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TMPP2

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TMPP2

Chapter 13.

    Mechanics Of Breathing And Lung Disorders

    Study Objectives

    ( To define and apply the law of ideal gasses, gas partial pressures and fractions, solubility coefficients, Poiseuille?s and

    Laplace?s laws.

    ( To describe flow-limitation in the airways, dynamic airway compression, respiratory work, and surface tension (and how it is

    affected by pulmonary surfactant). To describe obstructive and restrictive lung disorders respiratory failure, cystic fibrosis, and

    the respiratory distress syndrome in new-borns.

    ( To explain the function of the lung from its structure, respiratory volumes, normal and abnormal airway resistance, static and

    dynamic pressure-volume relations including compliance, with their measurement and normal values. ( To use these concepts in diagnosis, problem solving and apply them to case histories.

    Principles

    ( The law of conservation of matter (see Chapter 8). This principle is used to measure physiological volumes and volume rates.

    ( The law of ideal gasses is defined in Eq. 13-1 (late in this Chapter).

    ( Poiseuille?s law is used both in the circulatory and the respiratory system (Eq. 13-3).

    ( The law of Laplace (Eq. 13-4).

    ( Bernouille?s principle (Eq. 13-6).

    Definitions

    ( Alveolar ventilation-perfusion ratio (V? /Q?-ratio) is an estimate of the gas exchange capacity. This key point is the A

    cardinal variable of cardiopulmonary function - see Chapter 14.

    ( Apnoea is a temporary stop in breathing.

    ( Asthma is an inflammatory lung disease characterised functionally by broncho-constriction, hypersecretion and oedema of

    the bronchial wall - all contributing to obstruction of the airflow.

    ( Chronic bronchitis refers to an inflammatory process in the wall of the bronchioles with excessive production of mucus and

    sputum from hypertrophic glands. The small airways are narrow, and there is morning cough more than 3 months per year

    (WHO).

    ( Compliance is an index of expandability of elastic organs and defined as the change in volume per unit change in pressure. ( Emphysema refers to destruction of lung tissue distal to the terminal bronchioles (a lung unit termed a primary lobulus or

    acinus). There is degenerative loss of radial traction of the bronchial walls.

    ( Expiratory reserve volume (ERV) is the volume of air, which can be expired following a normal expiration at rest. ( Forced expiratory volume in one second (FEV) is the 1-s-volume exhaled with forceful pressure from maximal inspiration. 1

    FEVis often expressed in relation to the total forced expiratory volume (FEV). 1

    ( Functional residual capacity (FRC = ERV + RV) is the lung volume in the normal end-tidal expiratory position (airways open

    and relaxed respiratory muscles).

    ( Obstructive lung disorders are characterised by an abnormally low airflow.

    ( Restrictive lung disorders are characterised by small lung volumes (low total lung capacity). ( Residual volume (RV) represents the volume of air left in the lungs after a maximal expiration - normally1.2 litre (l) in

    adult persons.

    ( Solubility (~ or Bunsen’s solubility coefficient) is the volume of a particular gas (ml at Standard Temperature Pressure Dry,

    STPD) dissolved per ml of body warm blood at a partial pressure of one atmosphere (101.3 kPa or 760 mmHg). The solubility

    coefficients for nitrogen, carbon monoxide, oxygen, and carbon dioxide are listed in Box 13-1. ( Spontaneous pneumothorax means that the pleura surface suddenly ruptures without known cause. The rupture typically

    occurs apically, where the mechanical tension is largest due to expansion. The sudden pain is pleuritic (accentuated by inspiration

    or coughing), there is dyspnoea, drum sounds by percussion of the affected area and no breath sounds by auscultation.

    ( Total lung capacity (TLC) is the total volume of air in the lungs, when they are maximally inflated (RV + VC) - approx. 6 l

    of air.

    ( Vital capacity (VC) is the largest volume of air that can be exhaled after a maximal inspiration. VC is measured with or

    without forced expiration. The size is typically around 4 litres, but it depends on age, sex, and height in the healthy individual.

    Box 13-1: Solubilities or Bunsen’s solubility coefficients (~) for gasses in body-warm blood. The unit for the solubility is ml

    -1-1STPD*(ml of fluid)*(101.3 kPa)

    Carbon dioxide: 0.52

    Carbon monoxide: 0.018

    Nitrogen: 0.012 (Water: 0.013; Fat: 0.065)

    Oxygen: 0.022

    Essentials

    This paragraph deals with 1. Air, 2. Lung volumes, 3. Pneumotachography, 4. The lungs, rib cage and compliance, 5. Dynamic

    airway compression, 6. Dynamic flow-volume loops, 7. Elastic recoil, 8. Airway resistance, 9. Surface tension, 10. Pulmonary

    defence mechanisms.

