Pathophysiology of the respiratory system I Structural properties of airways and lungs Defense mechanisms of the respiratory system Respiration and gas exchange - ventilation & diffusion & perfusion Pulmonary mechanics Ventilation - perfusion (in)equality Control of ventilation Bronchus Cut end of rib Lun.q Pleural membranes Alveoli Pleura] fluid Bronchiole Figure 17.1 Diagrammatic view of human respiratory system (Sectional view of the left lung Is also shown) 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 • lungtissue 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 Structure of airways Sourca; M&>hmm SJ. Q*nong WFi Pttttophy siet&gy of Dis*»x*. An lAtr&ductwn to ClutKaf M+dtdn*, 3th Edition: http »cc« c smtdmn* com Copyright 6 Th* Mfjuv-Hill Comp *m«i. Inc Alt right* r*f*rv*d. 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 Wall structure of conducting conducting airways and alveolar region Mucus blanket Cilia- Goblet cell -Pseudostratified epithelium- Smooth muscle Mucous gland Submucosal connective tissue Cartilage BRONCHUS BRONCHIOLE Simple epithelium ALVEOLUS Alveoli There are approximately 300-400 million alveoli in each lung with the J£fralwy 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 Macrophage C ElMvler Seien« Ltd 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 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 Fluid Air Type I pneumocyte Cuiton. Option in '-......i .n 8 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. ©2010 by American Physiological Society Perez-Gil J , Weaver T E Physiology 2010;25:132-141 Pulmonary vasculature and lymphatics 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 arranged in five main groups: • paratracheal, superior tracheobronchial, subcarinal, bronchopulmonary and pulmonary Defense mechanisms of the resp. tract These can be divided into two kinds of mechanisms: — physical • humidification • particle removal — over 90% of particles greater than 10 u.m diameter are removed in the nostril or nasopharynx (incl. most pollen grains which are typically >20 microns in diameter) — particles between 5 -10 microns become impacted in the carina — particles smaller than 1 micron tend to remain • mucus • particle expulsion — by coughing, sneezing or gagging — immunological • humoral • cellular Pulmonary disease often results from a failure of the many defense mechanisms that usually protect the lung in a healthy individual Luminal eel-—___ eg- ~ macrophage J lymphocyte polymorph Lumen Sol phase Epithe urn Secretory component Secretory IgA Lamina propria Basement membrane IgG IgA + J í Mucus gland Plasma cells p Elsevier Science Ltd 11 The ciliated epithelium Spoke Very important defense mechanism Each cell contains approx. 200 cilia beating at 1000 beats per minute in organized waves of contraction Each cilium consists of nine peripheral pairs and two inner longitudinal fibrils in a cytoplasmic matrix — nexin links join the peripheral pairs — dynein arms consisting of ATPase protein project towards the adjacent pairs. Bending of the cilia results from a sliding movement between adjacent fibrils powered by an ATP-dependent shearing force developed by the dynein arms — congenital absence of dynein arms leads to immotile cilia, syndrome Dynein arm Mucus, which contains macrophages, cell debris, inhaled particles and bacteria, is moved by the cilia towards the larynx at about 1.5 cm/min (the „mucociliary escalator") Nexin link 12 Respiratory tract secretions - mucus Humoral defense mechanisms gelatinous substance (~5 mm thick) consisting of acid and neutral polysaccharides relatively impermeable to water - mucus floats on a liquid or sol layer that is present around the cilia of the epithelial cells secreted from goblet cells and mucous glands as distinct globules that coalesce increasingly in the central airways to form a more or less continuous mucus blanket under normal conditions cilia are in contact with the under surface of the gel phase and coordinate their movement to push the mucus blanket upwards - it may only take 30-60 minutes for mucus to be cleared from the large bronchi - there may be a delay of