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Advance physiology Respiratory system physiology Assist. Prof. Dr. Majida Al-Qayim Department of physiology and pharmacology Textbook Ganongg;s Review of Medical Physiology. 23rd edition Respiratory System The respiratory system is made up of gas-exchanging organ (the lungs) a"pump" that ventilates the lungs. The pump consists of the chest wall; the respiratory muscles, which increase and decrease the size of the thoracic cavity and the areas in the brain that control the muscles; and the tracts and nerves that connect the brain to the muscles. FUNCTION AND STRUCTURE OF THE LUNGS Lungs are cone-shaped organs situated in the thoracic cavity. The left lung is divided by an oblique fissure into superior and inferior lobes. The right lung is divided by oblique and horizontal fissures into superior, middle and inferior lobes. Each lobe receives a secondary (lobar) bronchus from the primary bronchi. Inside the lungs, the secondary bronchi give rise to smaller bronchi called 'tertiary (segmental) bronchi', which in turn divide into smaller tubes called 'bronchioles'. Bronchioles branch repeatedly to form the terminal bronchioles that divide into respiratory bronchioles. Air passages Between the trachea and the alveolar sacs, the airways divide 23 times. The first 16 generations of passages form the conducting zone of the airways that transports gas from and to the exterior. They are made up of bronchi, bronchioles, and terminal bronchioles. Volume of conducting zone is about 150 ml The remaining seven generations form the respiratory zones where gas exchange occurs; they are made up of respiratory bronchioles, alveolar ducts, and alveoli. volume of respiratory zone is 3 litters Components of Respiratory zone a. Respiratory bronchioles b. Alveolar ducts i. Smooth muscle ii. Elastic and collagen fibers iii. Alveoli iv. Terminate into clusters of alveolialveolar sacs c. Alveolar sacs i. Groups of alveoli d. Alveoli Air ways crosssectional area These multiple divisions greatly increase the total crosssectional area of the airways, from 2.5 cm2 in the trachea to 11,800 cm2 in the alveoli . Consequently, the velocity of air flow in the small airways declines to very low values . As a result, forward velocity of gas during inspiration falls to a very low level in this zone because of the extremely rapid increase in total cross-sectional area in the respiratory zone. Respiratory membraneA layer of fluid lining the alveolus and (Blood-Gas barrier) containing surfactant that reduces the surface tension of the alveolar fluid 2. The alveolar epithelium composed of thin epithelial cells 3. An epithelial basement membrane 4. A thin interstitial space between the alveolar epithelium and the capillary membrane 5. A capillary basement membrane .� that in many places fuses with the alveolar epithelia basement membrane 6. The capillary endothelial membrane Alveolar wall The alveoli are lined by two types of epithelial cells. Type I cells are flat cells with large cytoplasmic extensions and are the primary lining cells of the alveoli, covering approximately 95% of the alveolar epithelial surface area. Type II cells (granular pneumocytes) are thicker and contain numerous lamellar inclusion bodies. A primary function of these cells is to secrete surfactant; however, they are also important in alveolar repair as well as other cellular physiology. Although these cells make up approximately 5% of the surface area, they represent approximately 60% of the epithelial cells in the alveoli. The alveoli also contain other specialized cells, including pulmonary alveolar macrophages (PAMs, or AMs), lymphocytes, plasma cells, neuroendocrine cells, and mast cells. The mast cells contain heparin, various lipids, histamine, and various proteases that participate in allergic reactions Airway’s cellular types Cells within airway Pulmonary epithelial cells Goblet cells Clara cells Fibroblast cells Smooth muscle cells Structure of the mucociliary system Mechanics of Breathing The aim of the breathing is to ventilate the lung . So the pulmonary ventilation is the physical movement of air into and out from the lung . Ventilation results from bulk flow of air as the result of pressure gradients which created between alveoli and atmospheric pressure as a result of volume changes. Boyle's law :-This law states that the pressure of gas in any container is inversely related to the volume of the