Respiratory physiology

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Information about Respiratory physiology
Health & Medicine

Published on March 15, 2014

Author: bilalnatiq


Physiology of Respiratory system Dr.Bilal Natiq Nuaman Lecturer at Ibn-Sina Medical College C.A.B.M. ,F.I.B.M.S. ,D.I.M. ,M.B.Ch.B. 2014

The respiratory system is divided anatomically to : 1-upper respiratory tract : The airway from the nose through the larynx (the respiratory organs in the head and neck) 2- lower respiratory tract : The regions from the trachea through the lungs (the respiratory organs of the thorax)

Respiratory System

The respiratory system is divided functionally to : The conducting division : consists of those passages that serve only for airflow, essentially from the nostrils through the bronchioles. The respiratory division : consists of the alveoli and other distal gas-exchange regions.

Respiratory System Functions • Gas exchange: Oxygen enters blood and carbon dioxide leaves • Regulation of blood pH: Altered by changing blood carbon dioxide levels • Voice production: Movement of air past vocal folds makes sound and speech • Olfaction: Smell occurs when airborne molecules drawn into nasal cavity • Protection: Against microorganisms by preventing entry and removing them

Non-Respiratory Lung Functions • Filter for circulation: – thrombi, microaggregates etc • Metabolic activity: – activation: • angiotensin III – inactivation: • noradrenaline • bradykinin • 5 H-T • some prostaglandins • Immunological: – IgA secretion into bronchial mucus

The Respiratory Defense System • Consists of a series of filtration mechanisms • Removes particles and pathogens Components of the Respiratory Defense System • Goblet cells and mucous glands: produce mucus that bathes exposed surfaces • Cilia: sweep debris trapped in mucus toward the pharynx (mucus escalator) • Filtration in nasal cavity removes large particles • Alveolar macrophages engulf small particles that reach lungs

The main (vital) function of the respiratory system is to provide oxygen (O2) to the tissues and to remove carbon dioxide (CO2) generated during metabolism. Internal respiration: is the exchange of these gases (O2 & CO2) between tissue cells and their fluid environment. External respiration: is the exchange of these gases (O2 & CO2) between the body and the external environment.

• The term respiration includes 3 separate functions: – Ventilation: Movement of air in and out of the lungs – Gas exchange: • Between alveoli and capillaries in the lungs. • Between systemic capillaries and tissues of the body. – 0xygenutilization: • Cellular respiration.

Ventilation • Mechanical process that moves air in and out of the lungs. • [O2]of air is higher in the lungs than in the blood, O2 diffuses from air to the blood. • C02 moves from the blood to the air by diffusing down its concentration gradient. • Gas exchange occurs entirely by diffusion: – Diffusion is rapid because of the large surface area and the small diffusion distance. Insert 16.1

Mechanics of Pulmonary Ventilation I-Muscles of Respiration: Respiratory cycle includes inspiration and expiration.  1- Muscles of inspiration: Inspiration is active during which the respiratory muscles contract. Inspiratory muscles involved: A- Diaphragm : It is important muscle for inspiration, when it contracts; it pulls the lower surfaces of the lungs downward. As it become flattened, it pushdown the abdominal contents thus, it lengthen the chest cavity i.e. increasing the volume of thoracic cavity. B- External intercostals : When they contract, ribs and sternum move upward & outward thus, they increase the anterioposterior diameter of the chest.

C- Accessory muscles include: 1-Sternocleidomastoid muscles which lift upward on the sternum. 2-Trapezius, which lift many of the upper ribs. 3-Scaleni muscles which lift the first two ribs. These accessory muscles are not used for inspiration during normal quiet breathing rather than they are used during exercise or in diseased conditions like in Bronchial asthma.

2-Muscles of expiration: Expiration is normally passive, brought about by: 1-Relaxation of inspiratory muscles (external intercostals). Thus the ribs and sternum move downwards and inwards so the width of the chest diminishes. When diaphragm relaxes, it ascends thus, diminishes the length of the chest. 2-Elastic recoil of the lung, it returns to its resting position after inspiration. However expiratory muscles are used during heavy breathing, exercise & in diseases as in bronchial asthma. They include: A- Abdominal recti: Which have powerful affect of pulling downward on the lower ribs. At the same time compress the abdominal contents upward toward the diaphragm to push the air out. B- Internal intercostals: Which pull the ribs downward & inward.

II – Pressure gradient between atmosphere and lung : Atmospheric pressure: Is the pressure of the air surrounding the body or at the nose and mouth, it is 760mmHg at sea level . Pressure changes during respiratory cycle: Air will move or flow from region of high pressure to one of low pressure. Therefore air enters the lungs during inspiration because pressure within the lungs (alveolar pressure) is less than that of atmospheric pressure. Conversely during expiration, the alveolar pressure exceeds atmospheric pressure and air expelled.

Boyle’s Law • Changes in intrapulmonary pressure occur as a result of changes in lung volume. Pressure of gas is inversely proportional to its volume. • Increase in lung volume decreases intrapulmonary pressure. • Air goes in. • Decrease in lung volume, raises intrapulmonary pressure above atmosphere. • Air goes out.

Alveolar Pressure Changes

Inspiration Active process – requires ATP for muscles contraction

Expiration Passive process –muscles relax

III -Physical properties that affect lung function Compliance.Compliance. Elasticity.Elasticity. Surface tensionSurface tension

Lung compliance: (Expansibility) Is the change in volume per unit change in pressure The compliance of both lungs together is normally about 200ml/cmH2O which mean a 1cmH2O change in intrapleural pressure causes the lungs to change their volume by 200ml. The greater the lung compliance, the easier it is to expand the lung at any given transpulmonary pressure, a low lung compliance mean that greater than normal transpulmonary pressure must be developed to produce a given lung expansion; this is performed by more vigorous contractions of inspiratory muscles.

Compliance generally reduced in all diseases affecting the lung, bronchial tree and thoracic cage as in case of pulmonary edema, fibrosis, bronchial obstruction (e.g., Bronchial asthma), except in emphysema, lung compliance increased.

