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Respiratory System Continued Chapter 18 Gas Exchange and Transport  Gas Exchange and Transport Overview of oxygen and carbon dioxide exchange and transport Air is brought into the alveoli of the lung...

Respiratory System Continued Chapter 18 Gas Exchange and Transport  Gas Exchange and Transport Overview of oxygen and carbon dioxide exchange and transport Air is brought into the alveoli of the lungs where gas exchange occurs with the blood across the alveolar- capillary interface. (1, 6) Oxygenated blood is returned to the left side of the heart that pumps it to the systemic circulation. (2) In the tissue capillary beds, O2 and CO2 flow down their respective pressure gradients. (3,4) Deoxygentated blood flows back to the right side of heart that pumps it to the lungs. (5)  Gas Exchange The movement of O2 and CO2 across the alveolar- capillary interface and capillary-tissue interface occurs as a result of simple diffusion. The primary determinant of the movement of these gases across the interface is the pressure gradient for these gases in accord with the 2nd gas law. (Remember: a gas will move from regions where it is in higher pressure to where they are in lower pressure.)  Gas Exchange The Rate of Gas Diffusion The rate of diffusion of O2 and CO2 between alveoli and pulmonary capillaries or between the tissue capillaries and the tissues is affected by a number of factors that are summarized in Fick’s Law of Diffusion: Diffusion Rate a surface area for gas exchange X membrane permeability X concentration gradient membrane thickness Because all of these factors are normally constant, with the exception of concentration gradient, the diffusion rate in gas exchange is proportional to its concentration gradient.  Gas Exchange: Gas Solubility The movement of a gas between the air and blood is also affected by the solubility of the gas in the liquid part of the blood (the plasma). Solubility is an expression of the ease with which a gas will dissolve in a liquid. It is a property of both the gas and the liquid. Different gases have different solubilities in different liquids. If the gas is very soluble in the liquid, it will dissolve into solution at a low pressure. If the gas is not very soluble in the liquid, it will take a higher pressure of the gas at the surface of the liquid to dissolve even just a few molecules of the gas in the liquid. CO2 is 20 X more soluble in water than O2 is. So, you can dissolve a lot more CO2 in the blood plasma than O2. The reason for this is that CO2 reacts with the water molecules: CO2 + H2O H2CO3 H+ + HCO3- (Carbonic acid) (Bicarbonate) This reaction effectively removes some of the dissolved CO2 from the diffusion equilibrium for this gas, so more CO2 can move into the liquid. The amount of gas that is dissolved in a solution is called the partial pressure of the gas in the solution and is written as Pgas. For example, the PCO2 is the partial pressure of CO2 in the solution. The pressure of a gas is expressed as mmHg.  Gas Exchange: Gas Solubility The relatively low solubility of O2 in water is thought to be the reason that animals evolved oxygen binding blood proteins, such as hemoglobin. By binding some of the O2 that is dissolved in the blood plasma, these blood proteins effectively remove dissolved O2 from the diffusion equilibrium so that more O2 can be dissolved in the blood plasma. Without these oxygen binding blood proteins the blood would not be able to carry enough O2 to adequately supply O2 to the tissues. Gas Exchange Remember from last lecture: Normal resting breathing gives an AV of about 4.2L/min (@ 12 brths/min and VT of 500ml). At an AV of 4.2L/min the PO2 in the alveolar air is 100mmHg, and the PCO2 is 40mmHg Normal arterial blood plasma PO2 is 100mmHg, and the normal PO2 in the extra cellular fluid of the tissues is < 40mmHg (it may be lower depending on the metabolic activity level of the cells in the tissue). Normal arterial blood plasma PCO2 is 40mmHg, and normal PCO2 in the extra cellular fluid of the tissues is > 46mmHg (it may be higher depending on the metabolic activity level of the cells in the tissue). The pressure gradients across the Alveolar-Capillary interface and Tissue-Capillary interface determine the movement of these gases (O2 and CO2) across these interfaces.  