container. In other words, when volume increases, pressure decreases and when volume decreases, pressure increases. P1V1 = P2V2 P = pressure of a gas in mm Hg V = volume of a gas in cubic millimeters Alveolar volume and pressure changes In respiratory cycle During inspiration, alveolar volume increases and intra-alveolar pressure falls causing air molecules to enter down the pressure gradient created by the inspiration. The air flow stops when pressure is equal to atmospheric pressure (0 mm Hg). During expiration, alveolar volume decreases and intra-alveolar pressure increases causing air molecules to leave down a pressure gradient in the reverse direction until the pressure returns to 0 mm Hg. The movement of air into and out of the alveoli is due to the changes in the volume of the thoracic cavity produced by the muscles of ventilation. . Mechanics of respiration As the external intercostals & diaphragm contract, the lungs expand. The expansion of the lungs causes the pressure in the lungs (and alveoli) to become slightly negative relative to atmospheric pressure. As a result, air moves from an area of higher pressure (the air) to an area of lower pressure (our lungs & alveoli). During expiration, the respiration muscles relax & lung volume decreases. This causes pressure in the lungs (and alveoli) to become slight positive relative to atmospheric pressure. As a result, air leaves the lungs. Elastic Recoil of lung and chest A negative force is always required on the outside of the lungs to keep the lungs expanded. This is provided by negative pressure in the normal pleural space. The basic cause of this negative pressure is pumping of fluid from the space by the lymphatics. Because the normal collapse tendency of the lungs is about –4 mm Hg, the pleural fluid pressure must always be at least as negative as –4 mm Hg to keep the lungs expanded. The pumping forces results from the elastic forces exerted on the intrapleural space by the chest wall and the lungs. The chest wall is compressed and the elastic forces are pulling it outward. The lung walls are stretched and the elastic forces are pulling them inward . Pressure – volume curve (lung Compliance ) This curve explain the relation ship between the lung volume with intrapleural pressure . The more –ve intrapleural the greatest lung volume. Charcterized by It is non linear Hysteresis behavior Volume changes to constant transpolmunary pressure Animal species Lung compliance Lung Compliance:- C= ∆ v∕∆ p The ease with which lungs can be expanded Specifically, the measure of the change in lung volume that occurs with a given change in intrapleural pressure Determined by three main factors 1- elastic recoil of lung and chest, the lung tissue and surrounding thoracic cage collagen fiber and elastine in alveoli wall 2- Lung surface tension 3- Airway resistance Pressure – volume curve (lung Compliance )in normal and disease Increased in age, emphysema, reduced elastic recoil Decreased in lung congestion, fibrosis, atalactasis( un ventilated area) Factors That Diminish Lung Compliance • Scar tissue or fibrosis that reduces the natural resilience of the lungs • Blockage of the smaller respiratory passages with mucus or fluid • Reduced production of surfactant • Decreased flexibility of the thoracic cage or its decreased ability to expand Physiological dead space Anatomical dead space + Alveolar dead space • • • Definition - It is the volume of the respiratory tract that does not participate in gas exchange. It is approximately 300 ml in normal lungs. It is important to distinguish between the anatomic dead space (respiratory system volume exclusive of alveoli) and the total (physiologic) dead space (volume of gas not equilibrating with blood; ie, wasted ventilation). Alveolar ventilation (VA) is the volume of air reached the alveoli in per minute that (1) reaches the alveoli and (2) takes part in gas exchange. Alveolar ventilation is often misunderstood as representing only the volume of air that reaches the alveoli. Physiologically, VA is the volume of alveolar air/minute that takes part in gas exchange (transfer of oxygen and carbon dioxide) with the pulmonary capillaries. Factors influencing alveolar dead space:-Low cardiac output can increase 10/min 30/min Respiratory alveolar dead space (increasing West's zone 1) rate Pulmonary embolism 600 mL 200 mL Tidal volume 6L 6L Minute volume (600 – 150) x (200 – 150) x Alveolar 10 = 4500 mL 30 = 1500 