several days before clearance is achieved from respiratory bronchioles reduction in mucociliary transport - one of the major long-term effects of cigarette smoking • contributes to recurrent infection and in the larger airways it prolongs contact with carcinogens - air pollutants, local and general anaesthetics - bacterial and viral infections - congenital defects in mucociliary transport (characterized by recurrent infections and eventually with the development of bronchiectasis) • the 'immotile cilia' syndrome and cystic fibrosis: an abnormal mucus composition is associated with ciliary dyskinesia 13 • Non-specific soluble factors — characteristic for lungs • a-Antitrypsin (a-antiprotease) — present in lung secretions derived from plasma — inhibits chymotrypsin and trypsin and neutralizes proteases and elastase • Surfactant protein A (SPA) — one of four species of surfactant proteins which opsonizes bacteria/particles, enhancing phagocytosis by macrophages — generally found on biological barriers • Lysozyme — an enzyme found in granulocytes that has bactericidal properties • Lactoferrin — synthesized from epithelial cells and neutrophil granulocytes and has bactericidal properties. • Interferon (produced by most cells in response to viral infection) — a potent modulator of lymphocyte function. It renders other cells resistant to infection by any other virus. • Complement — present in secretions and is derived by diffusion from plasma — in association with antibodies, it plays an important cytotoxic role • Defensins — bactericidal peptides present in the azurophil granules of neutrophils 14 Cellular defense mechanisms Pulmonary alveolar macrophages — derived from precursors in the bone marrow and migrate to the lungs via the bloodstream — phagocytose particles, including bacteria, and are removed by the mucociliary escalator, lymphatics and bloodstream — dominant cell in the airways at the level of the alveoli • comprise 90% of all cells obtained by bronchoalveolar lavage — work principally as scavengers and are not particularly good at presenting antigens to the immune system Dendritic cells — form a network throughout the airways and are thought to be the key antigen-presenting cell in the airway Lymphoid tissue — the lung contains large numbers of lymphocytes which are scattered throughout the airways. Sensitized lymphocytes contribute to local immunity through differentiation into IgA-secreting plasma cells. IgG and IgE are found in low concentrations in airway secretions from a combination of local and systemic production. — In addition to these resident cells, the lung has the usual range of acute inflammatory responses and can mobilize neutrophils promptly in response to injury or infection and play a major part in inflammatory conditions such as asthma. 15 Summary - lung defense 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 0.- transport COa Uansport Gas diffusen Tissues m o/Ff** % Trachea up and out Spine -Diaphragm Lung inflated Diaphragm curved down VENTILATION & PULMONARY MECHANICS 17 18 Mechanika dýchání Ventilation Inspiration Expiration \ Volume (L) / • tlaky a tlakové gradienty ■ \ / — tlak na povrchu těla (Pbs), většinou totožný s atmosferickým (Pao) \ — tlak v alveolu (PaJ r Intrapleural i > 1 pfessure i S \ CcmHjO) i / — „elastický" tlak vyvíjený parenchymem plic a povrch. A / napětím (Pel) — tlak v pleurální dutině (Pp|) — transpulmonální tlak = tlakový Flow / \ (Us) ; / \ rozdíl mezi alveolem a pleurální _Y \ dutinou (PL) \ P vy — transtorakální tlak = rozdíl mezi Alveolar /"""N, alveoly a tělesným povrchem (Prs), (cm H;0) / \ určuje zda probíhá inspirium nebo expirium • • p - p .p rrs ralv rbs PB = 0 End of expiration Pb = Palv No air movement Pb = 0 I During inspiration Pb > Palv Air moves in Thorax P=iv = 0 expands jj (alveolar volume * increases) Diaphragm contracts 1. Barometric air 2. Increased thoracic volume results in increased alveolar volume and decreased alveolar pressure. Barometric air pressure is greater than alveolar pressure, and air • moves into the lungs. pressure (PB) is equal to alveolar pressure (Pai„) and there is no air movement. Hill