Elasticity • Tendency to return to initial size after distension. • High content of elastin proteins. Very elastic and resist distension. • Elastic tension increases during inspiration and is reduced by recoil during expiration.

Surface Tension • Force exerted by fluid in alveoli to resist distension. • Lungs secrete and absorb fluid, leaving a very thin film of fluid. – This film of fluid causes surface tension. – Fluid absorption is driven (osmosis) by Na+ active transport. – Fluid secretion is driven by the active transport of Cl- out of the alveolar epithelial cells. • H20 molecules at the surface are attracted to other H20 molecules by attractive forces. – Force is directed inward, raising pressure in alveoli.

Surface Tension • Law of LaplaceLaw of Laplace:: – Pressure in alveoli is directly proportional to surface tension; and inversely proportional to radius of alveoli. – Pressure in smaller alveolus would be greater than in larger alveolus, if surface tension were the same in both. Insert fig. 16.11

Surfactant • Phospholipid produced by alveolar type II cells. • Lowers surface tension. – Reduces attractive forces of hydrogen bonding by becoming interspersed between H20 molecules. – Surface tension in alveoli is reduced. • As alveoli radius decreases, surfactant’s ability to lower surface tension increases. • Disorders: – RDS. – ARDS. Insert fig. 16.12

Function of Surfactant: 1-Reduces the surface tension of alveolar fluid. 2-Stabilizing the size of the alveoli: When the alveolus becomes smaller, it’s surfactant become more concentrated so that it’s surface tension more reduced preventing further decrease in it’s size and vise versa, i.e., when alveolus becomes larger, surfactant less concentrated, the surface tension becomes much greater tending to reduce it’s size. So surfactant helps to stabilize the size of the alveoli causing larger alveoli to contract more and smaller alveoli to contract less. This effect helps to ensure that the alveoli in any one area of the lung all remain the same size. 3-preventing accumulation of edema fluid in the alveoli (help to keep alveoli dry): Since the surface tension also tends to draw fluid into the alveoli causing alveolar edema but this drawn amount of fluid normally reabsorbed again into the interstitioum.

Structure of the respiratory tree: • The term upper respiratory tract: refers to the nasal cavity, pharynx and associated structures. • • The term lower respiratory tract : includes larynx, trachea, bronchi, bronchioles and alveoli.

Respiratory functions of the nose: 1-Warming of the air by conchea and septum surface (160 cm2 area). Rises in temperature to within ( 1o F) of body temperature. 2-Humidification of air: i.e., saturation with H2O vapors. These above functions together are called air conditioning function of upper respiratory passageways. 3-Filtration of air by: A-The hairs. B-Turbulent precipitation by obstructing walls of conchae, pharynx and septum. C-Entrapment of foreign particles in the mucous coat and transported by the cilia toward the pharynx to be swallowed.

DEFENCE MECHANISMS OF THE RESPIRATORY TRACT • Physical and physiological mechanisms Humidification This prevents dehydration of the epithelium. Particle removal Over 90% of particles greater than 10 μm diameter are removed in the nostril or nasopharynx. This includes 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 airborne, thus the particles capable of reaching the deep lung are confined to the 1-5 micron range. Particle expulsion This is effected by coughing, sneezing or gagging.

Size of particles entrapped in the respiratory passages: 1- > 6 µm (micrometer) by nasal turblent mechanism. 2-1-5 µm settles out in smaller bronchioles as in case of coalminers by gravitational precipitation. 3-< 1 µm adhere to the alveolar fluid. 4-< ½ µm suspended in alveolar air and expelled by expiration like the particles of cigarette smoke. However 1/3 of them do precipitate in the alveoli by diffusion process (harmful effect of smoking). 5- Many of the particles that become entrapped in the alveoli are removed by alveolar macrophages, others removed by Lymphatics. An excess of particles causes growth of fibrous tissue in the alveolar septa leading to permanent damage (debility).

Respiratory tract secretions The mucus of the respiratory tract is a gelatinous substance consisting chiefly of acid and neutral polysaccharides. The gel layer is 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 the tips of the cilia are in contact with the under surface of the gel phase and coordinate their movement to push the mucus blanket upwards. Whilst 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. One of the major long-term effects of cigarette smoking is a reduction in mucociliary transport. This contributes to recurrent infection and in the larger airways it prolongs contact with carcinogens.

Humoral and cellular mechanisms  Non-specific soluble factors α1-Antitrypsin is present in lung secretions derived from plasma. It inhibits chymotrypsin and trypsin and neutralizes proteases and elastase. Antioxidant defences include enzymes such as superoxide dismutase and low-molecular-weight antioxidant molecules (ascorbate, urate) in the epithelial lining fluid. In addition, lung cells are protected by an extensive range of intracellular defences, especially members of the glutathione S- transferase (GST) superfamily. Lysozyme is an enzyme found in granulocytes that has bactericidal properties. Lactoferrin is synthesized from epithelial cells and neutrophil granulocytes and has bactericidal properties.

Interferon is produced by most cells in response to viral infection. It is a potent modulator of lymphocyte function. It renders other cells resistant to infection by any other virus. Complement is present in secretions and is derived by diffusion from plasma. In association with antibodies, it plays a major cytotoxic role. Surfactant protein A (SPA) is one of four species of surfactant proteins which opsonizes bacteria/particles, enhancing phagocytosis by macrophages. Defensins are bactericidal peptides present in the azurophil granules of neutrophils.  Pulmonary alveolar macrophages These are derived from precursors in the bone marrow and migrate to the lungs via the bloodstream. They phagocytose particles, including bacteria, and are removed by the mucociliary escalator, lymphatics and bloodstream.

The uvula has two main functions : It blocks the passage into the nasal cavity when swallowing. This ensures that foods or fluids do not enter the nasal passages. It plays a role in articulation – assisting with the speech

During the process of swallowing, as soon as the bolus reaches the pharynx, it triggers the contraction of extrinsic muscles. As a result, the entire larynx moves upwards. Due to this shift, the epiglottis comes in contact with the base of the tongue, and gets lowered to block the glottis.