mL ventilation Regional differences for alveolar ventilation The upper part are less ventilated because streach of the lung in the lower are much graeter because: In rest compartments in the top will be more expanded greater volume V) than basal lung compartments because the intrapleural pressure in the upper part is more negative than the lower . As the pressure-volume curve for the same change in pleural pressure during inspiration the volume change (ΔV) will be greatest in basal parts of the lung, and progressively smaller towards the top. Due to this gravitational effect on the lung the ratio ΔV/V, an index of alveolar ventilation, is smallest in upper lung regions. This differences in the intrapleural -ve pressure between upper and lower due to the gravity and the lung mass. This situation changed with position Note the extremely rapid increase in total cross-sectional area and reduced resistance of airways in the respiratory zone. As a result, forward velocity of gas flow during inspiration falls to a very low level in the base with better ventilation and gas exchange .A unit with increased resistance, increased compliance, or both will take longer to fill and longer to empty . In normal adults, the respiratory rate is ~12 breaths per minute, with an inspiratory time of approximately 2 seconds and an expiratory time of about 3 seconds. In normal individuals, this is sufficient time to almost reach equilibrium in the alveolar pressure . However, in the presence of an increased resistance (or an increased compliance), equilibrium is not reached. This contributes to the air trapping seen in diseases associated with increased resistance (e.g., chronic bronchitis) or increased compliance (e.g., emphysema). Lung Blood Flow( circulation) • The pulmonary circulation In the pulmonary circulation, almost all the blood in the body passes via the pulmonary artery to the pulmonary capillary bed, where it is oxygenated and returned to the left atrium via the pulmonary veins . They form capillaries, which drain into bronchial veins or anastomose with pulmonary capillaries or veins . The bronchial veins drain into the azygos vein. • The bronchial circulation includes the bronchial arteries that come from systemic arteries, it nourishes the trachea down to the terminal bronchioles and also supplies the pleura and hilar lymph nodes. It should be noted that lymphatic channels are more abundant in the lungs than in any other organ. Lung perfusion (Pulmonary blood flow) The term “perfusion” refers to the amount of blood flowing through an organ in a given period of time, usually one minute, the lungs receive Cardiac Output (about 5 L per minute).This is because the right and left sides of the heart have to output the same volume of blood. So, the same volume passing through systemic circulation also has to pass through the lungs. Therefore, you have a numerical value for perfusion, 5 L / min Regional differences for alveolar perfusion (Un even perfusion ) Causes: Lung mass Gravity Random variations in the resistance of blood vessels. Some evidence that proximal regions of an acinus receive more blood flow than distal regions. In some animals some regions of the lung have an intrinsically higher vascular resistance. Three pressures control the capillary blood flow: Pa: arterial pressure Pv: venous pressure PA: alveolar pressure Ventilation- perfusion ratio Gas exchange is only optimal when individual regions are ventilated in proportion to their capillary blood flow. Well ventilated regions ideally have high capillary blood flows. Poorly ventilated regions ideally have little capillary blood flow. Three regions or 3 zones in standing position and 2 zones in laying and animals Extreme alterations of V/Q • An area with no ventilation (and thus a V/Q of zero) is termed "shunt." • An area with no perfusion (and thus a V/Q undefined though approaching infinity) is termed dead space.The V/Q ratio in normal person, equals approximately to 1 and V/Q’s above 1 are termed hyperventilation disorders. Those below 1 are termed hypoventilation disorders. Pathophysiology • A lower V/Q ratio (with respect to the expected value for a particular lung area in a defined position) impairs pulmonary gas exchange and is a cause of low arterial partial pressure of oxygen (paO2). Excretion of carbon dioxide is also impaired but a rise in arterial partial pressure of carbon dioxide (paCO2) is very uncommon because this leads to