Companies, Inc. 19 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 02 consumption) but increases dramatically when resistance increases (up to 30%) —» subjective perception as a dyspnea 20 Ventilation (breathing) as a mechanical process Volume of breath 4 seconds elapsed Inspiration +2 IE e É Of-S ž , e S "2 5» . S o £ e o. b -8 Expiration Intrapulmonary pressure CopyrighiOSOOl Benjamin Cumniinss. an imprint of Addison WesJey Longman, Ii Inspiration - an active process that results from the descent of the diaphragm and movement of the ribs upwards and outwards underthe influence of the intercostal muscles • in resting healthy individuals, contraction of the diaphragm is responsible for most inspiration - respiratory muscles are similarto 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, allowingthe lungs to collapse underthe influence of their own elastic forces (elastic recoil) - forced expiration is also accomplished with the aid of accessory muscles • abdominal wall 21 Elastic properties of the lung 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 o ä 50- TRANSMURAL PRESSURE (cm H20) TLC (full breath in) 6 f~ Elastic recoil is determined by two kinds of forces Closing -30 -20 -10 0 +10 +20 +30 +40 Alveolar pressure - Intrapleural pressure (cmH20} lung compliance ("distensibility") — 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) PaT/r (Law of Lapiacej 23 Lung Volumes and Capacities Maximum possible inspiration Tidal volumo set by opposing recoil forces of the chest and lungs and the effort of respiratory muscles 25 Abnormalities of elastic properties change of lung compliance (J'TLC, -l FRC, -l RV) — T pulmonary emphysema, aging (T TLC, T FRC, T RV) — I interstital disease (^TLC, I FRC, I RV), e.g. pulmonary fibrosis or bronchopneumonia lack of surfactant (4 26 Medium-sized bronchi \ Terminal bronchioles Airflow 5 10 15 20 23 Airway generation (stage of branching) 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 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! 27 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 (PpJ — 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 u 10 8 1 6 o S 4 h S 0 ä Peak expiratwy flow The relationship between maximal flow rates on expiration and inspiration is demonstrated by the maximal flow-volume (MFV) loops 28 Airflow obstruction Other examples of flow-volume loops 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 Flow-Volume Loops .PCFR Normal 29 30 Airway 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 ■>.-„.■■ ■ law 8/7/ 70" Q • Flaw iiaj iP ■ Pt - P, ' Jl n•vncouty I ■ length Airflow resistance - bronchoconstriction Q = AP R Q = aPnr* Q Flow raw p assure i Radius n Fluid vjyro&itv i : i'h-j-'ühMilImtim Q = kW 877/ (b) Brorichoconstfiction vr=0.5> (0.5)" 16 = 0.1 Bronchocorslriction (0.9) 1 (0,24)" = 0.26 r = 0.24 = 300 Current Opinion in Pharmacology 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 31 32 Dynamic compression In forced expiration, the driving pressure raises both the PALVand 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' A. PromsptratKXi B. During irupration C.EmHnpimwn Dynamic Airway Collapse Forced expiration Narrow cartilagen ous bronchus (equal pressure point) Expiration P„=0 Total energy = (h*p *G+ VipV+P^JdV Bronchiole Expiratory effort — Increased kinetic energy — Reduced lateral pressure — Dynamic Airway Collapse Fig. 13-5 KMC D.F»i*d 33 Dynamic compression in various situations la) Retting Intrapleural pressure p,..is O - 1-0.5) ♦ (♦0.5) Norma, restos (b) Forced expiration [normal) No.5 .2.5 +2.S « *2 * 0.5 (c) Forced «xpiraäon (airflow Normal dynamic (compression) oithrrv» and COPO) .2.0 »1.5 J 0.13kPa (lmmHg) = kritická tenze kyslíku organizmus potřebuje kyslík: — cca 250ml/min —» 3501/den v klidu — při zátěži mnohem více Význam kyslíku v organizmu vnéjSÍ mitochondrial™ membráne vilitrni ^mmimmmmnb^hů^^^^^^^^_ ATP-$yntetáz3 nitochondrialni membrána pyruvát mastná kyseliny 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 lOs • 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 p02 méně kritický — hydroxylace steroidů — detoxikace (hydroxylace) cizorodých