    1. Air

    Air passes through the nose and mouth further into the airways, where it is warmed, humidified and filtered. From the trachea to the

    alveoli, there are 23 branching generations of airways. The first 16 (as an average) constitute the conducting zone, which is an

    anatomic dead space, because no gas exchange takes place. The 17-23 generations form the respiratory zone. Each generation of

    branching increases the total cross-sectional area of the airways, but reduces the radius of each airway and the velocity of air flowing

    through that airway. The exchange effective respiratory zone comprises of the respiratory bronchioles, alveolar ducts and alveolar sacs. At this dead end of the airways, there are approximately 300 million alveoli. Each alveolus has a diameter of 100 -300 ?m and

    is surrounded by approximately 1000 capillaries. Each capillary is in contact with several alveoli, so the capillaries present a sheet of

    2blood to the alveolar air for gas exchange. The total area between pulmonary capillary blood and alveolar air ranges from 70-140 m

    in adult humans (increased during exercise) through recruitment of new capillaries in particular in the apical parts of the lungs.

    Turbulent flow is the agitated random movement of molecules, which accounts for the sounds heard over the chest during breathing.

    This flow develops at the branch points of the upper airways even in quiet breathing. Turbulence also develops when constriction,

    mucus, infection, tumours, or foreign bodies decrease the radius of the airways. Vagal stimulation (by smoke, dust, cold air, and

    irritants) leads to airway constriction, whereas sympathetic stimulation dilatates the airways. 2. Lung volumes

    Lung volumes are measured by spirometry (Fig. 13-1). A spirometer consists of a counterbalanced bell, which is connected to a pen writing on a rotating drum. The air-filled bell is inverted over a chamber of water, so an airtight chamber is formed. The bell is

    counterbalanced so it moves up and down with respiration with minimal resistance (Fig. 13-1). Volume changes can be recorded on

    volume and time calibrated paper. - If the spirometer includes a CO absorber, the device is called a metabolic ratemeter (construction 2

    Benedict-Krogh).

    The residual volume (RV) represents the volume of air left in the lungs after a maximal expiration (1.2 l in Fig. 13-1). The vital

    capacity (VC) is the maximum volume of air that can be exhaled after a maximal inspiration (4.8 l in Fig. 13-1). VC has three

    components. The first is the inspiratory reserve volume (IRV), which is the quantity of air that can be inhaled from a normal end

    inspiratory position. The second component of VC is the tidal volume (V), which is the volume of air inspired and expired with each T

    breath (about 0.5 l at rest).

    Fig. 13-1: A healthy person, connected to a spirometer, is performing a vital capacity manoeuvre from maximal inspiration to

    maximal expiration (RV).

    The third component of VC is the expiratory reserve volume (ERV), which is the amount of air that can be exhaled from the lungs

    from a normal end-tidal expiratory position that is characterised by a relaxed expiratory pause (Fig. 13-1). This is the easiest position

    to reproduce, and the lung volume in this position is called functional residual capacity (FRC = ERV + RV). The total lung capacity

(TLC) is the total volume of air in the lungs, when they are maximally inflated (RV + VC) - approx. 6 l of air.

    When the person in Fig. 13-1 exhales with maximal effort, the forced expiratory volume in one-second (FEV) may be recorded by 1

    spirometry.

    The forced vital capacity manoeuvre is performed with all the expiratory and accessory muscles. When we contract our strong

    expiratory accessory muscles, we generate high airflows at lung volumes near total lung capacity (Fig. 13-6). Just following

    peak-expiratory flow (PEF) the airflow velocity decreases linearly with volume no matter how hard the subject tries. This is the

    effort-independent airflow (Fig. 13-6) caused by dynamic airway compression (see later). 3. Pneumotachography

    A pneumotachograph is a device for measuring airflow. It consists of a respiratory tube with a small resistance (typically a fine

    network) to airflow (Fig. 13-2). The two chambers separated by the resistance, connects to the differential transducer chambers by

    thin tubes. A transducer consists of 2 chambers separated by a membrane, whose position in space reflects the pressure difference.

    During respiration through the pneumotachograph tube, a small pressure difference (P) is generated across the resistance, and this pressure difference is directly proportional to the laminar airflow across the resistance according to Poiseuille’s law: Resistance =

    P/V?. E

    Fig. 13-2: Pneumotachograms from a healthy person at rest: The upper curve is the classical flow curve and below is the flow

    integrated to a volume curve with a tidal volume of 500 ml.

    4.The lungs, rib cage and compliance

    The lung-thoracic wall system consists of two elastic components that work together: The lungs, which behave like a balloon trying

    to collapse and the thoracic cage trying to expand. The following three important pressures influence the elastic properties of these two components:

    1. The barometric pressure (P). The barometric or atmospheric pressure is one atmosphere and is used as reference pressure. B

    2. The alveolar pressure (P). - The pressure in the alveoli is equal to the static mouth pressure when there is no airflow (during alv

    apnoea with the glottis open). The static mouth pressure (= P) depends upon the lung volume (Fig. 13-3). alv

    3. The intrathoracic pressure (P). - The intrathoracic pressure is the pressure in the fluid-filledpleural space between the parietal and it

    visceral layers of pleura (Fig. 13-3). The intrapleural fluid reduces the friction between the two layers. The P can be measured as the it

    pressure in a sensitive balloon, which is passed into the oesophagus. Pressure changes in the intrapleural space equal the oesophageal

    balloon pressure changes, because the oesophagus traverses the intrapleural space. The Pis subatmospheric due to the opposing it

    directions of the elastic recoil of lungs and thoracic cage (Fig. 14-5).

