MED1001 Human Physiology: Respiratory System I & II Lecture Notes PDF

MED1001: Human Physiology Respiratory system I and II Dr. Michael Chau [email protected] Sep 18 & 25, 2024  Learning objectives  Airway resistance  Gas exchanges  Chemoreception  Lung volumes & capacities  O2 transport i...

MED1001: Human Physiology Respiratory system I and II Dr. Michael Chau [email protected] Sep 18 & 25, 2024  Learning objectives  Airway resistance  Gas exchanges  Chemoreception  Lung volumes & capacities  O2 transport in blood  Neural control of ventilation  Mechanics of breathing  CO2 transport in blood  Relate the structure of the respiratory system (lungs, thorax and airways) to the function of gas exchange  Describe the roles of the diaphragm and other respiratory muscles in breathing  Describe how the alveolar capillary membrane is well adapted to gas diffusion  Distinguish the processes of inspiration and expiration (external vs. internal)  Describe the transport of gases by blood, and list and discuss the volumes of air exchanged during pulmonary ventilation.  Identify and discuss the mechanisms that regulate respiration, and identify breathing patterns.  References Barrett KE, Brooks HL, Barman SM and Yuan JXL (2019) Respiratory physiology. In Ganong’s review of medical physiology, pp. 609‐58. USA: McGraw Hill. Silverthorn DU (2019) Chapters 17‐18. In Human physiology: an integrated approach, pp. 532‐86. USA: Pearson. Widmaier E, Raff H and Stran K (2023) Respiratory physiology. In Vander’s human physiology: the mechanisms of body function, pp. 445‐89. USA: McGraw Hill.  Respiratory system: functions  To supply the body with oxygen and eliminate carbon dioxide  Respiration: 4 distinct processes must happen  pulmonary ventilation: breathing  external respiration: gas exchange between the alveolar air and blood in lung capillaries  transport: transport of oxygen and carbon dioxide in blood  internal respiration: gas exchange between blood in tissue capillaries and cells in tissues  Regulation of blood pH in coordination with the kidneys: altered by changing blood carbon dioxide levels  Voice production (phonation): movement of air past vocal folds makes sound and speech  Olfaction: smell occurs when airborne molecules drawn into nasal cavity  Protection: against inhaled microorganisms by preventing entry and removing them  Respiration Respiration has two meanings: Internal or cellular respiration: the utilization of oxygen in the metabolism of organic molecules Pulmonary physiology: the exchange of oxygen and carbon dioxide between an organism and the external environment Phases of the respiratory cycle: Inspiration (inhalation): movement of air from the external environment through the airways into the alveoli during breathing Expiration (exhalation): movement of air from the alveoli through the airways into the external environment Respiration: steps 1. Ventilation: Exchange of air (1) between atmosphere and alveoli by bulk flow 2. Exchange of O2 and CO2 between (2) alveolar air and blood in lung capillaries by diffusion 3. Transport of O2 and CO2 through (3) pulmonary and systemic circulation by bulk flow 4. Exchange of O2 and CO2 between blood in tissue capillaries and cells in tissues by diffusion 5. Cellular utilization of O2 and production of CO2 (4) (5) Respiratory system: organization  Respiratory system (consists of the respiratory and conducting zones)  Respiratory zone*  site of gas exchange  consists of bronchioles, alveolar ducts and alveoli  Conducting zone  provides rigid conduits for air to reach the sites of gas exchange  includes all other respiratory structures, e.g. nose, nasal cavity, pharynx and trachea  respiratory muscles: diaphragm and other muscles that promote ventilation * defined by the presence of alveoli. It begins as terminal bronchioles feed into respiratory bronchioles which lead to alveolar ducts, then to terminal clusters of alveolar sacs composed of alveoli  Conducting zone: bronchial tree Air passages undergo:  23 orders of branching in the lungs  bronchiole: ≤1 mm in diameter Respiratory zone: alveoli Pulmonary arteries:  supply systemic venous blood (deoxygenated) for gaseous exchange  branch profusely, along with bronchi  ultimately feed into the pulmonary capillary network surrounding the alveoli Pulmonary veins: carry oxygenated blood from respiratory zones to the heart Pleurae  Pleurae Each lung is surrounded by a completely closed sac, the pleural sac, consisting of a thin sheet of cells called pleura. The pleural surface coating the lung known as the visceral pleura is firmly attached to the lung by connective tissue. Similarly, the outer layer, called the parietal pleura, is attached to and lines the interior thoracic wall and diaphragm. The pleura are separated by an extremely thin layer of intrapleural fluid (few mm thick), totally surrounds the lungs, and lubricates the pleural surfaces so that they can slide over each other during breathing. Changes in the hydrostatic pressure of the intrapleural fluid: intrapleural pressure (Pip) cause the lungs and thoracic wall to move in and out together during normal breathing.  