• The lungs are the principle organs of the respiratory system. They form the surface over which O2 is absorbed and CO2 is excreted. During quiet breathing air normally taken in through the nose which is able to trap particles of air dust and to moisten and warm the air during its passage to the lungs. • The trachea of an adult is about (2cm) in diameter and (12cm) in length, it is the first part of respiratory tree. In the upper chest, the trachea branches into two primary (main) bronchi at the level of the angle of the sternum ,Each continues for 2 to 3 cm and enters the hilum of its respective lung. • The right bronchus is slightly wider and more vertical than the left; consequently, aspirated (inhaled) foreign objects lodge in the right bronchus more often than in the left.

After entering the hilum, the primary bronchus branches into one secondary (lobar) bronchus for each pulmonary lobe. Thus, there are two secondary bronchi in the left lung and three in the right. Each secondary bronchus divides into tertiary (segmental) bronchi—10 in the right lung and 8 in the left.

• Within each lobe, the bronchi divided more and more until we obtained what is called bronchioles, terminal bronchioles, respiratory bronchioles and alveolar ducts, from which the gas exchange structure arise which are the alveolar sacs, which consist of the two or more alveoli.

• The trachea and pulmonary bronchi have C- shaped rings of cartilage while the bronchioles have not.

From a functional point of view, the morphology of the human airways was greatly clarified by the studies of Weibel. He measured the number, length, width, and branching angles of the airways, and he proposed models that, although they are idealized, make pressure-flow and other analyses much more tractable.

Weibel model

The first seven divisions are bronchi that 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 and produce serotonin .

• The next 16 divisions are bronchioles that have: no cartilage and a muscular layer that progressively becomes thinner a single layer of ciliated cells but very few goblet cells granulated Clara cells that produce a surfactant-like substance.

• In all area of the trachea and bronchi not occupied by cartilage plates, the walls are composed mainly of smooth muscles. • The walls of the bronchioles are almost entirely smooth muscles, with the exception of respiratory bronchioles that have only a few smooth muscle fibers. • Many obstructive diseases of the lung result from excessive contraction of the smooth muscle itself. • The chief site of airway resistance in the airway passages is at the medium-size segmental bronchi (segments related to the lung) where the radius of the individual bronchi is decreased. • The least resistance to air flow is in the very small bronchioles and terminal bronchioles because of their large cross sectional area.

These smooth muscles are under nervous and humoral control: 1-Nervous and local control of the bronchiolar musculature: *Sympathetic stimulation: direct control of the bronchioles by sympathetic nerves fibers is relatively weak, because few of these fibers penetrate to the central portions of the lung. However, the bronchial tree is very much exposed to circulating norepinephrine (noradrenaline) and epinephrine (adrenaline) released into blood by sympathetic stimulation of the adrenal medulla (suprarenal glands) causing bronchodilatation through stimulation of B2 receptors which are distributed over the bronchial tree.

*Parasympathetic stimulation: parasympathetic nerve fibers of vagus nerves secrete acetylcholine and when activated cause mild to moderate constriction of the bronchioles. In asthma, parasympathetic superimposed stimulation often worsens the condition, that is why anticholinergic drugs like atropine, can sometimes relax the respiratory passages enough to relieve the obstruction. Local reactions that cause bronchoconstriction mediated through a parasympathetic reflexes that originate in the lungs through irritant receptors of the epithelial membrane of respiratory passageways occurs by noxious gases, dust, cigarette smoke, or bronchial infection, and microemboli of small pulmonary arteries.

• Parasympathetic (from the vagus) and sympathetic (from the adjacent sympathetic chain) nerve supplies a plexus at the nerve root and branches accompany the pulmonary arteries and the airways. • Airway smooth muscle is innervated by vagal afferents, postganglionic muscarinic vagal efferents and vagally derived non-adrenergic non-cholinergic (NANC) fibres. Neurotransmitters (peptides and purines) may be involved. • Three muscarinic receptor subtypes have been identified: M1 receptors on parasympathetic ganglia, a smaller number of M2 receptors on muscarinic nerve terminals, and M3 receptors on airway smooth muscle. The parietal pleura is innervated from intercostal and phrenic nerves but the visceral pleura has no innervation.

2-Humoral control of the bronchioles: Local factors often cause bronchoconstriction. Two of the most important substances that causes bronchoconstriction are histamine and slow reactive substance of anaphylaxis (SRA) that are released in the lung tissues by mast cells during allergic reactions as in case of allergic asthma. Also the same irritants that cause parasympathetic vasoconstrictor reflexes of the airways like smoke, dust, SO2 (sulfur dioxide) can initiate local, non-nervous reactions that cause bronchoconstriction. In addition, the airway smooth muscle is highly responsive to blood CO2 level in such way that high blood CO2 (hypercapnia) produce bronchodilatation and low blood CO2 level (hypocapnia) produce bronchoconstriction. •

Cough Reflex: The trachea and bronchi are so sensitive to light touch by foreign material. The larynx, carina (tracheal bifurcation), terminal bronchioles and even alveoli are sensitive to corrosive chemicals such as SO2 and chlorine. Afferent impulses pass from the respiratory passages through the vagus nerves to the medulla, there in medulla, an automatic sequence of events occur causing the following effects: 1- 2.5 liters of air inspired. 2- The epiglottis closes. To trap air inside 3- Vocal cords shut tightly. the lung 4-Abdominal muscles contract forcefully. Expiratory muscles contract forcefully (internal intercostals). Consequently, the pressure in the lungs rises to more than 100 mmHg.

5- Vocal cords and epiglottis suddenly open widely by the high pressure in the airways so the air under pressure in the lungs explodes outward at a velocity of 75-100 miles/hour. 6- Invagination of noncartilaginous parts of bronchi and trachea brought about by the strong compression of the lungs, so the air actually passes through bronchial and tracheal slits that increase the air movement carrying foreign or any material outside the bronchi or trachea. This reflex dislodges some of the mucus covering the epithelium of the airways and helps to carry the irritant away with it via the mouth or nose. •

Sneeze Reflex: The sneeze reflex is very much similar to cough reflex but it applies to the nasal passageways. It is initiated by irritation of the nasal passageways. Here, the afferent impulses passing in the 5th nerve (trigeminal nerve) to the medulla oblongata where the reflex is triggered. A similar cough sequence of events occurs. However, the uvula is depressed so that large amount of air passes rapidly through the nose to clear the nasal passageways of foreign matter.

