)
– ↑ breathing effort and thus dyspnea
• ↓dynamic ventilatory parameters (spirometry)
– more time needed to exhale FVC (↓FEV1)
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
57
Ventilation disorders due to bronchial obstruction – basic
pathophysiological characteristics
shift towards inspiration reserve volume
with greater static resistances of airways
(increased breathing effort)
Chronic obstructive pulmonary disease (COPD)
• COPD is not solely pulmonary disease but
systemic syndrome
• definition of pulmonary component of
COPD:
– permanent bronchial obstruction, not fully
reversible, usually progressive, characterized by
an abnormal inflammatory response to
environmental harmful stimuli
– bronchial obstruction in COPD is caused by an
individually variable combination of:
• chronic bronchitis (with excessive resp. secretion)
• pulmonary emphysema (i.e. destruction of lung
parenchyma)
• obstructive bronchiolitis (with obstruction of
small airways)
• systemic component comprises:
– changes in pulmonary vasculature
– hypoxic hypoxia
COPD
• COPD is one of the most frequent chronic illnesses and one of the commonest causes of mortality
worldwide
– 4th place leading cause of death in countries with high prevalence of smoking
• after MI, tumors and stroke
• 85-90% of COPD patients are smokers
– Incidence is increased up to twentyfold in smokers compared to non-smokers
– even more so in workers exposed to air pollution
Chronic bronchitis ( 2mm) and bronchiolitis ( 2mm)
• symptomatic definition
– hypersecretion of mucus and chronic productive
cough that continues for at least 3 months of years for
at least 2 consecutive years
• however patients typically suffer from chronic
bronchitis without obstruction for a long time and
only then develop bronchial obstruction (i.e.
COPD)
– there are of course patients with COPD without clinical
signs of chronic bronchitis
– some chronic bronchitis cases never progress to COPD
• in manifest COPD presence of chronic bronchiolitis
is obligatory dominantly responsible (together with
pulmonary emphysema) for obstruction
– chronic persistent inflammation of small airways
( ≤ 2 mm)
– the ratio between chronic bronchiolitis and pulmonary
emphysema is entirely individual
Chronic bronchitis – pathological anatomy
• inhaled irritants not only increase mucus production but also
increase the size and number of mucous glands and goblet
cells in airway epithelium
– mucus produced is thicker and more tenacious than normal
– sticky mucus coating makes it much more likely that bacteria,
such as H. influenze and S. pneumoniae, will become embedded
in the airway secretions, there they reproduce rapidly
• cilia function is impaired, reducing mucus clearance further
– lung´s defense mechanisms are therefore compromised,
increasing susceptibility to pulmonary infection and injury
• bronchial wall becomes inflamed and thickened from edema
and accumulation of inflammatory cells
• initially chronic bronchitis affects only the larger bronchi, but
eventually all airways are involved
• thick mucus and hypertrophied bronchial smooth muscle
obstruct the airways and lead to closure, particularly during
expiration, when the airways are narrowed
– airways collapse early in expiration, trapping gas in the distal
portions of the lung.
– obstruction eventually leads to ventilation-perfusion mismatch,
hypoventilation (increased PaCO2) and hypoxemia
Lung emphysema
• abnormal permanent enlargement of gas-exchange
airways = acini (i.e distally from terminal
bronchioles) accompanied by destruction of
alveolar walls and without obvious fibrosis
– obstruction results from changes in lung tissues, rather
than mucus production and inflammation, as in chronic
bronchitis
• functional consequence:
– major mechanism of airflow limitation is loss of elastic
recoil leading to the collapse of small airways during
expiration
– expiration becomes difficult because loss of elastic recoil
reduces the volume of air that can be expired passively,
– combination of increased RV (and FRC) in the alveoli and
diminished caliber of the bronchioles causes part of each
inspiration to be trapped in the acinus
– hyperinflation of alveoli causes large air spaces (bullae)
and air spaces adjacent to pleura (blebs) to develop
Healthy (left) vs. emphysematous lung (right)
Emphysema types in COPD
• Centrilobular (centriacinar):
– septal destruction occurs in the
respiratory bronchioles and alveolar
ducts, usually in the upper lobes of the
lung
– alveolar sac (alveoli distal to the
respiratory bronchiole) remains intact
– tends to occur in smokers
• Panacinar (panlobular):
– involves the entire acinus with damage
more randomly distributed and
involving the lower lobes of the lung
– tends to occur in patients with 1antitrypsin
deficiency
Variable overlap in COPD
Etiology of COPD - multifactorial
• smoking
– cigarette smoke and air pollution, tip the normal balance of elastases (proteolytic
enzymes) and anti-elastases (such as 1-antitrypsin) so that elastin is destroyed at an
increased rate
–  number of neutrophil granulocytes in inflamed airways
• source of elastases and proteases favoring emphysema development
– tissue injury due to reactive oxygen and nitrogen species
• healing with the participation of macrophages (source of matrix metaloprotinases)
– hypertrophy of mucus glands and thus CHB
– impairment of surfactant
• airway hyper-reactivity
• genetics (= variable consequences in two persons with equal „smoking“ history)
– α1-antitrypsin deficiency
• α1-antitrypsin inhibits neutrophil elastase which has the ability to destroy lung tissue
• identified more than 75 alleles in the gene for α1-antitrypsin
– other genes
• pro-inflammatory cytokines, growth factors, protease/anti-protease balance, antioxidants etc.