respiratory stimulation and the resultant increase in alveolar ventilation returns paCO2 to within the normal range. These abnormal phenomena are usually seen in chronic bronchitis, asthma and acute pulmonary edema. • A high V/Q ratio increases paO2 and decreases paCO2. This finding is typically associated with pulmonary embolism (where blood circulation is impaired by an embolus). Ventilation is wasted, as it fails to oxygenate any blood. A high V/Q can also be observed in COPD as a maladaptive ventilatory overwork of the undamaged lung parenchyma. Gases diffusion Importance's of a thin blood gas barier • Diffusion of any gas is judged by the Fick’s law of diffusion , in which transfer of any gas ( v• )through a sheet of tissue is proportional to tissue surface area (A) and the difference in gas partial pressure (P1- P2) between the two sides of the tissue , and inversely to thickness of the tissue(T ) Lung is big A( 50-100 m2 ) and Low T( microne) D :- diffusion coaffeciant of any gas it depends on :a. property of tissue b. molecular of gas c. solubility of gas Gas Exchange in the Lungs and tissues is derived by the partial pressures gradient There must be a pressure gradient for gases to be exchange between air in the alveoli and blood in the capillary in lung and between blood in capillary and tissues. This results from the different partial pressure for gases in aire, blood, and tissue. Partial pressure of any gas is the pressure of that gas if it alone occupied the volume of the mixture at the same temperature Oxygen Transport • • • • • Dissolved oxygen This obeys Henry’s law , that is , the amount dissolved isoproportional to the partial pressure of the gas . For each mmHg there is 0. 003 ml O2 per 100 ml of blood so for adult man at PO2 100 mmHg contains 0.3 ml of oxygen per 100 mi blood , which is inadequate , and must be another method for the sopply of oxygen. Reaction of Hemoglobin & Oxygen The dynamics of the reaction of hemoglobin with O2 make it a particularly suitable O2 carrier. Hemoglobin is a protein made up of four subunits, each of which contains a heme moiety attached to a polypeptide chain. In normal adults, most of the hemoglobin molecules contain two and two chains. Heme is a porphyrin ring complex that includes one atom of ferrous iron. Each of the four iron atoms in hemoglobin can reversibly bind one O2 molecule. The iron stays in the ferrous state, so that the reaction is oxygenation, not oxidation. It has been customary to write the reaction of hemoglobin with O2 as Hb + O2 ¨Æ HbO2 The reaction is rapid, requiring less than 0.01 s. The deoxygenation (reduction) of Hb4O8 is also very rapid. The quaternary structure of hemoglobin determines its affinity for O2. In deoxyhemoglobin, the globin units are tightly bound in a tense (T) configuration, which reduces the affinity of the molecule for O2. When O2 is first bound, the bonds holding the globin units are released, producing a relaxed (R) configuration, which exposes more O2 binding sites. The net result is a 500-fold increase in O2 affinity. In tissue, these reactions are reversed, releasing O2. The transition from one state to another has been calculated to occur about 108 times in the life of a red blood cell. The Oxygen-Hemoglobin Curve association and dissociation • This curve explain the relationship between the percentage of hemoglobin saturation with O2 and the partial pressure of O2 in the lung capillary Factors Affecting the Affinity of Hemoglobin for Oxygen Three important conditions affect the oxygen– hemoglobin dissociation curve: pH, temperature concentration of 2,3-biphosphoglycerate (BPG; 2,3-BPG). A rise in temperature or a fall in pH shifts the curve to the right. When the curve is shifted in this direction, a higher PO2 is required for hemoglobin to bind a given amount of O2. Conversely, a fall in temperature or a rise in pH shifts the curve to the left, and a lower PO2 is required to bind a given amount of O2. A convenient index for comparison of such shifts is the P50, the PO2 at which hemoglobin is half saturated with O2. The higher the P50, the lower the affinity of hemoglobin for O2. Carbon Dioxide transporting:The solubility of CO2 in blood is about 20 times that of O2; therefore, considerably more CO2 than O2 is present in simple solution at equal partial pressures. The CO2 that diffuses into red blood cells is rapidly hydrated to H2CO3 because of the presence of carbonic anhydrase. The H2CO3 