    Fig. 13-3: Transmural, static pressures and lung volumes in a healthy person. The red compliance curve is for the total system (see later). The blue and green compliance curves are for the lungs and the chest wall, respectively.

    Compliance is an index of distensibility of elastic organs and defined as the change in volume per unit change in pressure (dV/dP).

    The following is a description of the measurement of the combined lung plus rib cage compliance, the lung compliance and the rib

    cage compliance alone.

    The combined lung plus rib cage compliance

    The subject expires completely to residual capacity (RV in Fig. 13-3), and then inspires a measured volume of air from a spirometer.

    The subject then relaxes the respiratory muscles during apnoea while the glottis is open at each volume. The alveolar pressure

    gradient to the ambient air (P - P) can then be measured as the mouth pressure by a manometer (Fig. 13-3). The procedure is alvB

    repeated by varying the inspired lung volume between residual volume (RV) and total lung capacity (TLC), and the red relaxation

    curve of Fig. 13-3 is recorded. This relaxation curve shows the specific standard compliancefor the combined system (defined at static conditions as the slope of the curve at functional residual capacity, FRC). In healthy persons, the specific standard compliance

    for the combined system is 1 ml per Pascal (0.1 l BTPS per cm of water) at FRC. The lungs and chest wall move together and support

    each other. This is what makes the standard compliance of the combined system less than that of the lungs or rib cage alone (Fig. 13-3).

The lung compliance

    The volume of the lungs before each apnoea is varied in the same way as when measuring the lung compliance for the combined

    system. The pressure difference between the mouth and intrathoracic (oesophageal) pressure (P - P) is the blue curve marked alvit

    Fig. 13-3. In healthy persons, the specific lung compliance is 2 ml per Pascal (0.2 l BTPS per cm of water) transmural lung pressure in

    at FRC, where the blue lung curve is almost linear (dV/dP at FRC).

    Normal lungs are very distensible at functional residual capacity (FRC), but stiffen progressively towards total lung capacity (TLC).

    The falling compliance is caused by an increase in the air-liquid surface tension, because the liquid contains tension-reducing

    molecules (surfactant, see below) that are spread further and further apart. Thereby the compliance of the lung is reduced.

    Compliance also decreases with age; there are corresponding decreases in lung volumes. The rib cage compliance

    This is a calculated variable. The static transmural wall pressure (P - P) is indirectly obtained from the two static transmural itB

    pressures measured above. With the two elastic systems in static equilibrium (P - P) must be equal to the difference between the itB

    static transmural pressure of the combined system and that of the lungs: (P - P) - (P - P). According to this equation a minimal alvBalvit

    increase in lung volume (dV) implies the following relationship: d(P - P)/dV = d(P - P)/dV - d(P - P)/dV. Each of the entities itBalvBalvit

    is an elastance (dP/dV). The elastance of the thoracic cage is equal to the combined elastance minus the lung elastance.

    The specific compliance of the thoracic or rib cage (dV/dP) is the specific reciprocal elastance, and equal to 2 ml per Pascal (0.2 l BTPS per cm of water). The chest wall compliance curve is constructed by using the above equation (green curve in Fig. 13-3).

    5. Dynamic airway compression

    The driving pressure for air to move is (P - P). The driving pressure and airway resistances are studied when air moves into and alvB

    out of the lungs, and the condition is therefore called dynamic. The driving pressure for inspiration is a negative alveolar pressure

    (P) relative to P (Fig. 13-4). alvB

    Respiratory volume is recorded graphically with a (x, y)-recorder. The tidal volume is plotted against the driving pressure, which is

    equal to the dynamic alveolar pressure (Fig. 13-4).

    The resistance to airflow, and the viscous resistance of lung tissue, causes the dynamic pressure-volume curve (Fig. 13-4) to deviate

    from the static (Fig. 13-3). The slanting straight line (diagonal) is sometimes called dynamic compliance for the combined system

    (Fig. 13-4).

    Integrating pressure with respect to volume gives the two green areas corresponding to the elastic workof one inspiration (Fig. 13-4).

    This is the work needed to overcome the elastic resistance against inspiration. The red area to the right of the diagonal is the extra

    work of inspiration called the flow-resistive work or alternatively non-elastic work (Fig. 13-4).

    During expiration, the flow-resistive work is equal to the light green area (Fig. 13-4). The inspiratory and expiratory curve forms a

    so-called hysteresis loop. The lack of coincidence of the curves for inspiration and expiration is known as elastic hysteresis. With

    deeper and more rapid breathing the hysteresis loop becomes larger, and the non-elastic work relatively greater.

    Fig. 13-4: Tidal volume (V) and the dynamic transmural pressure (P - P) in a healthy person during one respiratory cycle. TalvB

     The expiratory curve from a patient with obstructive lung disease is shown to the left (see pathophysiology).