Pulmonary ventilation  The physiology of ventilation, i.e. the process of inspiration and expiration and rest, during forced breathing  Clinical significance: processes of inspiration and expiration are vital for providing oxygen to tissues and removing carbon dioxide from the body.  Determinants of airway  Lung Volumes  Process of inspiration resistance: diameter  Lung Capacities  Process of passive expiration  Turbulent vs. laminar flow  Forced breathing  Surface tension (surfactant)  Airway resistance  refers to the degree of resistance to air flow through the respiratory tract during inspiration and expiration.  degree of resistance depends on multiple factors: e.g. airway diameter and whether flow is laminar or turbulent.  Alveolar expansion is also dependent on surfactant Work of breathing Pressure‐volume work performed in moving air into and out of lungs Air: essentially a low viscosity fluid Airway diameter: small changes can have dramatic impact on airflow resistance. Large airways: contribute most to airway resistance; arranged in series with small total cross‐ sectional area Small airways provide relatively little resistance: arranged in parallel; large total cross‐sectional area; slow/laminar flow  Airway resistance: determinants Physical, neural, and chemical factors affect airway radii and therefore resistance. Nervous system control The autonomic nervous system usually determines airway diameter: Sympathetic innervation causes relaxation of bronchial smooth muscle via 2 receptors, which causes an increase in airway diameter to allow more airflow. Sympathetic stimulation, adrenaline (epinephrine) and salbutamol (common asthma therapy) cause bronchodilatation via β2‐ adrenoceptors on the smooth muscle. Parasympathetic innervation works on muscarinic (M3) receptors to increase smooth muscle contraction and reduce diameter, i.e. bronchoconstrictors. These include reflex release of muscarinic neurotransmitters from parasympathetic nerve endings, generally due to the activation of irritant receptors. Mediators released by inflammatory cells, e.g. histamine, prostaglandins, leukotrienes in asthma, increased mucus production also narrows the lumen and increases resistance. Surfactant Surface tension refers to the tendency of fluid to shrink to the smallest possible volume. Fluid lining the alveolar surface resists stretching of the alveoli. The higher the surface tension, the harder it is for the lungs to stretch. Type II alveolar cells secrete surfactant which is a mixture of phospholipids (hydrophilic & hydrophobic components) Surfactant molecules disrupt the hydrogen bonds between water molecules on the surface ‐ helps to overcome surface tension and allows the alveoli to expand. prevents alveolar collapse and helps maintain similar alveolar sizes, and reduces lung stiffness and transudation.  Surfactant: functions Increasing compliance  Lung compliance is a measure of the lung distensibility, i.e. amount of pressure needed to inflate lungs to a given volume (V/P).  Surface tension decreases lung compliance and thereby increases the effort required for inflation.  Surfactant reduces the adverse effect of surface tension on compliance and thereby makes the lungs easier to inflate. Keeping lungs dry  The collapsing fluid bubble within an alveolus exerts a negative pressure on the alveolar lining. This pressure creates a driving force for fluid movement from the interstitium onto the alveolar surface.  The presence of fluid within an alveolar sac interferes with gas exchange and negatively impacts lung performance.  Surfactant reduces the pressure gradient and thereby helps keep lungs fluid free.  