PULMONARY CIRCULATION The lung is unusual in having a dual blood supply. It receives deoxygenated blood from the right ventricle via the pulmonary artery and also has a systemic supply via the bronchial circulation.  The pulmonary artery divides to accompany the bronchi. The arterioles accompanying the respiratory bronchioles are thin- walled and contain little smooth muscle. The pulmonary venules drain laterally to the periphery of the lobules, pass centrally in the interlobular and intersegmental septa, and eventually join to form the four main pulmonary veins.  The bronchial circulation arises from the descending aorta. These bronchial arteries supply tissues down to the level of the respiratory bronchiole. The bronchial veins drain into the pulmonary vein, forming part of the physiological shunt observed in normal individuals.

Pulmonary vessels include: -Pulmonary Artery: (trunk) with its left and right divisions, carrying deoxygenated systemic venous blood pumped out of the right ventricle. -Pulmonary Veins: drain oxygenated blood from lungs into left atrium. -Bronchial Vessels: carry oxygenated blood, emerge from aortic arch, their blood volume represent 1-2 % of cardiac output. They supply the supporting tissues of the lungs which include the connective tissues and septa, in addition to the large and small bronchi. They drain again into left atrium through pulmonary veins.

Pulmonary Pressures: 1-The right ventricle average normal pressure is 25/4mmHg (systolic/diastolic). 2-Pulmonary artery pressure is equal to right ventricle pressure, 25/10 mmHg (mean=15 mmHg). 3-Pulmonary capillary pressure is about 7 mmHg as a mean (low; its importance being in relation to fluid exchange functions of the capillary). 4-Left atrial and pulmonary veins pressure range 8-10 mmHg

Lymphatic vessels: from supportive tissues of the lungs beginning round terminal bronchioles and coursing to the hilum of the lung to be drained into the Right Lymphatic Duct. In other words, lymphatics of the lungs drain to the right side, it’s clinical importance is that metastasis of left lung carcinoma could occur to the right lung through lymphatic spread but not the opposite. Particles entering the alveoli are partly removed; plasma protein leaking from lung capillaries is also removed from the lung tissues by these lymphatic channels, thereby helping to prevent edema.

Blood volume of the lungs: The blood volume of the lungs is about 450ml, represents about 9% of the total blood volume of the circulatory system. About 70 ml of this is in the capillaries, and remainder (380 ml) in the pulmonary arteries and veins. Lungs as a blood reservoir: lungs serve as blood reservoir i.e., there is a shift of blood from the lungs into the systemic circulation in case of: 1-Blowing (when a person blows out air so hard such as when blowing a trumpet). There is a shift of 250ml of blood from the lungs into systemic circulation. 2-Hemorrhage (bleeding) which can be partly compensated by automatic shift of blood from the lungs into the systemic circulation.

Blood Flow through the Lungs: This is achieved by the following mechanism: 1-Automatic control of pulmonary blood flow: In such away that low O2 concentration leads to local (alveoli) vasoconstriction. This is opposite to systemic circulation in response to hypoxia i.e., vasodilatation. Local vasoconstriction to low O2 level < 70% of normal (Po2 < 70mmHg) induced by secretion of vasoconstrictor substance from alveolar epithelial cells when they become hypoxic. This response is protective i.e., allowing most blood to flow through areas of the lungs that are better aerated (good O2 level) from poorly aerated alveoli with low O2 concentration. Therefore, automatic control for distributing blood flow to different pulmonary areas is in proportion to their degree of ventilation.

2-Effect of alveolar pressure on pulmonary blood flow: Pulmonary capillaries blood flow affected by alveolar pressure as the capillaries are in the wall of the alveoli, they are distendable by the blood pressure inside them and as they are compressed by the alveolar pressure on their outsides. Therefore, any time the alveolar air pressure becomes greater than the capillary blood pressure, the capillaries close and there is no blood flow.

3-Effect of hydrostatic pressure gradients on regional pulmonary blood flow: In the normal, upright adult, the pulmonary arterial pressure in the uppermost (apex) portion of the lung are about 15 mmHg less than the pulmonary arterial pressure at the level of the heart, and the pressure in the lowest portion of the lung is about 8 mmHg greater, such pressure differences (23 mmHg) have profound effect on blood flow through the different areas of the lungs. In such away that there is little blood flows in the top of the lung but about five times this much flow in the lower lung (base). In other words, the hydrostatic pressure (that is, by the weight of the blood itself) is higher on the base of the lung than the apex so more blood flow in the base of the lung (this is in upright posture).This base-to-apex gradation disappears on lying down and if supine, the blood flow is now greater in the gravity-dependent dorsal region.

Gravity Dependent distribution of pulmonary Perfusion

Zone I  corresponds to a region in which alveolar pressure exceeds vascular pressure, which results in essentially no perfusion. Zone II  is characterized by pulmonary artery pressure exceeding alveolar pressure, which in turn exceeds venous pressure. The driving pressure will then be arterial minus alveolar pressure.

Zone III,  both arterial pressure and venous pressure exceed alveolar pressure. The difference between arterial and venous pressure creates the driving force through this zone. Zone IV  In the bottom of the lung there is a decrease in blood flow that is explained by increasing interstitial pressure compressing extra-alveolar vessels

DIFFERENCES IN VENTILATION & BLOOD FLOW IN DIFFERENT PARTS OF THE LUNG In the upright position, ventilation per unit lung volume is greater at the base of the lung than at the apex. The reason for this is that at the start of inspiration, intrapleural pressure is less negative at the base than at the apex , and since the intrapulmonary intrapleural pressure difference is less than at the apex, the lung is less expanded. Blood flow is also greater at the base than the apex. The relative change in blood flow from the apex to the base is greater than the relative change in ventilation, so the ventilation/perfusion ratio is low at the base and high at the apex.