Gas Exchange at the Alveoli and Cells Alveolar-capillary O2 moves into CO2 into interface blood alveoli O2 moves Into Tissue-capillary tissues CO2 into interface blood  Gas Transport: Transport of O2 in Blood O2 is transported in the blood in 2 ways: 2% is transported dissolved in the blood plasma. 98% is transported bound to the hemoglobin contained within the red blood cells.  Gas Transport: Transport of O2 in Blood Hb molecules consist of 4 protein subunits called globins β globin subunit Hb molecule: 2a globin subunits α globin 2b globin subunits subunit Heme group The iron atom of each heme group can reversibly bind to an O2 molecule Iron atom So, each Hb molecule can reversibly bind up to 4 O2 molecules.  Gas Transport: Transport of O2 in Blood Hemoglobin Binding The amount of O2 bound to the Hb in the blood depends primarily on the PO2 in the plasma. If the PO2 increases, the amount of O2 bound to the Hb in the blood increases until all the O2 binding sites are occupied by an O2. The amount of O2 bound to Hb in a given amount of blood is expressed as the % saturation of the Hb. When all the O2 binding sites on the Hb in the blood are bound to an O2 molecule the Hb is said to be 100% saturated.  Gas Transport: Transport of O2 in Blood Oxygen-Hemoglobin Dissociation Curve All the O2 binding sites At a PO2 of 100mmHg, In blood are Hb normally only 98% of available releases 25% of O2 binding sites are bound to O2 it is carrying at a occupied by an O2 tissue PO2 of 40. As long as plasma PO2 is 75% remains bound more than 60, over 90% of to Hb Hb binding sites are and acts as a occupied by an O2. So, Half the O2 reserve when near normal levels of O2 metabolic will be delivered to the binding sites in activity tissues. increases. blood are bound to O2 Below PO2 60mmHg, O2 binding affinity of Hb decreases, so Hb releases O2 more readily. Reflects available O2 binding sites PO2 in PO2 in arterial blood tissues  Gas Transport: Transport of O2 in Blood Factors that affect O2 binding affinity of Hb (how tightly the Hb binds to O2) : pH of blood Temperature of blood PCO2 in blood Concentration of 2,3 Diphosphoglycerate ( 2,3 DPG, a.k.a. 2,3 Biphosphoglycerate, 2,3 BPG) a metabolic by-product synthesized by RBCs. Changing any of these factors changes how readily the Hb binds/releases its O2, i.e. will change the O2 binding affinity of Hb. A change in the O2 binding affinity will change the shape and position of the oxy-hemoglobin dissociation curve. A shift in the curve the right (away from the y-axis side) reflects a decrease in the O2 binding affinity of the Hb (so a higher PO2 is required to achieve a particular % saturation of the Hb). A shift in the curve to the left (towards the y-axis side) reflects an increase in O2 binding affinity of the Hb (so a particular % saturation is achieved at a lower PO2). Gas Transport: pH and O2 binding Affinity of Hb Normal blood pH is 7.4. Increasing the pH of the blood (i.e. making the blood more basic) increases O2 binding affinity of Hb. This is reflected by a leftward shift in the position of the oxy-Hb dissociation curve. Normal pH of blood Decreasing the pH of blood (acidic) decreases O2 binding affinity of Hb. This is reflected in a rightward shift in the position of the oxy-Hb dissociation curve. The relationship between pH and O2 binding affinity is called the “BOHR EFFECT”  Gas Transport: pH and O2 binding Affinity of Hb Physiologic significance of the Bohr effect: When a tissue increases its metabolic activity it releases H+ that diffuses into the blood in the capillaries of the tissue, causing the pH of the blood in local capillaries to fall (i.e. it becomes more acidic). This results in a decrease in O2 binding affinity of Hb in the blood in the capillaries of the tissue, so Hb releases its O2 more readily as the blood passes through the capillaries of this tissue. So, more O2 is released into the metabolically active tissue where it is needed. Gas Transport: Temperature and O2 binding Affinity of Hb Normal body temperature is 37oC (98.6oF). As temperature of the blood increases above 37oC, the O2 binding affinity of Hb decreases, and as temperature drops below this, the O2 Normal binding affinity above increases. body temp. The changes in the O2 binding affinity of Hb with changes in temperature of the blood are reflected in a shift in the position of the Oxy-Hb dissociation curve. Increases in blood temperature cause a rightward shift and decreases in blood temperature cause a leftward shift.  