    During a forceful expiration, the intrathoracic or pleural pressure (P) rises and causes the alveolar pressure (P) to exceed the italv

    downstream pressure at the airway openings (P). As flow resistance dissipates the driving energy along the bronchial tree, the B

    driving pressure of the cartilaginous bronchi falls towards zero at the mouth (Fig. 13-5). At a certain point the forces that expand the airway equal the forces that tend to collapse. This is the equal pressure point. Beyond the equal pressure point the driving pressure falls below the external pressure, and the bronchi are compressed (Fig. 13-5). At this point the person cannot voluntarily increase the

    rate of expiratory airflow, because increased effort also increases the external pressure. This phenomenon is called dynamic airway

    compression with airway collapse.

    The maximum expiratory airflow is effort-independent according to Bernoulli’s law (Fig. 13-6). Bernoulli’s law states that the driving energy equals the sum of the kinetic energy, the constant positional energy and the laterally directed energy (ie, the lateral pressure

directed towards the walls). Thus, during expiration the lateral pressure is lowest where the cross sectional area is smallest (the

    trachea), and the last part of the trachea collapses (Fig. 13-5).

    Coughing causes momentary collapse of the tracheal wall. The airway closure occurs when the equal pressure point has moved to a part of the airway that is not supported by cartilage and has the smallest cross sectional area (highest kinetic energy). Fig. 13-5: Alveolar sac, bronchiole and a cartilaginous bronchus collapsing during expiration.

    ththThe peak airway resistance, where flow limitation takes place, is found in the medium-sized segmental bronchi around the 4-7

    generation moving peripherally as lung volume decreases. In healthy people the least resistance to airflow is found in the numerous

    terminal bronchioles. At low lung volumes the elastic pull in the bronchioles becomes smaller (the structures relax with falling

    volume) and the airways tend to collapse more easily (Fig. 13-5).

    6. Dynamic flow-volume-loops

    Fig. 13-6 shows a dynamic flow-volume loop generated by plotting airflow velocity measured at the mouth with a pneumotachograph against lung volume (integrated airflow velocity). The computer makes a mark after one s of forced expiration.

    The large loop is from a healthy person performing a forced expiration from full lung inflation (Total Lung Capacity, TLC) to full lung deflation (Residual Volume, RV) that is the vital capacity, VC. This is a so-called forced vital capacity manoeuvre (Fig. 13-6).

    The inspiratory airflow velocity increases rapidly when inspiring from maximal expiration, and reaches a plateau dependent on muscle force until maximal inspiration, at which point the velocity falls rapidly to zero (Fig. 13-6). Inspiration is limited by the

    force-velocity relationship of the inspiratory muscles - not flow-limited, as is forceful expiration. Fig. 13-6: Dynamic flow-volume loops for forced vital capacity from a healthy person (yellow area/Residual Volume = 1.2 l). Patients with restrictive (red area/RV 0.6 l) and obstructive lung disease (blue area/RV 2.4 l) are also shown see

    pathophysiology.

    The COLD patient inspires maximally and starts a maximal expiration, but due to the high airway resistance, the flow is abnormaly

    low causing a 'hammock' curve (Fig. 13-6). The inflammed airways are obstructed by secretion and smooth muscle contraction. The

    number of airways are reduced as is the pulmonary elastic recoil with loss of alveolar walls and traction causing the airways to

    collapse. Some patients also have a 'saw-tooth' pattern, due to cardiac contractions.

    A forced expiration increases both the pleural and the alveolar pressure and the external pressure tend to close the airways. At the

    point where the airway pressure has fallen due to the flow and is identical with the external pressure, we have the compression or

    equal pressure point (EPP). An external pressure above this value causes airway compression. Flow is determined by transmural pressure differences at the compression point. The transmural pressure difference is the static expansion pressure of the lung. This is

    solely dependent of lung volume and stiffness - and independent of increased expiratory strain. Collapse at EPP occurs around the

    lobar bronchi early during expiration . During further reduction of the lung volume, the airway calliber is reduced and airway resistance decreases (Fig 13-6). This is why the flow-pressure is reduced further and EPP moves to more and more distal airways.

    Late during forced expiration, the flow is thus determined by the the small airway characteristics. 7. Elastic recoil

    Two forces oppose lung expansion:

    A. The overall elastic recoil (dP/dV) is the sum of the pulmonary elastic recoil and its surface tension. These forces relate to

    the elastic work of Fig. 13-4. - Traditionally, the reciprocal elastance or the compliance (dV/dP) is preferred as an index of

    the distensibility of the lungs and the rib cage. There is a thin fluid layer on the inner surface of the alveolus. Because of the

    alveolar fluid - air interface a surface tension is created that tends to collapse the alveolus (just like the elastic recoil). The

    contribution of surface tension to the overall lung elasticity is more than 50%.

    B. The airflow resistance forces relate to the non-elastic work of Fig. 13-4. The total airflow resistance is the sum of all the

    resistances of the nose and mouth (a substantial portion of the total) and of the 23 generations of the tracheobronchial tree.

    The friction between gas molecules and between gas molecules and the walls also contributes to airway resistance. The

    airway resistance is important and makes the sliding of lung tissue over each other (viscous tissue resistance) a minor issue.