The ratio of pulmonary ventilation to pulmonary blood flow for the whole lung at rest is about 0.8 . The ventilation and perfusion differences from the apex to the base of the lung have usually been attributed to gravity; they tend to disappear in the supine position, and the weight of the lung would be expected to make the intrapleural pressure lower at the base in the upright position.

Hypoxic Pulmonary Vasoconstriction • compensatory mechanism aimed at reducing blood flow in hypoxic lung regions • Alveolar hypoxia • Vasoconstriction • Reduction in blood flow in hypoxic area • Diversion of blood to the oxygenated area • Normal arterial oxygen saturation maintained

Ventilation-Perfusion ratio • VA/Q • Both ventilation and perfusion increase down the lung due to gravity • However, perfusion increases at a more rapid rate than ventilation. Hence the ratio decreases. • 3.3 at the apices • Over ventilated but underperfused • 0.6 at the base • Over perfused but underventilated • Mean is 0.8

Pulmonary capillaries and interstitial fluid exchange dynamics: differences between pulmonary and non pulmonary capillaries 1-The pulmonary capillary pressure is low, about 7 mmHg in comparison with 17 mmHg in capillaries of peripheral tissues. 2-The interstitial fluid pressure in the lung is slightly more negative than in the peripheral subcutaneous tissues; the absorption pressure of fluid from the alveoli into the pulmonary interstitium is about (-8 mmHg). 3-The pulmonary capillaries are relatively leaky to protein molecules into the interstitial fluid so that the colloid osmotic pressure of the pulmonary interstitial fluid is about 14 mmHg, which is higher than that of peripheral tissues ( < 7mmHg).

The forces and net filtration pressure at the capillary membrane: Forces tending to cause movement of fluid from capillaries into the pulmonary interstitial fluid: Pulmonary capillary pressure………………. (7 mmHg) Interstitial fluid colloid osmotic pressure…... (14 mmHg) Negative interstitial fluid pressure………….. (8 mmHg)  Total outward force………………………… (29 mmHg) Forces tending to cause absorption of fluid into capillaries: Plasma colloid osmotic pressure ....………… (28 mmHg)  Total inward force ....………………………..(28 mmHg)

Thus, the normal outward forces are slightly greater than inward forces. The net mean filtration pressure at pulmonary capillary membrane can be calculated as +1mmHg (29- 28=1) which causes a slight continual flow of fluid from the pulmonary capillary into the interstitial spaces which pumped back to circulation (venous) through the pulmonary lymphatic system in the interstitial spaces. Negative interstitial pressure helps to keep the alveoli dry: The pulmonary capillaries and pulmonary lymphatic system normally maintain a slight negative pressure in interstitial spaces. So whenever extra Fluid appears in the alveoli, it will simply be absorbed mechanically into the lung interstitium through small openings between alveolar epithelium (pores) which then this excess fluid is carried away through pulmonary lymphatics keeping the alveoli dry.

Pulmonary edema: Pulmonary edema is the accumulation of fluid in interstitial spaces of the lung or in the air spaces (alveoli). Any factor that causes the pulmonary interstitial fluid pressure to rise from the negative range into the positive range will cause sudden filling of the pulmonary interstitial spaces and alveoli with large amounts of free fluid (pulmonary edema). It is a large amounts, since that there is fluid in the interstitium (< 100 ml) and in the alveoli. The most common causes of pulmonary edema are: 1- Left-sided heart failure or mitral valve diseases with consequent increase in venous pressure and engorgement of pulmonary capillaries. 2- Damage to pulmonary capillary membrane caused by infections such as pneumonia

Pulmonary edema safety factor: Three factors must be overcome to induce pulmonary edema: 1- The normal negativity of interstitial fluid pressure. 2- Lymphatic pumping of fluid out of the interstitial space. 3- The increased osmosis of fluid into the pulmonary capillaries caused by decreased protein in the interstitial fluid when lymph flow increases. •

Regulation of respiration Neural regulation of respiration: Respiratory Center: The respiratory center is composed of several groups of neurons located bilaterally in the medulla oblongata and pons (brain stem). It is divided into 3 major collections of neurons: 1- The dorsal respiratory group (DRG): located in the dorsal portion of the medulla; causes inspiration. DRG stimulates inspiratory muscles, 12-15 times / minute 2- The ventral respiratory group (VRG): located in the ventrolateral part of the medulla which can cause either expiration or inspiration. VRG active in forced breathing 3- The pneumotaxic center: located dorsally in the superior portion of the pons; which helps control the rate and pattern of breathing. Pontine respiration centre: finetuning of breathing /

Hering-Breuer Inflation Reflex: Reflex nerve signals from the lungs help to control respiration through stretch receptors which are distributed in the airways smooth muscle layer that transmit signals through the vagi nerves into the DRG of neurons when the lungs become overly inflated. In human beings, this reflex probably is not activated until the tidal volume increases to greater than about 1.5 liters. Therefore, it is protective mechanism for preventing excess lung inflation. • •

Control of overall respiratory center activity: Control of ventilation in response to the needs of the body through: 1- Chemical control. 2- Peripheral chemoreceptors. Chemical control of respiration: (H+ ion, CO2, O2) The ultimate goal of respiration is to maintain proper concentration of O2, CO2 and hydrogen ions in the tissues, therefore, respiratory activity is highly responsive to changes in O2, CO2 and hydrogen ions. • Direct effect on respiratory center through excess CO2 and hydrogen ions, while O2 have no significant direct effect but it acts on peripheral chemoreceptors (carotid and aortic bodies) and these in turn transmit nervous signals to the respiratory center for control of respiration.

