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The Respiratory System Part III Dr. Adelina Vlad Pulmonary Circulatory System CO2 O2 O2 CO2 LA RV ATP CO2 O2 Normal anatomic right-to-left-shunt: after passing through capillaries, about half of the bronchial blood anastomoses with oxygenated blood in the pulmonary venules Characteristics of Pulmonary Circulation • - Low pressure system it needs to pump blood only to the top of the lung important for avoiding the flooding of lung with edema fluid • - Low resistance system, less than 1/10 that of systemic circulation due to: shorter and wider vessels ( ) higher number of less muscular arterioles with a low resting tone • High compliance vessels - due to the thin walls and the paucity of smooth muscle - can accept large amounts of blood - can dilate in response to modest increases in PA pressure - the pulse pressure is low Pressures in the Pulmonary System Pressure pulse contours Pressures in the pulmonary system D, diastolic; M, mean; S, systolic Pulmonary Capillaries • • • • • Pulmonary blood volume = 450 mL (220-900 mL) Capillary blood volume = 75 ml at rest, up to 200 ml during exercise There are 280 billion highly anasomosing capillary segments = nearly 1000/ alveolus, creating a gas exchange surface of 100 square meters Blood passes through the pulmonary capillaries in about 0.8 s at rest and can shorten to 0.3 s when the cardiac output increases Alveolar capillaries are collapsible: If capillary pressure falls below alveolar pressure, the capillaries close off, diverting blood to other pulmonary capillary beds with higher pressures. Influence of Gravity on Regional Perfusion • At rest and in orthostatic position, hydrostatic pressure gradient is about 15 mm Hg at the apex, resulting in a 25 – 15 = + 10 mm Hg systolic Pa and an 8 – 15 = – 7 mm Hg diastolic Pa the capillary beds located at more than 10 cm above the midlevel of the heart are closed during RV diastole (zone 2) Ppc<PAlv because the diastolic value (8 mm Hg) cannot overcome the hydrostatic pressure gradient • In the lower regions of the lung, capillaries remain continuously open (zone 3) because Ppc remains greater than zero (= PAlv) during both systole and diastole Blood is directed toward the base of the lung. • Zone 1 occurs only under abnormal conditions: very high PAlv or exceedingly low systolic Ppc Influence of Gravity on Regional Perfusion • In an upright subject, perfusion is greatest near the base of the lung and falls towards the apex Influence of Gravity on Regional Ventilation • Because of the action of gravity, for an upright subject PIP is lower at the apex (- 7.5 cm H2O) compared to the base of the lung (- 2.5 cm H2O) alveoli at the top of the lung are more distended compared to the alveoli at the base the alveoli at the base are more compliant = during inspiration, the same DPIP produces a grater DVL near the base than near the apex for an upright subject, regional ventilation is greater at the base than at the apex of the lungs Matching Ventilation and Perfusion • The local ventilation-perfusion ratio (VA/Q) determines the local alveolar concentration of O2 and CO2 • In the lungs of an upright subject VA/Q varies with height: – Is lowest near the base where Q exceeds VA (VA/Q < 1) – Gradually increases to 1 (VA/Q = 1) at the level of the 3rd rib, where Q = VA – Further increases toward the apex, where Q falls more than V A (VA/Q > 1) • When alveoli are ventilated but not perfused = alveolar dead space ventilation, VA/Q ∞; although the alveoli are ventilated, they are not engaged in gas exchange • Compensatory changes correct the mismatch: blood flow is redirected toward the normal parts of the lung that become hyperperfused VA/Q decreases in these areas alveolar dead space ventilation lowers local alveolar PCO2 and triggers compensatory bronchiolar constriction airflow diverts toward normally perfused areas starved pneumocytes II in the hipoperfused alveoli produce less surfactant, resulting a local decrease in compliance with a further decrease of local ventilation the compensation tends to correct VA/Q in both hypoperfused and normal areas, improving gas exchange A natural cause is pulmonary embolism; as lungs are filtering small emboli, they deal will small regions of dead space ventilation on a recurring basis • When alveoli are perfused but not ventilated (shunt, VA/Q tends to zero) - airflow is redirected to normal parts of the lung, - the decrease in local alveolar O2 triggers a compensatory hypoxic pulmonary vasoconstriction blood is redirected towards normally ventilated areas The normal areas are better ventilated and perfused, whereas the shunt zone looses the blood flow the compensation tends to correct VA/Q in both hypoventilated and normal areas, improving the alveolar gas exchange Natural causes generating a functional shunt: atelectasis (collapse of the alveoli), foreign bodies or tumors inside the airway Local Control of Arterioles and Bronchioles