Stabilizing effect of surfactant No surfactant If Ta  Tb then Pa  Pb Air flows from b to a b collapses into a With surfactant 2T P If Tb  Ta (due to unique property of surfactant) r ra  rb then Pa  Pb No flow from b to a; smaller alveoli do not collapse into bigger alveoli  Lung volumes and capacities (recorded on a spirometer) Typical Value Measurement Definition Notes at test Respiratory Volumes depicts the functions of the respiratory centres, respiratory muscles and the mechanics of the lung and chest wall Tidal volume (TV) 0.3‐0.5L Amount of air inhaled or exhaled in one breath changes with pattern of breathing e.g. shallow breaths vs deep breaths increased in pregnancy/on exercise Inspiratory reserve Amount of air in excess of tidal inspiration that can be relies on muscle strength, lung compliance (elastic recoil) and a normal 1.9‐3.0L volume (IRV) inhaled with maximum effort (inspired forcibly) starting point (end of tidal volume) relies on muscle strength and low airway resistance Expiratory reserve Amount of air in excess of tidal expiration that can be exhaled 1.0‐1.2L reduced in pregnancy, obesity, severe obstruction or proximal of volume (ERV) with maximum effort trachea/bronchi obstruction Amount of air remaining in the lungs after maximum cannot be measured by spirometry Residual volume (RV) 1.2L expiration; keeps alveoli inflated between breaths and mixes increases in obstructive lung diseases with features of incomplete with fresh air on next inspiration emptying of the lungs and air trapping Respiratory Capacities (fixed as they do not change with the pattern of breathing) often changes in disease, age and body size; reduces in obstructive Amount of air that can be exhaled with maximum effort after disorders; Vital capacity (VC) 4.5‐4.7L maximum inspiration (ERV + TV + IRV); used to assess requires adequate compliance, inspiratory/expiratory muscle strength strength of thoracic muscles as well as pulmonary function and low airway resistance Maximum amount of air that can be inhaled after a normal Inspiratory capacity (IC) 3.5L tidal expiration (TV + IRV) affected by height, gender, posture, changes in lung compliance; Functional residual Amount of air remaining in the lungs after a normal tidal 2.2‐2.4L reduces in obstructive disorders; capacity (FRC) expiration (RV + ERV) height has the greatest influence restriction: < 80% predicted Hyperinflation: > 120% predicted Total lung capacity (TLC) 5.7‐5.9L Maximum amount of air the lungs can contain (RV + VC) increased in patients with obstructive defects, e.g. emphysema and decreased in patients with restrictive abnormalities including chest wall abnormalities measured with helium dilution Spirometer (measuring volumes and capacities)  The subject breathes from a closed circuit over water  The chamber is filled with oxygen and as they breathe, gas increased and reduces the volumes within the circuit  A weight above the chamber changes height with each ventilation according to the circuit volume  The height is recorded with a pen to reflect the volume inspired or expired over time Lung volumes and capacities (recorded on a spirometer) Dead spaces Conducting zone Fresh air (anatomical dead space) “Old air” Volumes of inhaled air that do not undergo gas exchange with the blood: Alveolus Anatomic dead space: Volume of inhaled air that is not exchanged, i.e. it remains in the conduction pathway (~ 150 mL out of the tidal volume of 500 mL). Expiration (a) Inspiration Alveolar dead space: Volume of inhaled air that is not exchanged, i.e. it enters alveoli with little or no blood supply; this is normally minimal, but can increase in certain lung diseases. Physiologic dead space (PDS): Total volume of inhaled air that is not exchanged; sum of anatomic & alveolar dead space (wasted ventilation). (c) (b) CO2 O2 Exchange with blood  Mechanics of breathing Lung mechanics characterize the physical interactions of the lungs, diaphragm, and chest wall during breathing and breath holding. Breathing (or pulmonary ventilation) is a mechanical process that depends on volume changes in the thoracic cavity. It consists of two phases:  Inspiration – air flows into the lungs  Expiration – gases exit the lungs Volume changes lead to pressure changes, which lead to the flow of gases to equalize pressure: V  P  F (flow of gases) F = P/R Flow (F) is proportional to the pressure difference (ΔP) between two points and inversely proportional to the resistance (R). Lungs and breathing Pleural space (space between the outer surface of the lungs and inner thoracic wall) is usually filled with pleural fluid, forming a seal which holds the lungs against the thoracic wall by the force of surface tension. This seal ensures that when the thoracic cavity expands or reduces, the lungs undergo expansion or reduction in size accordingly. During breathing, the contraction and relaxation of muscles acts to change the volume of the thoracic cavity. As the thoracic cavity and lungs move together, this changes the volume of the lungs, in turn changing the pressure inside the lungs. Boyle’s law states that the volume of gas is inversely proportional to pressure (when temperature is constant). Therefore: When the volume of the thoracic cavity increases, the pressure within the lungs decreases. When the volume of the thoracic cavity decreases, the pressure within the lungs increases.  