Chemosensitive area of the respiratory center: It is believed that none of 3 areas of the respiratory center are affected directly by changes in blood CO2 or H+ ion concentration. Instead, an additional neuronal area; chemosensitive area which is affected directly by changes in blood CO2 and hydrogen ion concentration. It is located bilaterally beneath the ventral surface of the medulla. This area is highly sensitive to changes in either blood CO2 or H+ ion concentration, and it in turn excites the other portions of the respiratory center (DRG

Factors that influence respiration • Hypothalamus (emotions / pain) • Cortex (voluntary control) • Chemoreceptors: Central (in medulla oblongata): responds to CO2 ↑ • CO2 passes blood brain barrier • CO2 + H2O H2CO3 H+ + HCO3 - • H+ stimulates receptors  breathing depth ↑ + rate ↑ Peripheral (in aortic / carotid bodies): • responds when O2 < 60 mm Hg  increase ventilation • Responds to pH ↓  increase ventilation

5 Sensory Modifiers of Respiratory Center Activities • Chemoreceptors are sensitive to: PCO 2 , PO 2 , or pH of blood or cerebrospinal fluid • Baroreceptors in aortic or carotid sinuses: sensitive to changes in blood pressure

• Stretch receptors: • respond to changes in lung volume • Irritating physical or chemical stimuli: • in nasal cavity, larynx, or bronchial tree • Other sensations including: • pain • changes in body temperature • abnormal visceral sensations

Chemoreceptor Reflexes • Respiratory centers are strongly influenced by chemoreceptor input from: cranial nerve IX -The glossopharyngeal nerve: – from carotid bodies – stimulated by changes in blood pH or PO 2 cranial nerve X -The vagus nerve: – from aortic bodies – stimulated by changes in blood pH or PO 2 receptors that monitor cerebrospinal fluid- – Are on ventrolateral surface of medulla oblongata – Respond to PCO 2 and pH of CSF

Pulmonary Volumes and Capacities: Pulmonary volumes and capacities are measured by a spirometer by which volume of air that is moved in and out of the lung can be recorded.

Pulmonary Volumes • There are four pulmonary volumes; including : Tidal volume (TV), Inspiratory reserve volume (IRV), Expiratory reserve volume (ERV), and Residual volume (RV) Pulmonary volumes except for residual volume can be measured directly by spirometer.

1-Tidal volume (TV): is the amount of air inspired and expired with each normal breath, it equals 500ml in average young adult man. 2-Inspiratory reserve volume (IRV): is the amount of air that can be inspired over and beyond the inspired tidal volume (3000ml). It is used during exercise and other strenuous activities. 3-Expiratory reserve volume (ERV): is the amount of air that can be expired by forceful expiration at the end of a normal tidal expiration (1100ml). 4- Residual volume (RV): is the amount of air remaining in the lungs after a maximal expiration (1200ml). it can not be measured by spirometer but by: • Helium dilution method. • Plethysmographic method (body box).

Pulmonary Capacities • Pulmonary capacity can simply be described as the sum of more than one primary lung volume. • There are four pulmonary capacities; including : Inspiratory capacity (IC), Functional residual capacity (FRC), Vital capacity (VC),and Total lung capacity (TLC). • They can be measured by spirometer except Functional residual capacity (FRC) because it includes the RV.

1-Vital capacity (VC): is the range in lung volume from maximum inspiration to maximum expiration (VC = IRV + ERV + VT = 4600ml). In other words, it is the maximum amount of air that a person can expel (expire) from the lungs after taking a deep inspiration. It is a useful clinical measurement in which a person is expiring tidal volume and IRV just inspired plus the ERV. Forced vital capacity is an index of restrictive airways disease (e.g., paralysis of the respiratory muscles).

2-Inspiratory capacity (IC): is the maximum volume of air a person inspire beginning from the end of a normal expiration (IC = TV+ IRV = 3500ml). 3-Functional residual capacity (FRC): is the volume of air in the lungs after a normal expiration (FRC = ERV + RV =2300ml). 4-Total lung capacity (TLC): is the maximum volume of air that the lungs can hold after the greatest possible inspiration (TLC = IRV + ERV + VT+ RV = 5800ml).

Graph of Lung Volumes/Capacities

All pulmonary volumes and capacities are about 20-25% less in women than men, and they are greater in large athletic persons than in small and asthenic persons. Pulmonary volumes and capacities change with the position of the body, most of them decreasing when the person lies down and increasing on standing. This positional change is caused by two factors: 1- A tendency of abdominal contents to press upward against the diaphragm in the lying position. 2- An increase in the pulmonary blood volume in the lying position which decreases the space available for pulmonary air.

Pulmonary Function Studies Dynamic flow rate tests: From a spirometer, the following screening pulmonary function parameters can be measured. These measurements are useful diagnostic tools to differentiate between obstructive and restrictive airway diseases. They include: 1-Forced vital capacity (FVC): which is a restrictive index, however it can be reduced in obstructive airway disease but to lesser extent. 2-Forced expiratory volume in one second of forced vital capacity (FEV1): which is greatly reduced in obstructive airway disease, e.g., Bronchial asthma.

3-FEV1/FVC ratio (FEV1 % FVC): It is obtained from the following equation: FEV1/FVC ratio = FEV1/FVC x 100 (normally ≥ 75%) If it is reduced it indicates obstructive airway disease. 4-Peak Expiratory Flow Rate (PEFR): again it is an obstructive index if it is reduced. Peak flows normally are equal to 400-600 L/min., for young healthy males and 300-500 L/min., for young healthy females.

Clinical significance  Vital capacity reduced in 1. Alterations in muscle power- • any drug that depresses the activity of ventilatory mechanism • Cerebral tumor, poliomyelitis. 1. Pulmonary disease • Chronic bronchitis.pneumonia,asthma,atelectasis • pleural effusion, Pneumothorax 1. Abdominal tumors, Abdominal pain/splinting 4. Alterations in the posture

Postural variation Trendelenburg 14.5 Lithotomy 18 Left lateral 10 Right lateral 12 Bridge in dorsal position 12.5 Prone position unsupported 10 Percentage of reduction in vital capacity in different postures

Dead space • Anatomic- conducting airways. Estimated to be about 1ml per pound of ideal body weight • Alveolar- normal lung volume that has become unable to take part in gas exchange because of reduction in pulmonary blood flow • Eg. Pulmonary embolism • Physiologic- Sum of anatomic and alveolar dead space volumes

• Anatomic dead space: is the air in the conducting airways (conducting zone; from the nose to the level of terminal bronchioles) that does not involved in gas exchange and is normally about 150ml. Thus, with each normal tidal volume of air, 150ml of the 500ml fails to reach the alveoli since it remains in the conducting zone. The portion of air that does reach the alveoli is called the alveolar ventilatory air and normally amounts to about 350ml with each breath (500- 150=350).