dissociates to H+ and HCO3–, and the H+ is buffered, primarily by hemoglobin, while the HCO3– enters the plasma. Some of the CO2 in the red cells reacts with the amino groups of hemoglobin and other proteins (R), forming carbamino compounds: Because deoxyhemoglobin binds more H+ than oxyhemoglobin does and forms carbamino compounds more readily, binding of O2 to hemoglobin reduces its affinity for CO2(Haldane effect). Consequently, venous blood carries more CO2 than arterial blood, CO2 uptake is facilitated in the tissues, and CO2 release is facilitated in the lungs. About 11% of the CO2 added to the blood in the systemic capillaries is carried to the lungs as carbamino-CO2. Fate of CO2 in the blood In plasma 1. Dissolved 2. Formation of carbamino compounds with plasma protein + – 3. Hydration, H buffered, HCO3 in plasma In red blood cells 1. Dissolved 2. Formation of carbamino-Hb + – 3. Hydration, H buffered, 70% of HCO3 enters the plasma – 4. Cl shifts into cells Chloride shift Because the rise in the HCO3– content of red cells is much greater than that in plasma as the blood passes through the capillaries, about 70% of the HCO3– formed in the red cells enters the plasma. The excess HCO3– leaves the red cells in exchange for Cl– (Figure 36–6). This process is mediated by anion exchanger 1 (AE1; formerly called Band 3), a major membrane protein in the red blood cell. Because of this chloride shift, the Cl– content of the red cells in venous blood is significantly greater than that in arterial blood. The chloride shift occurs rapidly and is essentially complete within 1 s. Diffusion &Perfusion limitation for gases:. Whether or not substances passing from the alveoli to the capillary blood reach equilibrium in the 0.75 s that blood takes to traverse the pulmonary capillaries at rest depends on their reaction with substances in the blood. Thus, for example, the anesthetic gas nitrous oxide (N2O) does not react and reaches equilibrium in about 0.1 s. In this situation, the amount of N2O taken up is not limited by diffusion but by the amount of blood flowing through the pulmonary capillaries; that is, it is flow-limited. On the other hand, carbon monoxide (CO) is taken up by hemoglobin in the red blood cells at such a high rate that the partial pressure of CO in the capillaries stays very low and equilibrium is not reached in the 0.75 s the blood is in the pulmonary capillaries. Therefore, the transfer of CO is not limited by perfusion at rest and instead is diffusionlimited. O2 is intermediate between N2O and CO; it is taken up by hemoglobin, but much less avidly than CO, and it reaches equilibrium with capillary blood in about 0.3 s. Thus, its uptake is perfusion-limited. The diffusing capacity for CO (DLCO) is measured as an index of diffusing capacity because its uptake is diffusion-limited. DLCO is proportionate to the amount of CO entering the blood (VCO) divided by the partial pressure of CO in the alveoli minus the partial pressure of CO in the blood entering the pulmonary capillaries. Except in habitual cigarette smokers, this latter term is close to zero, so it can be ignored and the equation becomes: • Innervations of air ways As with most organ systems, the CNS and PNS work in cohort to maintain homeostasis . There are four distinct components of the autonomic nervous system: parasympathetic originates from the medulla in the brainstem (cranial nerve X, the vagus) innervating smooth muscle cells, blood vessels, and bronchial epithelial cells (including goblet cells and submucosal glands), Two types of fibers: 1- excitatory motor neurons (cholinergic) Acetylcholine and substance P are neurotransmitters of 2- inhibitory (nonadrenergic) motor neurons. dynorphin andvasoactive intestinal peptide are neurotransmitters of inhibitory motor neurons Parasympathetic stimulation through the vagus nerve is responsible for: - the slightly constricted smooth muscle tone in the normal resting lung. - increase the synthesis of mucus glycoprotein, which raises the viscosity of mucus. - blood vessel dilation Parasympathetic innervation is greater in the larger airways, and it diminishes toward the smaller conducting airways in the periphery. Sympathetic innervation of the bronchi originate from about T1 to T5, Stimulation of the sympathetic system causes:airway relaxation, blood vessel constriction, inhibition of glandular secretion (causing a watary secretion ) nonadrenergic noncholinergic inhibitory (relaxation) innervation of the bronchioles that produces bronchodilation mediated by dynorphin and vasoactive intestinal peptide are neurotransmitters of inhibitory motor neurons. nonadrenergic noncholinergic stimulatory(constriction). Acetylcholine and substance P are neurotransmitters of excitatory motor There is no voluntary motor innervation in the lung, nor are there pain fibers. Pain fibers are found only in the pleura. Neural control of Respiration The chief function of the lung is to exchange O2 and CO2 between blood and gas , thus maintain normal PO2 and PCO2 in arterial blood . This control is under the three basic elements : 1. Sensors (Receptors ) 2. Central controller :Voluntary(in the cerebral cortex ) and Involutary(in the pons and medullary oblongata) 3.Effectors (Respiratory muscle) Central Controller: Medullary center Pacemaker for ventilation (Rythmicity center Controls automatic breathing , consist of interacting of tow groups of cells a-dorsal group :mainly inspiratory ( I ) neurons,control the descending spinal cord pathways to stimulate motor neurons that innervate muscles of inspiration to bring about inspiration b- ventral group : both inspiratory (I)and expiratory (E) neurons, which inhibit I neurons and control the descending spinal cord pathways to the motor neurons that innervating muscles of expiration to bring about expiration Apneustic center located in the pons stimulate I neurons ,to promote inspiration Apneuses: inspiratory arrest :prolonged inspiratory gasps interrupted by transient expiratory efforts. Pneumotaxic center located in the pons inhibit I neurons by inhibition of apneustic center aid in establishing the normal respiratory rhythm Reticular activating system (RAS) located in the reticular system of the brain stem activity associated the awake or conscious state Other neural structures 1- Hypothalamus :change in respiration associated with temperature regulation 2-Limbic system :respiratory changes in motion 3-Cerebral cortex :voluntary control Sensors A-Chemoreceptors Periphral Chemoreceptors Located in the carotid bodies at the bifurcation of the common carotid arteries and in the aortic bodies above and bellow aortic arch . They contains islands of these glomus cells surrounded by supportive cells and innervated with unmyelinated endings of gloss pharyngeal nerve fibers that carry signals to the respiratory centers in the medulla .They are sensitive to : -arise in the CO2 pressure , -a decrease in O2 pressur, - an increase in H+ concentration They account for approximately 20% of ventilatory response Central Chemreceptors Located in the ventral surface of the medulla They moniter the H+ concentration in the cerebrospinal fluid (CSF) and the brain interstitium . They are the major chemical control of respiration under normal conditions . They account for 70-80 % of the ventilatory response toincrease in PaCO2 . CO2 readily penetrates the blood –brain –barrier and the blood –CSF barrier ,and hydrated into H+ and HCO3¯ • B-Nonchemical Receptors In the airways & lungs receptors Stretch receptors :They are vagal myelinated nerv endings located among airway smooth muscle ,they stimulated by inflation of the lung . The response are : - Inspiratory time shortening - HeringBreuer inflation and deflation reflexes -Bronchodilatio -Tachycardia Irritant receptors : they are vagal myelinated nerv endings under and between the epithelial cells of airways and lungs .They respond to inhaled irritating substances ,like histamine, prostaglandins. The responses are :-Hyperpnea -Cough -Bronchoconstriction -Mucus secretions J receptors(juxtacapillary):located at the alveolar wall close to pulmonary capillaries .They respond to : -increase of interstitial fluid volume -engorgement of capillaries -exogenous and endogenous sub.(eg.bradykinin,serotonin) The responses are :-Apnea, followed by rapid breathing -Bronchoconstriction -Hypotension -Mucus secretion Out the airways & lungs receptors Respiratory muscle spindle receptors ; joint receptors; proprioceptors and tendons stimulate the inspiratory neurons ,contribute to respiratory drive during exercise Baroreceptors (in carotid sinuses; aortic arch; atria;and ventricles)inhibit respiration Higher centers afferent from limbic system and hypothalamus during pain and emotional stimuli. Visceral reflexes: during vomiting ;swallowing and sneezing by inhibition of respiration and closure of the glottis during these activities.