• exposure to other air pollutants (dust, smoke, professional exposure, car traffic
fumes, biomass burning etc.)
– the most risky are small particles ≤ 2.5 μm
• recurrent lower airways and lung infections
Effect of smoking
Pulmonary vessels in COPD
• remodelation (i.e. wall thickening, lumen
narrowing and increased resistance)
present very early in the time course of
COPD
– endothelial dysfunction
• due to oxidative stress
– hyperplasia of tunica intima
• cells (inflammatory cells and SMCs) as well as ECM
– hypertrophy of tunica media
• gradually hypoxia and loss of capillaries
(emphysema) contributes to remodelation
as well
– vasoconstriction
– later pre-capillary form of secondary
pulmonary hypertension
• cor pulmonale
Hypoxic pulmonary vasoconstriction  pulmonary
hypertension  cor pulmonale (hypertrophy) 
congestive heart failure
Clinical heterogenity of COPD
• Type A – “pink puffer” - dominance of emphysema
– patients with emphysema are able to maintain a higher
alveolar minute ventilation (“puffers”) than those with
chronic bronchitis
• therefore they tend to have a higher PaO2 and lower PaCO2 and are
indeed „pink “
– a thin, tachypneic patient using accessory muscles and pursed
lips to facilitate respiration
• thorax is barrel-shaped due to hyperinflation
– there is little cough and very little sputum production (in
„pure“ emphysema)
• Type B – “blue bloater”– dominance of bronchitis
– bronchitis patients are often „blue“ due to hypoxemia (and
central cyanosis)/hypercapnia
– they regularly exhibit right heart failure due to an increase in
pulmonary artery pressure impairing right ventricular
function
• this leads to peripheral edema (“bloaters”)
74
Bronchial asthma
• prevalence
– 5-10% children
–  5% adults
• definition (GINA 2006)
– a chronic inflammatory disorder of the airways
in which many cells play a role
– chronic inflammation causes an associated
increase in airway hyper-responsiveness that
leads to recurrent episodes of wheezing,
breathlessness, chest tightness, and coughing,
particularly at night or in the early morning
– these episodes are usually associated with
widespread but variable airway obstruction
that is often reversible either spontaneously or
with treatment
• types
– allergic (extrinsic)
• IgE-mediated bronchoconstriction
– non-allergic (intrinsic)
• IgE-independent = bronchial hyperreactivity
– damage of epithelium
– increased sensitivity to bronchoconstrictive
agents
IgE-mediated asthma
• due to the atopy
– genetic predisposition to the alteration
of immune response towards
immunopathological reaction of type 1
•  formation of IgE
•  activity of CD4+Th2 cells (cytokines IL-
4, 5, 6, 13)
• altered Ag presentation by APC
• different reactivity of target cells to
mediators (histamine)
•  suppressor activity of T cells
•  number of mast cells
•  concentration of FcεR1 on their
surface
– IgE antibodies directed often against
(aero)allergens
• domestic (dust mites)
• pollen
• infection agents (bacteria, viruses)
• others
genetics
Polygenic nature of asthma
Sensibilisation phase in atopic subjects
Proportions of asthmatic children sensitized to common allergens
Pathogenesis of allergic asthma
Inhaled antigen is processed by dendritic cells and presented to Th2 CD4+ T cells. B cells are stimulated to produce IgE, which binds to mast cells. Inhaled antigen binds to IgE, stimulating the
mast cell to degranulate, which in turn leads to the release of mediators of the immediate response and the late response. Histamine and the leukotrienes produce bronchospasm and airway
edema. Released chemotactic factors, along with factors from the Th2 CD4+ T cells, facilitate eosinophil traffic from the bone marrow to the airway walls. These late responses are proposed to
lead to excessive mucus production, airway wall inflammation, injury, and hyperresponsiveness. (GM-CSF—granulocyte-macrophage colony-stimulating factor; IFN-y—interferon gamma; IL—
interleukin)
Asthma – acute, late and chron. phase
• early phase (acute attack)
– 15-30 min, mediators of mast cells (histamine)
• immediate biological response but as wells as chemotaxis of other cell
types
–  secretion of mucus, edema of the bronchial wall
– contraction of SMCs (bronchospasms)
Asthma – acute, late and chron. phase
• late phase
– after 4-8 hrs
– mediators of
neutrophils,
eosinophils
• leukotrienes C, D and
E, basic and cationic
protein etc.