• Alveolar dead space: is the air in the gas exchange portions of the lung (alveoli) that can not involved in gas exchange because some alveoli, for different reasons, have little or no blood supply (non-functioning or partially functioning alveoli). Alveolar dead space is nearly zero in normal individuals. • Physiological dead space: is the sum of the anatomic dead space and alveolar dead space (i.e., the total dead space air). It is equal to the anatomic dead space in normal individuals.

Minute respiratory volume: Also called minute ventilation or total ventilation. Minute ventilation is the sum of all the air breathed during one minute. It is equal to the tidal volume (500ml) multiplied by the respiratory rate (12 breaths per minute) and is about 6000 ml/minute. But not all this air is available for exchange with the blood because of dead space. Minute respiratory ventilation can reach 200 L/min., or as low as 1.5 L/min., which is compatible with life. Minute ventilation = tidal volume x respiratory rate

Alveolar Ventilation: (VA) It represents the amount of air available for gas exchange. In other words, the total volume of fresh new air reaching and entering the alveoli per minute. 500 ml 150 ml Alveolar ventilation = (tidal volume – dead space volume) x respiratory rate (New air volume) VA = 4200 ml/min = 350 ml x 12. The pattern of breathing affecting the alveolar ventilation in such way that a slow, deep pattern of breathing is more effective in ventilating the alveoli than is rapid and shallow pattern as in case of fibrosis.

To evaluate the efficacy of ventilation, you should focus on alveolar ventilation, not the minute ventilation which is of fixed value (6000 ml) in the following example: As shown from above table, increased depth of breathing (increase TV) is far more effective than the increase in respiratory rate in elevating alveolar ventilation. So you have to increase the depth of breathing rather than the rate in exercise for proper gas exchange.

Diffusion and exchange of gases in alveoli and tissues • After the alveoli are ventilated with fresh air, the next step is diffusion of O2 and CO2. The process of diffusion is simply random molecular motion of molecules in both directions through the respiratory membrane. Therefore, O2 must move (diffuse) a cross the alveolar membranes into pulmonary capillaries to be transported by the blood to the tissues, then to leave the tissue capillaries and enter the extracellular fluid & finally cross the plasma membranes (cell membrane) to enter inside the cell for metabolism as a source of energy. CO2 must follow the same pathway but in opposite direction i.e., from the cell toward the lungs to be washed out.

Gas Exchange in the Lungs • Dalton’s Law: • Total pressure of a gas mixture is = to the sum of the pressures that each gas in the mixture would exert independently. • Partial pressure: • The pressure that an particular gas exerts independently. • PATM = PN2 + P02 + PC02 + PH20= 760 mm Hg. – 02 is humidified = 105 mm Hg. • H20 contributes to partial pressure (47 mm Hg). – P02 (sea level) = 150 mm Hg. – PC02 = 40 mm Hg.

Significance of Blood P02 and PC02 Measurements • At normal P02 arterial blood is about 100 mm Hg. • P02 level in the systemic veins is about 40 mm Hg. PC02 is 46 mm Hg in the systemic veins. Provides a good index of lung function.

Alveolar–blood gas exchange: The systemic venous blood coming from the tissues enters the pulmonary capillaries. It has high PCO2 (46 mmHg) and low PO2 (40 mmHg). The differences in the partial pressures of O2 & CO2 on two sides of the alveolar-capillary membrane result in the diffusion of O2 from alveoli (PO2=104 mmHg) to blood (PO2= 40 mmHg) and CO2 from blood (PCO2= 46 mmHg) to alveoli (PCO2= 40 mmHg) until reaching equilibrium. Blood PO2 equals that of alveolar air (104 mmHg) by the time the blood has moved a third (3rd th) of the distance through the capillary.

Diffusion of gases through the respiratory membrane: The respiratory membrane consists of 6 layers: 1- The fluid lining layer of the alveoli. 2- Alveolar epithelium. 3- Alveolar epithelial basement membrane. 4- Thin interstitial layer between alveolar epithelium and capillary membrane. 5- Capillary basement membrane. 6- Capillary endothelial membrane. The overall thickness of this respiratory membrane averages about 0.6µm, with a total surface area of about 70 m2 in normal adult. Diffusion Capacity of the respiratory membrane: Diffusing capacity is defined as the volume of gas that diffuses through the membrane each minute for a pressure difference of 1 mmHg (ml/min/mmHg).

Factors that affect the rate of gas diffusion through the respiratory membrane: 1- Thickness of the membrane which is increased in cases of edema of interstitial spaces & alveoli and in fibrosis. 2- Surface area of the membrane which is reduced in case of lung resection, emphysema. 3- Diffusion coefficient of the gas in the substance of the membrane. Diffusion coefficient is proportional to Solubility/√ molecular weight. 4- The pressure difference across the respiratory membrane, from high pressure area into lower pressure area.

Transport of gases in the blood and body fluids: Once O2 has diffused from the alveoli into pulmonary blood, it is transported principally in combination with hemoglobin (Hb). Hb combination increases O2 transport 30 to 100 times as much as O2 as could be transported simply in the dissolved form in the blood. In the tissue cells, O2 react with various foodstuffs to form CO2. Transport of oxygen in the blood: 97 % of O2 transported from the lungs to the tissues is carried in chemical combination with hemoglobin (Hb) in the red blood cells. 3 % is carried in the dissolved state in water of the plasma and cells. Thus, under normal conditions, O2 is carried to the tissues almost

OXYGEN FLUX The amount of oxygen leaving the left ventricle per minute in the arterial blood Oxygen flux=cardiac output x arterial oxygen saturation x haemoglobinconcentrationx1.31ml/g =5000ml/min x 98/100 x 15.6/100g/mlx1.31 =1000ml/min 1.31 is the volume of oxygen which combines with one gram of Hb 250ml-used up in cellular metabolism and rest returns to the lungs in mixed venous blood

Hemoglobin and Oxygen Transport Reversible combination of oxygenwith hemoglobin: O2 molecule combines loosely and reversibly with heme portion of the Hb. When PO2 is high (in pulmonary capillaries), O2 binds with Hb. When PO2 is low (in tissue capillaries), O2 is released from Hb.