Gas Transport: Temperature and O2 binding Affinity of Hb Physiologic significance of the temperature and O2 binding affinity of Hb: When the metabolic activity in a tissue increases the reactions generate heat. So, as blood flows through the capillaries in this tissue the temperature of the blood rises. As the blood temperature rises the O2 binding affinity of the Hb in the blood decreases. So more of the O2 is released into this metabolically active tissue where it is needed. Also, when the blood passes through the lung capillaries it is cooled, and so the Hb in the blood more readily binds O2. This promotes the uptake of O2 into the blood as it passes through the lung capillaries. Gas Transport: PCO2 and O2 binding Affinity of Hb Normal PCO2 in the arterial blood is 40mmHg. If PCO2 rises above this, the O2 binding affinity of Hb in the blood decreases. This is reflected in a rightward shift in the oxy-Hb dissociation curve. Normal If the PCO2 falls below this, the O2 PCO2 binding affinity of Hb increases. This is reflected in a leftward shift in the oxy-Hb dissociation curve.  Gas Transport: PCO2 and O2 binding Affinity of Hb Physiologic significance of the relationship between PCO2 of the blood and O2 binding affinity of Hb: When the metabolic activity in a tissue increases, more CO2 will be produced. This CO2 will diffuse into the blood in the capillaries of this tissue. So, as blood passes through these capillaries, the PCO2 of this blood will increase. This will cause a decrease in the O2 binding affinity of the Hb in this blood, and so the Hb will release its O2 more readily into this metabolically active tissue. Also, as the blood passes through the capillaries in the lungs the PCO2 in the blood will decrease as the CO2 diffuses out of the blood across the alveolar- capillary interface. This will cause an increase in the O2 binding affinity of the Hb in the blood as it passes through the lung capillaries. This will promote the uptake of O2 by the blood as it passes through the lung capillaries. Gas Transport: 2,3 DPG and O2 binding Affinity of Hb 2,3 DPG is an organic phosphate synthesized by RBC’s that acts to lower the O2 binding affinity of Hb in the RBC. Increased levels of 2,3 DPG decrease the O2 Considered to be levels affinity of Hb in the blood, in the blood of people at sea level. this is reflected by a rightward shift in the oxy- Hb dissociation curve Decreases in the levels of 2,3 DPG increase the O2 binding affinity of Hb in the blood, reflected by a leftward shift in the oxy- Hb dissociation curve.  Gas Transport: 2,3 DPG and O2 binding Affinity of Hb Physiologic significance of 2,3 DPG: Synthesis of 2,3 DPG is stimulated by extended periods of low plasma PO2 (chronic hypoxia). A common situation that stimulates the synthesis of 2,3 DPG is travel from sea level to a higher altitude, ex. Denver, Colorado (elevation 5000ft) where the PO2 is lower in the atmosphere. After a day or 2 of extended hypoxia the RBCs will increase their synthesis of 2,3 DPG. Increased 2,3 DPG levels in the blood will decrease the O2 binding affinity of Hb, so overall more O2 will be released into the tissues. Over time, the body will also acclimate to low atmospheric PO2 by increasing the overall number of RBCs, increasing the number of capillaries in the tissues, and increasing the concentration of myoglobin in some tissues (particularly skeletal and cardiac muscle). However, these changes take weeks to years to occur.  Gas Transport: Transport of CO2 in the Blood CO2 is Transported in blood in 3 ways: 1. 7% is transported dissolved in the blood plasma. 2. 23% is transported bound to Hb in the RBCs. The CO2 transported in this way is bound to the globin proteins of the Hb, not the iron of the heme. 3. 70% is converted into HCO3-, which is transported dissolved in blood plasma. Remember: CO2 + H2O CA H2CO3 H+ + HCO3- In the blood, conversion of CO2 into HCO3- occurs in the RBCs and is catalyzed by an enzyme, Carbonic Anhydrase (CA) synthesized in the RBCs. CA catalyzes the reaction between CO2 and H2O.  