– inflammation
(hyperemia, edema),
hypersecretion of
mucus, event.
destruction of
epithelium
Mediators of mast cells and eosinophils
Asthma – acute, late and chron. phase
• chronic phase
– chronic inflammation + repair
processes lead to irreversible
structural (remodelation) and
functional (hyper-reactivity)
changes of airways constituting a
vicious cycle
– epithelium
•  cilia, desquamation
• hypertrophy of mucus glands and
hyperplasia of goblet cells
– basal membrane
• fibrotisation in subepithelialspace
(collagen)
– muscle layer
• hypertrophy and hyperplasia of
SMCs
Mucus pathophysiology in asthma and COPD: similarities and differences
• In asthmatics, there is increased luminal mucus, a similar or increased ratio of mucin (MUC) 5B (low charge glycoform [lcgf]) to MUC5AC,
small amounts of MUC2, epithelial ‘fragility’, marked goblet cell hyperplasia, submucosal gland hypertrophy (with normal mucous to
serous cell ratio), ‘tethering’ of mucus to goblet cells, and plasma exudation. Airway inflammation involves T lymphocytes and
eosinophils. In COPD, there is increased luminal mucus, an increased ratio of lcgf MUC5B to MUC5AC, small amounts of MUC2, goblet cell
hyperplasia, submucosal gland hypertrophy (with an increased proportion of mucous to serous cells), and respiratory infection (possibly
owing to reduced bacterial enzymatic ‘shield’ from reduced serous cell number). Pulmonary inflammation involves macrophages and
neutrophils.
The hyper-responsive airways in asthma respond to a widerange
of provoking factors
• parasympathetic nerve endings
are close to the surface
– damage leads to their exposure and
increase of bronchoconstriction
potential
• bronchomotoric tests
– bronchodilations tests - reversibility
of bronchial obstruction
• salbutamol 200-400 ug
• ipratropium 80 ug
– bronchoconstriction test – bronchial
hyperreactivity
• histamine 1g in 100 ml of physiol.
soution
• metacholin
Aspirin-induced asthma (AIA)
• typical features:
– first manifestation in 3rd-4th decade, more
often women
– whole year persisting cold
– nasal polyps and blockade
• frequency:
– 10% of adult cases of asthma is in fact AIA
• in general population 0.3-0.9%
• „aspirin trias“
– sensitivity to ASA
– asthma
– persisting rhinosinusitis with nasal
polyposis and eosinophilia
 aspirin
bronchoconstriction
Pathogenesis of virus-induced asthma
Inhaled virus infects epithelial cells and leads to apoptosis of some of them. The release of chemotactic factors promotes the recruitment of
macrophages into the lung parenchyma, where they ingest the dead epithelium. An acute response consisting of bronchospasm occurs at this
time. Similar to allergic asthma, the inhaled virus is processed by dendritic cells and presented to Th2 CD8+ T cells. These cells produce
copious amounts of IFN-y. Perforin released from the T cells leads to apoptosis of infected cells. B cells produce IgG, which is capable of
neutralizing the virus. These events are thought to be related to the chronic response, which consists of airway inflammation, goblet cell
hyperplasia, and airway hyperresponsiveness. (IFN-Y—interferon gamma; IL—interleukin; CCL—chemokine ligand)
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Asthma – clinical manifestation
• During full remission
– individuals are asymptomatic and pulmonary function
tests are normal
• During partial remission
– no clinical symptoms but pulmonary function tests are
abnormal
• During attacks
– dyspnea and respiratory effort, wheezing, nonproductive
coughing, tachycardia and tachypnea
• Diagnosis
– spirometry
•  expiratory flow rate, forced expiratory volume (FEV1), and
forced vital capacity (FVC)
•  FRC and total lung capacity (TLC)
– blood gas analysis shows respiratory insufficiency
• initially partial (i.e. hypoxemia with respiratory alkalosis)
• later global (i.e. hypercapnia and respiratory acidosis)