Inspiration  the phase of ventilation in which air enters the lungs.  is initiated by contraction of the inspiratory muscles: Diaphragm – flattens, extending the superior/inferior dimension of the thoracic cavity. External intercostal muscles – elevate the ribs and sternum, extending the anterior/posterior dimension of the thoracic cavity.  The action of the inspiratory muscles ‐ increase the volume of the thoracic cavity. As the lungs are held against the inner thoracic wall by the pleural seal, they also undergo an increase in volume.  As per Boyle’s law, an increase in lung volume results in a decrease in the pressure within the lungs. The pressure of the environment external to the lungs is now greater than the environment within the lungs, meaning air moves into the lungs down the pressure gradient. Mechanism of breathing on inspiration   Expiration is the phase of ventilation in which air Passive expiration is expelled from the lungs.  is initiated by the relaxation of the inspiratory muscles: Diaphragm – relaxes to return to its resting position, reducing the superior/inferior dimension of the thoracic cavity. External intercostal muscles – relax to depress the ribs and sternum, reducing the anterior/posterior dimension of the thoracic cavity.  relaxation of the inspiratory muscles ‐ decrease in the volume of the thoracic cavity.  The elastic recoil of the previously expanded lung tissue allows them to return to their original size.  As per Boyle’s law, a decrease in lung volume results in an increase in the pressure within the lungs. The pressure inside the lungs is now greater than in the external environment, meaning air moves out of the lungs down the pressure gradient. Mechanism of breathing on expiration Forced breathing an active mode of breathing which utilizes additional muscles to rapidly expand and contract the thoracic cavity volume. It most commonly occurs during exercise. Active Inspiration involves the contraction of the accessory muscles of breathing (in addition to those of quiet inspiration, the diaphragm and external intercostals). All of these muscles act to increase the volume of the thoracic cavity:  Scalenes – elevates the upper ribs.  Sternocleidomastoid – elevates the sternum.  Pectoralis major and minor – pulls ribs outwards.  Serratus anterior – elevates the ribs (when the scapulae are fixed).  Latissimus dorsi – elevates the lower ribs. Active Expiration utilizes the contraction of several thoracic and abdominal muscles. These muscles act to decrease the volume of the thoracic cavity:  Anterolateral abdominal wall – increases the intra‐abdominal pressure, pushing the diaphragm further upwards into the thoracic cavity.  Internal intercostal – depresses the ribs.  Innermost intercostal – depresses the ribs. Breathing: roles of the diaphragm & other respiratory muscles Gas exchange Saturation of Hb with oxygen against pO2  Gas exchange between blood and alveoli Alveolar gas composition  The atmosphere is mostly oxygen and nitrogen, while alveoli contain more carbon dioxide and water vapor  These difference result from:  gas exchanges in the lungs: oxygen diffuses from the alveoli and carbon dioxide diffuses into the alveoli  air is humidified by the conducting pathways  mixing of alveolar gas occurs with each breath Overview on exchange and transport of O2 and CO2 Partial pressures of CO2 and O2 in inspired air & in various places in the body: Venous Arterial Alveoli Atmosphere blood blood pO2 40 mmHg 100 mmHg* 105 mmHg* 160 mmHg pCO2 46 mmHg 40 mmHg 40 mmHg 0.3 mmHg  Gas diffusion at the alveoli and cells  Gases move from areas of high partial pressures to areas of low partial pressure  Venous blood has the same PO2 as tissues  Physics of gas diffusion  The movement of gases in a contained space (in this case, the lungs) is random.  The overall diffusion results in movement from areas of high concentration to those of low concentration. The rate of diffusion of a gas is primarily affected by  concentration gradient: the greater the gradient, the faster the rate  surface area for diffusion: the greater the surface area, the faster the rate  length of the diffusion pathway: the greater the length of the pathway, the slower the rate  Movement of gases between gas and fluid phases (e.g. alveolar air and capillary blood) will be dependent on the difference in partial pressures rather than the concentration. Henry’s law: dissolved gas concentration = partial pressure of gas above fluid × solubility of that gas in that fluid.  