by O2 and CO2 Gas composition Bronchioles Pulmonary arterioles Systemic arterioles ↑ PCO2 Dilate Constrict Dilate ↓ PCO2 Constrict Dilate Constrict ↑ PO2 Constrict Dilate Constrict ↓ PO2 Dilate Constrict Dilate Strong effects are marked in bold Local Control Compensates Ventilation Perfusion Mismatches Mechanisms for Keeping the Alveoli Dry • The pulmonary capillaries and the pulmonary lymphatic system - maintain a slight negative pressure in the interstitial spaces - are able to carry away the excess interstitial fluid (20 ml/ hour) Capillary Exchange of Fluid in the Lungs • Pulmonary edema safety factor - The protection mechanisms are overwhelmed when the capillary hydrostatic pressure (7) rises up to the plasma osmotic pressure (28) edema - In acute conditions the safety factor is 21 mmHg (7 28 mm Hg) - In chronic conditions, due to lymph vessels expansion, the safety factor rises to 30 - 35 mm Hg Examples: acute conditions left-sided heart failure chronic conditions mitral stenosis Diffusion of Respiratory Gases Partial Pressures of Respiratory Gases N2 O2 CO 2 H 2O TOTAL Atmospheric air (mm Hg) 597.0 (78.62%) 159.0 (20.84%) 0.3 ( 0.04%) 3.7 (0.50%) Humidified air (mm Hg) 563.4 (74.09%) 149.3 (19.67%) 0.3 (0.04%) 47.0 (6.20%) Alveolar air (mm Hg) 569.0 (74.9%) 104.0 (13.6%) 40.0 (5.3%) 47.0 (6.2%) Expiratory air (mm Hg) 566.0 (74.5%) 120.0 (15.7%) 27.0 (3.6%) 47.0 (6.2%) 760.0 760.0 760.0 760.0 (100%) (100%) (100%) (100%) • The pressure of a mixture of gases is equal to the sum of the pressures of all of the constituent gases alone: PressureTotal = Pressure1 + Pressure2 ... Pressuren • Each gas contributes to the total pressure of a mixture of gases in direct proportion to its concentration: Partial pressure = Total pressure x Gas concentration Slow replacement of alveolar air gas composition in the alveoli varies slightly during normal breathing prevent sudden changes in gas concentrations and the pH of the blood 350 mL fresh air/breath reaches alveoli ~ 1/7 of total lung volume at the end of a quiet inspiration Alveolar Air Composition • Is different from the composition of the atmospheric air because: – the alveolar air is only partially replaced by atmospheric air with each breath – oxygen is constantly being absorbed into the pulmonary blood from the alveolar air – carbon dioxide is constantly diffusing from the pulmonary blood into the alveoli – atmospheric air that enters the respiratory passages is humidified even before it reaches the alveoli Oxygen and carbon dioxide partial pressures in the expired air • Oxygen concentration in the alveoli is controlled by – the rate of absorption of oxygen into the blood – the rate of entry of new oxygen into the lungs by the ventilatory process • The alveolar PCO2 – increases directly in proportion to the rate of carbon dioxide excretion – decreases in inverse proportion to alveolar ventilation Types and patterns of ventilation Name Description Examples Eupnea Normal quiet breathing Hyperpnea ↑ respiratory rate and/or volume in response to ↑ metabolism Exercise Hyperventilation ↑ respiratory rate and/or volume without ↑ metabolism Emotional hyperventilation Hypoventilation Decreased alveolar ventilation Shallow breathing; asthma; restrictive lung disease Tachypnea Rapid breathing; usually ↑ respiratory rate with ↓ depth Panting Dyspnea Difficulty breathing (feel like ‘air hunger’) Various pathologies or hard exercise Apnea Cessation of breathing Voluntary breath-holding; depression of CNS control centers Respiratory Membrane 1. Alveolar fluid with surfactant 2. Alveolar epithelium 3. Epithelial basement membrane 4. Thin interstitial space between the alveolar epithelium and the capillary membrane 5. Capillary basement membrane 6. Capillary endothelial cells Has: 0.6 mm thickness 70 square meters Pulmonary capillary diameter: 5 mm Blood volume in pulmonary capillaries: 60 - 140 ml Gas Diffusion Trough the Respiratory Membrane Depends on: 1. 2. 3. 4. 5. The thickness of the membrane • increased in pulmonary edema, fibrosis The surface area of the exchange membrane • decreased in emphysema • increased during exercise when more capillaries are open The diffusion coefficient of the gas in the substance of the membrane The partial pressure difference of the gas between the two sides of the membrane The temperature • fairly constant in the body, therefore negligible Diffusion Rate D~ ΔP x A x S d x MW D = diffusion rate of the gas ΔP = pressure gradient across the membrane A = cross-sectional area S = solubility coefficient of the gas d = distance of diffusion MW = molecular weight of the gas The characteristics of the gas itself, S and MW, determine the diffusion coefficient of the gas ~ S/ MW Solubility Coefficient of a Gas • The partial pressure of a gas in a solution is determined not only by its concentration but also by the solubility coefficient of the gas • Henry’s law: Partial pressure = Concentration of dissolved gas/ Solubility coefficient • Solubility coefficient (S) of a gas depends on the physical or chemical attraction to water molecules; a higher attraction means a better solubility and a lower partial pressure developed for a given concentration Diffusing Capacity (DC) of the Respiratory Membrane Expresses the ability of the respiratory membrane to exchange a gas between the alveoli and the pulmonary blood DC = volume of gas diffused in 1 minute for a ΔP of 1 mm Hg allows the calculation of the diffusion rate (DC x ΔP) DC for O2 at rest = 21 ml/min/mm Hg during exercise = 65 ml/min/mm Hg DC for CO2 at rest = 400 - 450 ml/min/mm Hg during exercise = 1200 - 1300 ml/min/mm Hg Diffusion of O2 Through the Respiratory Membrane The blood Po rises almost to Po of the alveolar air by the time the blood has moved a third of the distance through the capillary 2 2 PO2 in Alveoli, Blood and Tissues The interstitial fluid PO2 depends on: - the rate of the blood flow through the tissue - the rate of tissue metabolism Diffusion of CO2 Through the Respiratory Membrane The blood Pco falls almost to Pco of the alveolar air by the time the blood has moved a third of the distance through the capillary 2 2 PCO2 in Alveoli, Blood and Tissues Effect of blood flow and metabolic rate on body tissues PCO2 Pulmonary pathologies that affect alveolar ventilation and gas exchange Hypoxia • Hypoxic hypoxia: low arterial PO2 (high altitude, alveolar hypoventilation) • Anemic hypoxia: decrease in total amount of O2 bound to Hb (blood loss, anemia, CO poisoning) • Ischemic hypoxia: reduced blood flow in tissue • Histotoxic hypoxia: failure of cell to use O2 due to poisoning (cyanide) Regulation of Ventilation Regulation of Ventilation • Breathing is a rhythmic process that usually occurs without voluntary command • Skeletal muscles do not contract spontaneously, but after receiving impulses from somatic motor neurons, controlled by the CNS • There is a central pattern generator (CPG) with intrinsic rhythmic activity (network of neurons with unstable membrane potentials) in the medulla oblongata that controls the respiratory muscles Central Pattern Generator • • • "Central pattern generators (CPGs) can be defined as neural networks that can endogenously (i.e. without rhythmic sensory or central input) produce rhythmic patterned outputs" or as "neural circuits that generate periodic motor commands for rhythmic movements“ CPGs have been shown to produce rhythmic outputs resembling normal "rhythmic motor pattern production" even in isolation from motor and sensory feedback from muscle targets To be classified as a rhythmic generator, a CPG requires: 1. two or more processes that interact such that each process sequentially increases and decreases 2. that, as a result of this interaction, the system repeatedly returns to its starting condition Respiratory Center • The primary control center for ventilation lies in the medulla, where the rhythm of ventilation is set Respiratory neurons in the medulla (CPG) control I and E – dorsal respiratory group (DRG) – inspiratory (I) neurons – ventral respiratory group (VRG) – expiratory (E) neurons and accesory inspiratory (I+) neurons (active during forced breathing) The rhythmic pattern of breathing arises from a network of spontaneously discharging neurons • Neurons in the pons (pneumotaxic and apneustic centers) influence the rate and depth of ventilation • Ventilation is subject to modulation by various chemical factors (CO2, O2, H+), stretch receptors from lungs and respiratory muscles, and by higher brain centers Central chemoreceptors Organization of the Respiratory Center Peripheral chemoreceptors Dorsal Respiratory Group • Plays the most fundamental role in the control of respiration • Located – within the nucleus of the tractus solitarius (NTS, sensory termination of vagal and glossopharyngeal nerves) – in the adjacent reticular substance of the medulla • Integrates sensory information from: – peripheral chemoreceptors – respiratory-related receptors in the lungs and airways Dorsal Respiratory Group • Emits repetitive bursts of inspiratory neuronal action potentials towards: • the motor neurons of the phrenic and spinal nerves • the neurons of VRG • The inspiratory signal is a ramp signal that increases steadily for about 2 s, then it ceases abruptly for the next 3 s causes a steady increase in the volume of the lungs during inspiration Rhythmic Activity of DRG I neurons stop firing • Gradual recruitment of skeletal muscle fibers (diaphragm) rib cage expands smoothly • In forced breathing I+ are activated by the increased activity of DRG inspiratory neurons • Elastic recoil of inspiratory muscles and elastic lung tissue • E neurons in VRG act during active expiration Pneumotaxic Center • Located dorsally in the nucleus parabrachialis of the upper pons • Controls the “switch-off” point of the inspiratory ramp limits inspiration and increases the rate of breathing: A strong pneumotaxic signal can increase the rate of