In the lungs, the term static compliance is used because the volume and pressure measurements are made when there is no airflow.

    Increased lung compliance is caused by reduced lung elasticity, and means that lungs with elastic tissue degeneration are easier to inflate. Reduced lung compliance is caused by increased lung elasticity and means that stiff, fibrotic lungs are harder to inflate see pathophysiology.

    8. Airway resistance (R) aw

    The driving pressure (P) for laminar airflow (V?) through the airway resistance is the intra-alveolar pressure (P) minus the Ealvambient or barometric pressure, P. B

    The airway resistance (R) is defined by Poiseuille’s law - see Eq. 13-3. aw

    thR is directly related to the air viscosity (?) and to the length (L) of the tube, and inversely related to its radius in the 4 power: aw4R = 8 ? L/r. Doubling the length of the airways only doubles the airway resistance, but halving the radius increases the resistance aw

    sixteen-fold. Such a rise in resistance takes place in the small airways during bronchiolitis. The walls of the bronchioles are inflamed causing oedema (swelling), constriction, sloughing of epithelium, and excessive secretion. A similar reversible bronchoconstriction takes place in hyperirritable airway disease (asthma see pathophysiology).

    In the clinic the airway resistance is sometimes measured in a body plethysmograph, which is technically demanding to operate, so

    in everyday clinical practice the Forced Expiratory Volume in 1 second (FEV) from total lung capacity is used as an indirect 1

    measure. This indirect method requires only simple, reliable and accurate spirometers. The patient is asked to expire as fast as possible from TLC by creating a high driving pressure. The driving pressure is considered an arbitrary unit, because it is a

    reproducible, fast muscle force in each patient. As long as a patient applies an expiratory pressure above the threshold pressure needed to create dynamic airway compression, its absolute size is immaterial. The airway resistance is obtained by dividing the arbitrary expiratory pressure unit by the airflow velocity, FEV. 1

    With increasing lung volume the expanding lung tissue pulls the airways open and thereby decreases the airway resistance. There is a continuum from the top to the bottom of the upright lung, with respect to the degree of airway and alveolar distension. The greatest relative lung distension - at any lung volume - is found at the top due to a more negative P. Consequently, the distended top of the it

    lung has the lowest relative ventilation. Thus airway calibre is larger at the top than at the bottom of the upright lung, causing airway resistance to increase progressively from the top to the base of the lung (Fig. 14-5).

    9. The surface tension

    When the pressure-volume curves in air (Fig. 13-4) are compared to those from saline-inflated excised lungs, it appears that the air-filled lungs are less compliant and show a larger hysteresis loop than when they are inflated with saline. Saline-filled lungs have no air-liquid interface, and thus no surface tension. More than half the total elastic recoil force of the lungs is caused by surface tension.

    The lungs are suspended in a gravity field tending to separate the parietal and the visceral pleura. The gravity causes the tendency to be greater at the lung apex than at its base. Thus, the intrathoracic pressure (P) is more subatmospheric at the apex of the lung than it

    at its base (-900 compared to -200 Pa or -9 to -2 cm of water at FRC). Since the alveolar pressure (P) is more or less the same alv

    throughout the alveoli, it follows that the transmural pressure gradient (P - P) over the lung tissue is larger at the apex than at the alvit

    base of the lung. Therefore, the alveoli at the apex always expand more than the alveoli at the base of the lung. However, the

    expanded apical alveoli will distend less during inhalation than the small, compliant alveoli located in the middle and basal regions. Pulmonary surfactant lowers the surface tension in the alveoli, which increases the lung compliance. Surfactant is secreted into the

    thin air-filled interface of the alveolar lining. Surfactant is a complex phospholipid that is a combination of dipalmitoyl

    phosphatidyl-choline (DPPC) and other lipids and proteins. DPPC orients perpendicular to the air-water interface, such that the charged choline base is dissolved in water (hydrophilic) and the nonpolar, hydrophobic fatty acids projects toward the alveolar air. The type 2 alveolar epithelial cells secrete surfactant. Surfactant prevents alveolar collapse. According to the law of Laplace, the transmural distending pressure in spherical alveoli is equal

    -1to T/(2r), where T is the total wall tension (elastic recoil plus surface tension; N m) and r is the radius (Fig. 8-9). Because the distending pressure is essentially the same in communicating alveoli, the total wall tension changes with diameter. During expiration

the diameter decreases, surfactant molecules are packed tightly together, separating the water molecules and reducing the total wall

    tension. During inspiration the diameter increases, the surfactant molecules scatter, and the water molecules move closer to each

    other so the total alveolar wall tension increases progressively; the lung becomes stiffer.

    10. Pulmonary defence mechanisms

    During normal breathing most of the particles of more than 10 ?m in diameter - such as pollen - are deposited and removed in the

    nose and nasopharynx. Particles below 1 ?m are deposited in the alveoli. Particles between 1 and 10 ?m are deposited in the bronchi

    - the smaller the particles are the lower they reach.