Oxygen-hemoglobin dissociation curve shows that hemoglobin is almost completely saturated when P02 is 80 mm Hg or above. At lower partial pressures, the hemoglobin releases oxygen. The curve is normally sigmoid in shape i.e., S-shaped, this is due to sequential binding of the four O2 molecules, one to each of the four heme groups where each combination facilitates the next (heme-heme interaction) until the Hb molecule becomes saturated with O2. A shift of the curve to the left because of an increase in pH, a decrease in carbon dioxide, or a decrease in temperature results in an increase in the ability of hemoglobin to hold oxygen

Significance of Sigmoid Curve Critical PO2 V

Hemoglobin and Oxygen Transport • A shift of the curve to the right because of a decrease in pH, an increase in carbon dioxide, or an increase in temperature results in a decrease in the ability of hemoglobin to hold oxygen • The substance 2.3-bisphosphoglycerate increases the ability of hemoglobin to release oxygen • Fetal hemoglobin has a higher affinity for oxygen than does maternal

Four (+one) Things Change Oxyhemoglobin Affinity • Hydrogen Ion Concentration, [H+ ] • Carbon Dioxide Partial Pressure, PCO2 • Temperature • [2,3-DPG] • Special Case: Carbon Monoxide

Factors that shift the O2-Hb dissociation curve: Shift to the right: The shift to the right decreases the affinity of Hb for O2 and facilitates the delivery of O2 to the tissue. For any level of PO2 the percent saturation of Hb is decreased.  Factors that shift the curve to the right: 1-Decrease in pH: when the blood became slightly acidic with the pH decreasing from the normal value of 7.4 to 7.2 (about 15 % shift to the right). 2-Increased CO2 concentration; increased PCO2, e.g., exercise. 3-Increased blood temperature, e.g., exercise. 4-Increased 2,3-DPG; a phosphate compound normally present in the blood but in different concentration under different condition. It is a metabolite of RBCs.

Shift to the left: The shift to the left increases the affinity of Hb for O2. The percent saturation of Hb with O2 is increased i.e., the delivery of O2 to the tissue is more difficult.  Factors that shift the curve to the left: 1-Increases in pH to 7.6 i.e., decreased H+ ion concentration; alkaline blood. 2-Decreased CO2 concentration; decreased PCO2. 3-Decreased blood temperature. 4-Decreased 2,3-DPG concentration. 5-The presence of large quantities of fetal Hb (HbF), causes increase O2 released to the fetal tissue under hypoxic condition in which the fetus exists. HbF does not bind 2,3-DPG strongly as does Hb A, decreased binding of 2,3-DPG result in increased affinity of HbF for O2 in the upper part of the curve to be released to the fetal tissue.

The Bohr effect: (CO2 & H+ ion) Shift of the curve in response to changes in the blood CO2 and H+ ion has the following significant effects: 1-Oxygenation of the blood in the lung (left shift). 2-Releases of O2 from the blood in the tissue (right shift). As the blood passes through the lungs, CO2 diffuses from the blood into the alveoli. This reduces the blood PCO2 and decreases H+ ion concentration because of the resulting decrease in the blood carbonic acid. CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3 - Both these effects (↓PCO2 & ↓H+ ion) shifts the curve to the left, therefore the quantity of O2 that bind with the Hb at any given alveolar PO2 becomes increased, thus allowing greater O2 transport to the tissues. When the blood reaches the tissue capillaries, the opposite effects occur. CO2 entering the blood shifts the curve to the right, which displaces O2 from Hb and therefore delivers O2 to the tissues.

Effect of DPG: The normal DPG in the blood keeps the O2-Hb dissociation curve shifted slightly to the right all the time. In hypoxic condition that last longer than a few hours, the quantity of DPG in the blood increase, thus is shifting the curve further to the right. This causes O2 to be released to the tissue. Therefore this can be an important mechanism for adaptation to hypoxia, especially to chronic hypoxia of people living at high altitude and hypoxia caused by poor tissue blood flow (ischemic hypoxia), as in heart failure, and shock. •

Transport of Carbon Dioxide • Carbon dioxide is transported as bicarbonate ions (70%) in combination with blood proteins (23%) and in solution with plasma (7%) • Hemoglobin that has released oxygen binds more readily to carbon dioxide than hemoglobin that has oxygen bound to it (Haldane effect) • In tissue capillaries, carbon dioxide combines with water inside RBCs to form carbonic acid which dissociates to form bicarbonate ions and hydrogen ions

Transport of Carbon Dioxide • In lung capillaries, bicarbonate ions and hydrogen ions move into RBCs and chloride ions move out. • Bicarbonate ions combine with hydrogen ions to form carbonic acid. • The carbonic acid is converted to carbon dioxide and water. The carbon dioxide diffuses out of the RBCs. • Increased plasma carbon dioxide lowers blood pH. The respiratory system regulates blood pH by regulating plasma carbon dioxide levels

Carbon Dioxide Transport • Bicarbonate ions Muscle: CO2 + H2O → H2CO3 → H+ + HCO3 - Lung: H+ + HCO3 - → H2CO3 → CO2 + H2O • Dissolved in blood plasma • Bound to hemoglobin (carbaminohemoglobin)

CO2 Transport and Cl- Movement

Carbon Dioxide Transport and Chloride Shift Insert fig. 16.38

At Pulmonary Capillaries • H20 + C02 H2C03 H+ + HC03 - • At the alveoli, C02 diffuses into the alveoli; reaction shifts to the left. • Decreased [HC03 - ] in RBC, HC03 - diffuses into the RBC. – RBC becomes more -. • Cl- diffuses out (reverse Cl- shift). • Deoxyhemoglobin converted to oxyhemoglobin. – Has weak affinity for H+ . • Gives off HbC02.

Reverse Chloride Shift in Lungs Insert fig. 16.39

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