breathing to 30 to 40 breaths per minute, whereas a weak pneumotaxic signal may reduce the rate to only 3 to 5 breaths per minute Ventral Respiratory Group • Located about 5 mm anterior and lateral to the DRG, in the nucleus ambiguus rostrally and the nucleus retroambiguus caudally • Is primarily motor • Remains almost totally inactive during normal quiet respiration • When high levels of ventilation are required, respiratory signals spill over into the VRG from the basic oscillating mechanism of the DRG Ventral Respiratory Group • Has three regions: – the rostral region (Botzinger complex), E, drives the expiratory action of the caudal region – the intermediate region, I, has somatic motorneurons whose fibers mediate the enlargement of the pharynx, larynx and other structures – the caudal region has premotor neurons that synapse motorneurons innervating accessory muscles of expiration Mechanisms of Rhythmic Output • The firing pattern of respiratory-related neurons (I, E) is determined by both intrinsic membrane properties (ion currents) and patterned synaptic input (excitatory and inhibitory postsynaptic potentials) Because of reciprocal inhibition between the early-burst neuron and the late-onset inspiratory neuron, only one can be maximally active at a time Chemical Control of Ventilation • The respiratory system regulates the arterial levels of O2, CO2 and pH • At the same time, these parameters are exerting the most important control on breathing via two sets of chemoreceptors: – peripheral chemoreceptors, stimulated mainly by hypoxia located in aortic and carotid bodies (glomus cells) - central chemoreceptors, stimulated mainly by increased plasma PCO2 and acidosis (low pH) located in the medulla (ventral surface) Hypoxia • Monitored by carotid and aortic bodies (peripheral chemoreceptors) • Changes in oxygen concentration have virtually no direct effect on the central chemoreceptor, due to the fact that hemoglobin is able to release enough oxygen to body tissues even when the pulmonary Po changes from a value as low as 60 mm Hg up to a value as high as 1000 mm Hg 2 O2 Sensor of the Carotid Body • Glomus cells in the carotid body are equipped with a gated K+ channel that has an extracellular O2 sensor (KO2) • When the sensor is activated by normal arterial levels of O2, the channels open K+ leaves the cell, hyperpolarizing the membrane • When arterial O2 decreases closure of K+ channels cell depolarization opening of voltage-gated Ca2+ channels ↑ [Ca2+]i exocytose with vesicles containing dopamine action potential in sensory neurons respiratory control centers ↑ventilation Chemosensitivity of the Carotid Body H+ Concentration • It is believed that hydrogen ions may be the only important direct stimulus for central chemoreceptors • However, hydrogen ions do not easily cross the blood-brain barrier changes in blood pH have less effect in stimulating the chemosensitive neurons than do changes in blood carbon dioxide • pH has little effect on peripheral chemoreceptors; acidosis increases their sensitivity for hypoxia Carbon Dioxide • Carbon dioxide: main respiratory regulator by a potent indirect effect on the central chemoreceptor • Increased PCO - has little effect on peripheral chemoreceptors; however, acts faster through this pathway, and increases their sensitivity for hypoxia - CO2 passes easily through the blood-brain barrier - central chemoreceptors detect CO2induced H+ concentration in brain cerebrospinal fluid (CSF) 2 Central chemoreceptor monitors CO2 in cerebrospinal fluid Chemoreceptor Reflex Nervous Modulation of Respiratory Output • • PO2, PCO2 and pH are the major parameters that feed back on the respiratory control system Apart from these, there are two other major sources that provide input (through IX and X up to DRG) for regulation of ventilation: – Stretch and chemical/irritant receptors, monitor the size of the airways and the presence of noxious agents • Pulmonary stretch receptors (PSR) are mechanoreceptors that detect changes in lung volume; example: the Hering-Breuer reflex • Irritant receptors, very sensitive to chemical stimuli (serotonin, bradykinin, prostaglandins, histamine, cigarette smoke etc.) – Higher CNS centers, coordinate ventilation with other behaviors (speaking, sniffing, regulating temperature, chewing, swallowing, vomiting) Hering-Breuer Inflation Reflex • • One of the first examples of negative feedback in physiology (1868) Lung inflation inhibits the output of phrenic motor neurons, protecting the lungs from overinflation • How? Lung inflation stretch receptors from bronchi and bronchioles are stimulated vagi inhibition of DRG in a similar manner with pneumotaxic influences amplitude of inspiration decreases, respiratory rate increases = the reflex maintains a constant alveolar ventilation The information provided by the sensor may be used by the medulla for choosing a combination of tidal volume and respiratory rate that minimizes the work of breathing