    Although sneezing and coughing with expectoration can eliminate many inhaled particles, the mucociliary escalator assisted by bronchus-associated lymphoid tissue (BALT) and alveolar macrophages perform the main clearance of the airways. Mucociliary escalator. The airways are protected by humidification all the way to the alveoli with a mucous layer, which prevents dehydration of the epithelium and surrounds the epithelial cilia (Fig. 13-7).

    Fig. 13-7: Bronchial wall during an attack of asthma. The protective layer in the lumen is abundant, and consists of a gel phase and a liquid phase surrounding the cilia of the epithelial cells. The lamina propria swells, and the smooth muscle layer is hypertrophic.

    The airway mucous consists of polysaccharides from goblet cells and from mucous glands in the bronchial wall. Serous and seromucous glands are also active. The mucous forms a gelatinous blanket on top of the liquid layer (Fig. 13-7). The cilia continuously move the gelatinous blanket with inhaled particles on the top upward towards the pharynx, where they are swallowed.

    Clearance of the respiratory bronchioles may take days, whereas clearance of the main bronchi is typically accomplished within an

    hour. Smoking reduces mucociliary transport, and indirectly impairs gas exchange. Smoking also reduces surfactant production and

    thus increases the work of breathing.

    The lung secretions contain bactericidal lysozyme and lactoferrin from granulocytes. The ~1-antitrypsin normally neutralises

    chymotrypsin, trypsin, elastase, and proteases secreted by granulocytes during inflammation, and thus prevents destruction of lung

    tissue.

    BALT.

    Bronchus-associated lymphoid tissue (BALT) in the walls of the main bronchi is part of the mononuclear phagocytotic system or Reticulo-Endothelial-System. These tissue aggregates contain macrophages originating from monocytes and lymphocytes. The lymphocytes are also present in the lamina propria (Fig. 13-7).

    Following sensitisation of B-lymphocytes to specific antigens, the cells produce specific antibodies or immunoglobulins (IgA, IgG

    and IgE) in response to new contact with the antigen (Fig. 33-4). IgA inhibits the attachment of poliovirus, bacteria and toxins in the

    respiratory tract. IgE is related to the pathogenesis of allergic disorders - see Ch. 33.

    Lungs do have endocrine functions. Alveolar macrophages are amoebic cells that swallow particles and bacteria in the alveoli. While

    they execute microbes in their phagolysosomes, the cells migrate to the mucociliary escalator, or they are removed by the blood or by

    the lymphatic system. Smoking impairs the normal macrophage activity.

    The inactive polypeptide, angiotensin I, is converted into the potent vasoconstrictor, angiotensin II, by the angiotensin converting

    enzyme (ACE), located on the pulmonary endothelial cells. Angiotensin is important for the regulation of the arterial blood pressure

     also during chock.

    Adrenaline, dopamine, histamine, prostaglandins A1 & A2, prostacyclin (PGI2) and vasopressin (ADH) pass unaffected through the lungs. Bradykinin, leucotrienes, prostaglandins E2 & F2~, and serotonin are almost completely cleared during passage through the lungs by enzymatic activity.

    Adrenergic sympathetic activity (and sympathomimetic drugs) relax bronchial smooth muscle via adrenergic?-receptors, whereas 2

    parasympathetic cholinergic activity (and parasympathomimetics) constrict bronchial smooth muscles via muscarinic receptors. Smoke, dust and other irritants (perhaps also adenosine, histamine and substance P) constrict the airway smooth muscles via a reflex

triggered by the rapidly adapting irritant-receptors (Chapter 16). Decreased P, thromboxane and leucotrienes (see Chapter 32) ACO2

    also act as bronchoconstrictors.

    Vasoactive intestinal peptide (VIP) can dilatate airways and reduces airflow resistance. Substances that dilatate airways include increased P, adrenergic alpha-blockers, catecholamines and atropine. ACO2

    Pathophysiology

    Lung volumes, as measured with a spirometer, are needed in order to differentiate between two major functional types of lung-airway disorders, and in quantifying the degree of abnormality. The two types are called A. obstructive and B. restrictive disorders (Box 13-2).

    Box 13-2. Classical respiratory disorders

    A. Obstructive disorders (increased flow-resistance)

    A1 Asthma: Acute attacks chronic inflammation of bronchial wall

    Expiratory flow-limitation - Hyper-reactive bronchial wall

    Eosinophils-Hypersecretion Bronchoconstriction.

    Criterion: A low FEV improves more than 15% following inhalation of 1

    broncho-dilatators

    A2 Chronic obstructive bronchitis & emphysema

    A3 Respiratory failure

    A4 Cor pulmonale

    A5 Sleep apnoea

    A6 Cystic fibrosis

    B. Restrictive disorders (small lung volumes - especially VC)

    B1 Restrictive disorders in the lung parenchyma

     Granulomatosis (sarcoidosis often also obstructive)

    Systemic connective tissue diseases (Rheumatoid arthritis, lupus, sclerosis)

    External allergic alveolitis (organic dust)

    Diffuse progressive pulmonary fibrosis

    Collapsed alveoli and alveolar oedema

    B2 Restrictive disorders in the chest wall

     Rib fractures - Kyphoscoliosis - Ankylosing spondylitis

    Pneumothorax - Pleural disorders and effusions (transudates and exudates)

    B3 Restrictive disorders in the newborn

    A. Obstructive lung disorders

    The most common disorders are A1. asthma and A2. chronic obstructice bronchitis and emphysema. A special condition called cystic

    fibrosis is also dealt with.