External respiration: pulmonary gas exchange Factors influencing the movement of oxygen and carbon dioxide across the respiratory membrane:  Partial pressure gradients and gas solubilities  Structural characteristics of the respiratory membrane: are only 0.5 to 1 m thick, allowing for efficient gas exchange have a total surface area (in males) of 50‐70 m2 (40 times that of one’s skin) thicken if lungs become waterlogged and edematous, whereby gas exchange is inadequate and oxygen deprivation results (NB: decrease in surface area with emphysema, when walls of adjacent alveoli break) Movement of gases  Pressure gradient: partial pressure change  Solubility: gas into liquid  Temperature: higher faster  Transport of oxygen in blood  More than 98% of the oxygen in blood is bound to hemoglobin in red blood cells, and less than 2% is dissolved in plasma.  Molecular oxygen (O2) is carried in the blood bound to hemoglobin (Hb) within RBCs and dissolved in plasma:  Each hemoglobin molecule binds 4 oxygen in a rapid and reversible process  The hemoglobin‐oxygen combination is called oxyhemoglobin (HbO2)  Hemoglobin that has released oxygen is called reduced hemoglobin (HHb): Lungs HHb + O2 ⇌ HbO2 + H+ Tissues Role of hemoglobin in oxygen transport Hemoglobin (Hb)  Chain  Chain Heme  Hemoglobin is composed of four polypeptide group chains, each with an iron‐containing heme group that reversibly binds oxygen  As such, each hemoglobin can reversibly bind up to four oxygen molecules (Hb + 4O2 = HbO8) (a) Porphyrin ring (b) Hemoglobin (Hb): T and R form  Hemoglobin saturation curve (oxygen‐hemoglobin dissociation curve)  Hemoglobin is almost completely saturated at a PO2 of 70 mmHg  Further increases in PO2 produce only small increases in oxygen binding  Only 20‐25% of bound oxygen is unloaded during one systemic circulation  If oxygen levels in tissues drop, more oxygen dissociates from hemoglobin and is used by cells Factors influencing Hb saturation / dissociation of O2 from Hb (i.e. O2 affinity) Factors influencing Hb saturation or dissociation of O2 from Hb Temperature CO2 concentration or PCO2 Higher temperature decreases saturation shifting curve to the right Increased CO2 decreases O2 saturation Factors influencing Hb saturation/dissociation of O2 from Hb pH or [H+] 2,3‐biphosphoglycerate (BPG) Release more O2 at pH 7.2 (during Released as a response to low O2 levels as exercise) than pH 7.4 can happen in anemia or high altitudes BPG / DPG: 2,3‐biphosphoglycerate or 2,3‐diphosphoglycerate  Factors that increase release of O2 from Hb Temperature, H+, PCO2 and BPG modify the structure of hemoglobin and alter its affinity for oxygen by either decreasing hemoglobin’s affinity for oxygen; enhancing oxygen unloading from the blood. All results are to decrease O2 binding to Hb. Metabolizing cells  As cells metabolize glucose, CO2 is released into the blood causing:  an increase in PCO2 and H+ concentration in capillary blood  a decline in pH (acidosis) weakens the hemoglobin‐oxygen bond (Bohr effect)  generate heat as byproduct. The rise in temperature increases BPG synthesis  All these factors results in oxygen unloading in the vicinity of working tissue cells Hb structure influences O2 binding & unloading Q: Which one has greater oxygen‐binding properties? O2 affinity: fetal vs. maternal Hb Hemoglobin vs. myoglobin in O2 affinity Fetal hemoglobin has greater affinity Factors contributing to the total O2 content of arterial blood  Transport of carbon dioxide in blood Carbon dioxide is transported in the blood in three forms:  Dissolved in plasma: 7‐10% (although CO2 is more soluble in plasma than oxygen, only a small amount is dissolved in it)  Chemically bound to hemoglobin:  20% is carried in RBCs as carbaminohemoglobin formed with CO2 and hemoglobin bind, it decreases affinity for O2;  Hemoglobin also binds H+ ‐ hemoglobin acts as a buffer binding H+ to resists pH changes  Bicarbonate ion in plasma: 70% is transported as bicarbonate (HCO3–) an enzyme converts of the CO2 in RBCs into bicarbonate carbonic anhydrase CO2 + H2O H2CO3 H+ + HCO3– Carbon dioxide diffuses into RBCs and combines with water to form carbonic acid (H2CO3), which quickly dissociates into hydrogen ions and bicarbonate ions.  Transport & Exchange of carbon dioxide At the tissues: As more carbon dioxide enters the blood,  More oxygen dissociates from hemoglobin (Bohr effect)  More carbon dioxide combines with hemoglobin, and more bicarbonate ions are formed.  