látek v játrech — syntéza oxidu dusnatého (—> vazodilatace) — degradace hernu hemoxygenázou Sumárně: plíce jako součást „02 dráhy" difúzni dráha Ventilation-perfusion inequality A Physiological deadspace Ventilation with reduced perfusion V<5=>i B Normal Ventilation and perfusion vo= i Causes Pulmonary embolism Pulmonary arteritis Necrosis or fibrosis (loss of capillary bed) C Physiological shunt Perfusion with reduced ventilation V0 © Elsevier Science Ltd 47 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 alveolu s redukovanou perfuzí (tzv. fyziologický mrtvý prostor, VQ = 3.3) — báze: perfuze alveolu s redukovanou ventilací (fyziologický zkrat, V^/Q = 0.7) ventilačně perfuzní (VA/Q) nepoměr se významně zvyšuje u některých plicních nemocí a zodpovídá za jejich projevy — T VA/Q poměru (tj. T mrtvého prostoru) • např. plieni embólie poměru (tj. T plicního zkratu) • obštrukční nemoci plic • kolaps plíce optimalizace 4- VA/Q - vazokonstrikční reflex — cévy okolo méně ventilované části plíce se kontrahují — ale!!! viz důsledky obstr. nemocí Top of Lung Bottom of Lung Ventilation-Perfusion Ratio 3 2 1 l/mif! % of lung volume CONTROL OF RESPIRATION & ITS DISORDERS 48 Control of respiration Other receptors (e.g, pain} and emotional stimuli acting through the hypothalamus Higher brain centers (cerebral cortex-voluntary control over breathing) Respiratory centers (medulla and pons) central chemoreceptors in medulla oblongata H* —Cerebrospinal fluid (CSF) Copyright £2001 Benjamin Cummings. an imprint ot Addison Wesley Longman, inc. peripheral chemoreceptors in aorta and glomus caroticum (via n. glossopharyngeus and vagus) — active when 4Pa02 below lOkPa — activation supported by hypercapnia pulmonary mechanoreceptors 49 Central chemoreceptors Cerebral capillary Q tpco2 r C02 + H20*; H2C0Ä H* + HC03" CA Blood-brain barrier Cerebrospinal fluid Medulla KEY Stimulus Receptor Afferent pathway Q Integrating center Systemic response sensitive to tPaC02 (and subsequent formation of H+in CF) H+ cannot go through hematoencephalic barrier therefore response to olther than respiratory acidosis slower — increase in [H+] due to metabolic acidosis (e.g. diabetic ketoacidosis) will subsequently increase ventilation with a fall in PaC02 causing deep (Kussmaul) respiration very quick adaptation to acute or intermittent hypercapnia, however, gets adapted to chronic hypercapnia due to tiHC03- in cerebrospinal fluid — problem in COPD - in these patients hypoxaemia is the chief stimulus to respiratory drive — oxygen treatment may therefore reduce respiratory drive and lead to a further rise in PaCO, 50 Peripheral chemoreceptors - oxygen senzors Blood vessel Dopamine receptor in sensory neuron £% Signal to medullary centers to increase Glomus caroticus and aortic bodies -sensitive to change of Pa02 — decrease of 0, in these cells closes K+ channels depolarization T intracellular Ca2+ —> excitation—>■ activation of the respiratory centre When hypoxemia is not accompanied with hypercapnia, activation of this sensors is when Pa02<7,3 kPa (55 mm Hg) 51 Respiratory stimuli Coordinated respiratory movements result from rhythmical discharges arising in interconnected neurones in the reticular substance of the brainstem (medulla oblongata), known as the respiratory centre - via the phrenic and intercostal nerves to the respiratory musculature (principal and aucilliary respiratory muscles) TIDAL VOLUME -500 ml VOLUMES ANATOMIC DEAD SPACE 150 ml MINUTE VOLUME 7.500 ml/min FLOWS ALVEOLAR GAS 3,000 ml PULMONARY CAPILLARY BLOOD 70 ml PULMONARY •>.> BLOOD FLOW 5.000 11 m n - the pulmonary blood flow of 5 L/min carries 11 mmoi/min (250 ml/min) of oxygen from the lungs to the tissues - ventilation at about 6 L/min carries 9 mmol/min (200 ml/min) of carbon dioxide out of the body - normal Pa02 is between 11 and 13 kPa (83 - 98 mmHg) - normal PaC02 is 4.8-6.0 kPa (36-45 mmHg) 52 Emotions and voluntary controi I Medullary Carotid and aortic chemoreceptors chemoreceptors Stimuli Integrating centers I I Sensory receptors [ i Efferent neurons Afferent neurons | | Effectors Respiratory centres Chemoreceptors Aortic and carotid bodies o a