    These disorders are all characterised by low expiratory airflow as measured by low Forced Expiratory Volume in one s (low FEV). 1The low FEV is due to narrowing of the airways with increased airflow resistance. 1

    The patient with obstructive lung disease has a smaller flow-volume-loop than that of a normal subject - performed as a forced vital

    capacity manoeuvre (Fig. 13-6). The RV of the patient is 2.4 l or twice as high as that of the healthy individual, because of air trapping (a large volume of trapped air). Sometimes the so-called saw-tooth phenomenon is observed (Fig. 13-6). This is an

    unspecific sign of intrathoracic airflow limitation neither related to obstructive sleep apnoea nor to body mass index (Chapter 20). Although the flow-volume curve in obstructive lung disease is consistently reduced in the flow direction, it is not always reduced in the total volume direction (Fig. 13-6).

    A1. Asthma

    Attacks of asthma occur acute and episodic, but the underlying cause is a chronic inflammation of the lung airways. Asthma is

    characterised by expiratory airflow limitation due to hyperactive bronchi with eosinophilic inflammation, mucous hypersecretion and bronchoconstriction. Asthma is diagnosed when there is an improvement of FEV greater than 15% following inhalation of 1

    broncho-dilatators. If necessary, airway hyperreactivity can be demonstrated by histamine or metacholine provocation of bronchoconstriction. Large numbers of eosinophils are present in the sputum, and often in the blood. Skin-prick tests often identify

    extrinsic causes, which the patient must avoid.

    Stimulation of the vagal nerve or metacholine provocation causes a forceful reflex bronchoconstriction in asthmatics. This probably

    explains the hypersensitivity to non-specific stimuli (eg, exercise, cold air or water, pollution, dust, vapours and fumes). Fig. 13-8: Asthma is an acute obstructive lung disease, with reduced lumen due to broncho-constriction, hypersecretion and oedema of the bronchial wall. Emphysema is a chronic obstructive lung disease with degenerative loss of radial traction of the bronchial walls. Diffuse lung fibrosis is characterised by the thick and stiff alveolar interstitium all over the lung. The

    Pickwick Syndrome is a restrictive lung disorder due to obesity.

    Asthma occurs in the form of extrinsic asthma, which is caused by a specific allergen (extrinsic) in an atopic person. A person

    suffering from atopy has a personal history of symptoms from nose, lungs and skin with hay fever (allergic rhinitis), eczema or urticaria often from childhood (childhood asthma). Common allergens are the house-dust mite or its faeces, pollen grains, moulds and

    domestic pets.

    When a middle-aged non-atopic person develops asthma, an allergen is seldom identified. The condition is sometimes called intrinsic

    asthma.

    Within minutes from inhalation of an allergen there is an immediate, anaphylactic reaction (Fig. 33-5). Eosinophils recognise the

    allergen and release allergen specific IgE antibodies. The allergen-IgE complex is bound to IgE-receptors on the surface of granule

    containing mast cells, eosinophils and basophils. Hereby, mediators of anaphylactic reactions are released from the mast cell granules:

    Leukotrienes (= SRS-A) are strong bronchoconstrictors and also cause mucosal inflammation with oedema and hypersecretion. Prostaglandin D2 is also contributing with bronchoconstriction and vasodilatation with increased capillary permeability. Eosinophils

    release leukotrienes C4, PAF, major basic protein and eosinophilic cation protein, all of which are toxic to epithelial cells. Histamine is a powerful vasodilatator and may play some role for the hypersecretion and bronchoconstriction in asthma, but antihistamins have no effect.

    During an attack of asthma the bronchial wall is suffering (Fig. 13-8). The hypertrophic smooth muscles contract, capillary leak of

    plasma water results in oedema of the lamina propria, and hypersecretion of the mucous glands produces thick mucous, which the cilia can hardly move. All of this causes universal narrowing of the airways or occlusion by mucous. The airflow limitation results in wheezing respiration, and the patient feels dyspnoa. The attacks usually occur during the night often

    with coughs. Stethoscopy of the lungs reveals wheezing. A severe asthmatic attack may continue for hours and days, in which case

    the condition is called status asthmaticus. There is tachycardia and sometimes pulsus paradoxus (the pulse disappears due to a

    marked fall in both systolic and pressure amplitude during inspiration).