The amount of carbon dioxide transported is markedly affected by the PO2  Transport & Exchange of carbon dioxide At the tissues:  Bicarbonate quickly diffuses from RBCs into the plasma  Chloride shift: to counterbalance the outrush of negative bicarbonate ions (HCO3–) from the RBCs, chloride ions (Cl–) move from the plasma into the RBCs  Transport & Exchange of carbon dioxide At the lungs: At the lungs, these processes are reversed:  Bicarbonate ions move into the RBCs and bind with hydrogen ions to form carbonic acid  Carbonic acid is then split by carbonic anhydrase to release carbon dioxide and water  Carbon dioxide then diffuses from the blood into the alveoli Summary: CO2 transport & exchange  Summary: transport & exchange of O2 and CO2 Comparison of the ways in which O2 and CO2 are transported between lungs and tissues. Overview: control of respiration/breathing Regulation of respiration/breathing Volunteer control center in cerebral cortex Automatic control centers in medulla and pons. Nerve impulses or electrical signals from the respiratory neurons in these centers regulate: the activity of respiratory muscles (including diaphragm) the rate and depth of breathing (ventilation). Mechanoreceptors sense the physical changes in the lungs and chest wall Chemoreceptors (central and peripheral) ‐ the chemical changes in the blood (e.g. arterial Pco2, arterial Po2 and [H+]) to further adjust the control of breathing.  Respiratory center: control of respiratory rhythm Medulla Ventral respiratory group (ventrolateral side of medulla) pre‐Bötzinger complex: respiratory rhythm generator (upper part of the VRG) composed of pacemaker cells and a complex neural network; stimulates expiratory muscles to control voluntary forced exhalation and acts to increase the force of inhalation; Dorsal respiratory group (dorsal portion of medulla) primarily fire during inspiration; have input to the spinal motor neurons that activate respiratory muscles involved in inspiration (diaphragm and inspiratory intercostal muscles) Pons (pontine respiratory group / PRG) Both centers coordinates speed of inhalation and exhalation; Pneumotaxic center (superior pons) inhibits inspiration, limiting the size of tidal volume, and secondarily increasing the breathing rate Apneustic center (inferior pons) increases the duration of inspiratory signals, increasing the duration of diaphragmatic contraction and resulting in more complete lung filling and a decreased breathing rate.  Neural control of ventilation Involuntary control (under subconscious control)  Primary respiratory muscles: diaphragm and intercostal muscles  stimulated by groups of neurons located in the pons and medulla which send impulses to the primary respiratory muscles, via the phrenic and intercostal nerves, which stimulate their contractions.  3 main groups of neurons involved in respiration: ventral respiratory group controls expiration The dorsal respiratory group controls inspiration The pontine respiratory group controls the rate and pattern of breathing Once the neurons stop firing, the inspiratory muscles relax and expiration occurs.  Neural control of ventilation Voluntary Control (under conscious control)  controlled via the motor cortex in the cerebrum, which receives inputs from the limbic system and hypothalamus.  mechanisms involved are not completely understood; but sends impulses to the respiratory motor neurons via the corticospinal tracts to the spinal cord, which are then passed onto the respiratory muscles.  The respiratory nerves in the medulla and pons also receive synaptic input from higher centers of the brain such that the pattern of respiration is controlled voluntarily during speaking, diving, and even with emotions and pain.  Emotions can cause yawning, laughing, sighing, social communication causes speech, song and whistling, while entirely voluntary overrides are used to blow out candles, and breath holding to swim underwater.  This voluntary control of respiration, however, has limits. Regardless of cerebral intent to the contrary, we resume breathing when our bodies sense the need for more oxygen or if carbon dioxide levels increase to certain levels.  Chemical control of respiration Chemoreceptors: groups of nerve terminals that are very sensitive to changes in pH, pO2, and pCO2, which lead to the firing of these afferent nerves to the brainstem respiratory centers. Peripheral chemoreceptors  located in the arterial aortic bodies and the carotid bodies.  