    Some asthma patients develop a relative insensitivity of the adrenergic ?-receptors of the bronchial smooth muscles 2

    (down-regulation of the ?-receptors). All ?-receptors act through activation of adenylcyclase and cAMP. When noradrenaline binds 2

    to ?- receptors it causes bronchodilatation, but not always sufficient in asthma. 2

    Therapy keypoints

    ?-adrenergic agonists interact with the bronchodilatating ?-receptors, but they also cause tachycardia by stimulating the 22

    ?-receptors of the myocardium. The ?-receptor agonists (salbutamol or terbutaline aerosols) are effective in mild asthma. - 12

    Cardioselective adrenergic ?-blockers must be administered with care to patients with a combination of asthma and cardiac disease. 1

    Anticholinergic bronchodilatators bind to muscarinic M and M receptors of the airways, and selective muscarinic antagonists such 13

    as ipratropium or oxitropium by aerosol are used as supplement to salbutamol. Previously, atropine - a non-selective muscarinic

    antagonist - was used. These drugs are rather ineffective in asthma.

    ++Anti-inflammatory drugs (Na -cromoglycate, nedocromil- Na) blocks a chloride channel in the inflammatory cells, thus preventing

    2+Ca influx, and thereby liberation of mediators. They are given to cases of mild asthma (children) before stimulation such as exercise.

Corticosteroids (beclomethasone dipropionate or fluticasone propionate) are administered by inhalation, and they are effective in

    severe cases. The activation of inflammatory cells is rapidly decreased by local corticosteroids, which have minor systemic side

    effects only.

    A2. Chronic bronchitis & emphysema

    Chronic obstructive bronchitis is an inflammation of the bronchioles characterised by excessive production of mucous from hypertrophic mucous glands. There is an increase in the number of gel secreting goblet cells (Fig 13-7). The lumen contains large

    amounts of mucus and pus. The ciliated columnar epithelium is ulcerated and sometimes replaced by squamous cells without cilia (metaplasia).

    The small airways are narrowed, and their walls thickened by inflammation and oedema. There is morning cough with sputum for at

    least 3 months of the year for at least two years (WHO). This is a clinical diagnosis based on the patient history. Emphysema is an patho-anatomical diagnosis characterised by enlargement of the air spaces and destruction of the lung tissue distal to the terminal bronchiole (a tissue unit called an acinus or a primary lobule). The emphysematous lung has increased compliance

    (increased dV/dP) because the elasticity is decreased. Destruction of the alveolar walls includes the capillary bed with increased pulmonary vascular resistance causing pulmonary hypertension. Emphysema is established at autopsy. The most common type of emphysema is centri-lobular emphysema, where the damage is limited to the central part of the lobule or acinus, whereas the

    -lobular or pan-acinar, because the peripheral alveolar ducts and alveoli are preserved. The rare type of emphysema is called pan

    entire lobule is destroyed. - Bullous emphysema is when the entire lung consists of large cysts or bullae with hardly any normal tissue

    left.

    Chronic bronchitis & emphysema is synonymous with many alternative terms: Chronic Obstructive Airway/Lung/Pulmonary Disease or abbreviated COAD/COLD/COPD.

    Both bronchitis and emphysema co-exist in many patients. Some of these patients are dominated by the first, others by the second,

    and some have elements of asthma too.

    These disorders are almost exclusively confined to smokers (cigarette smokers in particular), and the severity of the disease is

    proportional to the amount of tobacco (number of cigarettes) smoked per day. The disorders are progressive during years of smoking

    and cause impaired exercise capacity. A patient smoking more than 25 cigarettes per day have a mortality that is 20 times higher than

    that of a non-smoker. Other airway irritants such as atmospheric pollution contributes to the death rate. The maintained irritation of the epithelium from smoke causes the hypertrophy and the hypersecretion of the mucous glands in the

    larger airways (Fig. 13-7). Surfactant normally lowers the surface tension of the alveolar fluid layer, but smoke has an adverse effect on surfactant. A high frequency of acute airway infections increases the pulmonary damage. The small airways of smokers are infiltrated with neutrophils, which are also present in their lumen. Neutrophils release elastase and proteases. These enzymes destroy

    lung tissue and produce emphysema, when not balanced by antienzymes such as antiproteases. A typical antiprotease in normal

    serum is hepatic ~-antitrypsin, which is inactivated by smoking. The main phenotypes of the ~-antitrypsin gene are MM= normal, 11

    MZ= heterozygous deficiency, and ZZ= homozygous deficiency. Hereditary deficiency only accounts for a minor part of emphysema. In the population with the susceptible phenotypes (MZ and ZZ), smokers develop emphysema 20 years sooner than non-smokers. Smokers with the phenotype PiZ are at a high risk of developing emphysema.

    Symptoms and signs

    The patient complains of smoker’s cough with large morning expectoration (ie, large quantities of sputum - purulent during

    exacerbation). Fog and pollution worsen the condition. As the lung function deteriorates, breathlessness (dyspnoea) becomes so severe that even dressing or tooth brushing feels like heavy exercise.

    The patient expires for a long time and with a snapping inspiration. The intercostal space is drawn in under inspiration and the

    accessory respiratory muscles are active. The lungs are hyperinflated and extend between the heart and the chest wall. Some patients are thin ―pink puffers‖ or ―type A emphysematous fighters‖. Despite their severe dyspnoea, their arterial blood gasses are close to normal (point i in Fig. 14-7). They are often emphysematous with over-expanded lungs but with little bronchitis. As the term implies these patients are not cyanosed.

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