detect changes in the levels of oxygen and carbon dioxide in the arterial blood. They are stimulated by: significantly decreased pO2 (hypoxia) increased H+ concentration (metabolic acidosis) increased pCO2 (respiratory acidosis) Central chemoreceptors  located in the medulla oblongata near to the medullar respiratory groups of the respiratory center*  respond to changes in the brain cerebrospinal fluid (CSF). They are stimulated by increased CO2 concentration ‐ primarily sensitive to changes in the pH of the blood (resulting from changes in the levels of carbon dioxide) * From the respiratory center, the muscles of respiration, in particular the diaphragm, are activated to cause air to move in and out of the lungs. Peripheral chemoreceptors detect variation of the pO2 in the arterial blood, (~20%: arterial pCO2 and pH) Carotid bodies small distinct structures located at the bifurcation of the common carotid arteries; are innervated by the carotid sinus nerve and thence the glossopharyngeal nerve; is formed from glomus (type I) and sheath (type II) cells; Glomus cells are chemoreceptive, contain neurotransmitter‐rich dense granules and contact carotid sinus nerve axons. Aortic bodies located on the aortic arch and are innervated by the vagus; are similar to carotid bodies but functionally less important. Peripheral chemoreceptors: mechanism (stimulation by O2 deficiency) A number of responses are then coordinated which aim to restore pO2:  The respiratory rate and tidal volume are increased to allow more oxygen to enter the lungs and subsequently diffuse into the blood  Blood flow is directed towards the kidneys and the brain (as these organs are the most sensitive to hypoxia)  Cardiac output is increased to maintain blood flow, and therefore oxygen supply to the body’s tissues  Central chemoreceptors Chemosensitive area  is located bilaterally, lying only 0.2 mm beneath the ventral surface of the medulla;  is highly sensitive to changes in either blood pCO2 or [H+], i.e. responds indirectly to blood pCO2, but does not respond to changes in pO2.  As H+ and HCO3‐ cannot diffuse across the blood–brain barrier from the blood into the cerebrospinal fluid (CSF), the pH of the CSF around the chemoreceptor is determined by the arterial pCO2 and CSF [HCO3‐]  A rise in blood pCO2 makes the CSF more acidic and is detected by the chemoreceptor which increases ventilation to blow off CO2. Central chemoreceptors: mechanism (stimulation by pCO2 and [H+])  Peripheral chemoreceptors (stimulation by pCO2 and [H+])  An increase in CO2 or [H+] also excites the peripheral chemoreceptors and, in this way, indirectly increases respiratory activity.  However, the direct effects of both these factors in the respiratory center are much more powerful than their effects mediated through the peripherial chemoreceptors (~7 times as powerful).  Yet, the stimulation via the peripheral chemoreceptors occurs as much as 5 times as rapidly as central stimulation.  Peripheral chemoreceptors might be especially important in increasing the rapidity of response to CO2 at the onset of exercise. Respiratory system: responses to arterial pCO2 change  Mechanoreceptors (pulmonary reflexes) They are responsible for a variety of reflex responses. Stretch receptors  located in the bronchial walls.  stimulation (by stretch) causes short, shallow breaths, and delay of the next inspiratory cycle.  provide negative feedback to turn off inspiration.  are largely responsible for the Hering–Breuer inspiratory reflex, in which lung inflation inhibits inspiration to prevent overinflation. Juxtapulmonary (J) receptors  located on the alveolar and bronchial walls close to the capillaries.  stimulated by increased alveolar wall fluid, oedema, microembolisms and inflammation.  cause depression of somatic and visceral activity by producing rapid shallow breathing or apnea (cessation of breathing), a fall in heart rate and blood pressure, laryngeal constriction and relaxation of the skeletal muscles via spinal neurons.  Mechanoreceptors (pulmonary reflexes) Irritant receptors  located throughout the airways between epithelial cells;  cause cough in the trachea; and hyperpnoea (rapid breathing) in the lower airways;  stimulation also causes bronchial and laryngeal constriction;  stimulated by irritant gases, smoke and dust, rapid large inflations and deflations, airway deformation, pulmonary congestion and inflammation. Proprioceptors (position/length sensors)  located in the Golgi tendon organs, muscle spindles and joints;  important for matching increased load, and maintaining optimal tidal volume and frequency;  stimulated by shortening and load in the respiratory muscles (but not diaphragm)  input from non‐respiratory muscles and joints can also stimulate breathing.  Factors that affect breathing Emotional state Chemical Stretching of lung Exercise Summary: control of respiration