Gas Transport: Transport of CO2 in the Blood CO2 is a by-product of cell respiration. That diffuses out of the tissues and into the blood in the tissue capillaries. VENOUS BLOOD CO2 Cellular Tissue respiration in peripheral tissues Capillary endothelium Cell membrane Lungs Alveoli  Gas Transport: Transport of CO2 in the Blood VENOUS BLOOD CO2 Dissolved CO2 (7%) Cellular respiration Tissue in peripheral tissues Capillary endothelium Cell membrane Lungs Alveoli  Gas Transport: Transport of CO2 in the Blood VENOUS BLOOD CO2 Dissolved CO2 (7%) Cellular respiration Red blood cell CO2 Most Tissue in peripheral tissues enters the RBCs Capillary endothelium Cell membrane Lungs Alveoli  Gas Transport: Transport of CO2 in the Blood VENOUS BLOOD CO2 Dissolved CO2 (7%) Cellular respiration Red blood cell CO2 + Hb Hb CO2 (23%) Tissue in peripheral tissues Capillary endothelium Cell membrane Lungs Alveoli  Gas Transport: Transport of CO2 in the Blood VENOUS BLOOD CO2 Dissolved CO2 (7%) Cellular respiration Red blood cell CO2 + Hb Hb CO2 (23%) Tissue in peripheral tissues 70% CA CO2 + H2O H2CO3 CO2 reacts with H2O in presence of CA to form Capillary H2CO3 endothelium Cell membrane Lungs Alveoli  Gas Transport: Transport of CO2 in the Blood VENOUS BLOOD CO2 Dissolved CO2 (7%) Cellular respiration Red blood cell CO2 + Hb Hb CO2 (23%) Tissue in peripheral tissues 70% CA HCO3– CO2 + H2O H2CO3 H+ + Hb Capillary H2CO3 endothelium dissociates into Cell membrane H+ and HCO3- ions. H+ ions bind to globin of Hb Lungs Alveoli  Gas Transport: Transport of CO2 in the Blood VENOUS BLOOD CO2 Dissolved CO2 (7%) Cellular respiration Red blood cell CO2 + Hb Hb CO2 (23%) Tissue in peripheral tissues 70% CA HCO3– CO2 + H2O H2CO3 H+ + Hb Hb H Capillary H+ ions bind to endothelium globin of Hb Cell membrane Lungs Alveoli  Gas Transport: Transport of CO2 in the Blood VENOUS BLOOD CO2 Dissolved CO2 (7%) Cellular respiration Red blood cell CO2 + Hb Hb CO2 (23%) Cl– Tissue in peripheral tissues 70% CA HCO3– HCO3– in CO2 + H2O H2CO3 plasma H+ + Hb Hb H Capillary Bicarbonate ions are transported endothelium out by a transport mechanism called Cell membrane the Chloride shift, that moves a Cl- ion in exchange for HCO3- Lungs Alveoli  Gas Transport: Transport of CO2 in the Blood VENOUS BLOOD CO2 Dissolved CO2 (7%) Cellular respiration Red blood cell CO2 + Hb Hb CO2 (23%) Cl– Tissue in peripheral tissues 70% CA HCO3– HCO3– in CO2 + H2O H2CO3 Plasma H+ + Hb Hb H Capillary endothelium Cell membrane Transport to lungs in venous and pulmonary circulation Lungs Alveoli  Gas Transport: Transport of CO2 in the Blood VENOUS BLOOD CO2 Dissolved CO2 (7%) Cellular respiration Red blood cell CO2 + Hb Hb CO2 (23%) Cl– Tissue in peripheral tissues 70% CA HCO3– HCO3– in CO2 + H2O H2CO3 plasma H+ + Hb Hb H Capillary endothelium Cell membrane Transport to lungs in venous and pulmonary circulation Dissolved CO2 Dissolved CO2 CO2 Lungs Diffuses down pressure Alveoli gradient into alveolar air  Gas Transport: Transport of CO2 in the Blood VENOUS BLOOD CO2 Dissolved CO2 (7%) Cellular respiration Red blood cell CO2 + Hb Hb CO2 (23%) Cl– Tissue in peripheral tissues 70% CA HCO3– HCO3– in CO2 + H2O H2CO3 Plasma H+ + Hb Hb H Capillary endothelium Cell membrane Transport to lungs in venous and pulmonary circulation Dissolved CO2 Dissolved CO2 CO2 Lungs Hb CO2 Hb + CO2 Alveoli CO2 bound to Hb gets pulled off and diffuses down pressure gradient into alveolar air  Gas Transport: Transport of CO2 in the Blood VENOUS BLOOD CO2 Dissolved CO2 (7%) Cellular respiration Red blood cell CO2 + Hb Hb CO2 (23%) Cl– Tissue in peripheral tissues 70% CA HCO3– HCO3– in CO2 + H2O H2CO3 Plasma H+ + Hb Hb H Capillary endothelium Cell membrane Transport to lungs in venous and pulmonary circulation Dissolved CO2 Dissolved CO2 CO2 Lungs Hb CO2 Hb + CO2 Alveoli  Gas Transport: Transport of CO2 in the Blood VENOUS BLOOD CO2 Dissolved CO2 (7%) Cellular respiration Red blood cell CO2 + Hb Hb CO2 (23%) Cl– Tissue in peripheral tissues 70% CA HCO3– HCO3– in CO2 + H2O H2CO3 Plasma H+ + Hb Hb H Capillary endothelium Cell membrane Transport to lungs in venous and pulmonary circulation Dissolved CO2 Dissolved CO2 CO2 Lungs Hb CO2 Hb + CO2 Cl– Alveoli Chloride shift reverses HCO3– HCO3– in bringing HCO3- back in to RBC plasma in exchange for Cl-  Gas Transport: Transport of CO2 in the Blood VENOUS BLOOD CO2 Dissolved CO2 (7%) Cellular respiration Red blood cell CO2 + Hb Hb CO2 (23%) Cl– Tissue in peripheral tissues 70% CA HCO3– HCO3– in CO2 + H2O H2CO3 Plasma H+ + Hb Hb H Capillary endothelium Cell membrane Transport to lungs in venous and pulmonary circulation Dissolved CO2 Dissolved CO2 CO2 Lungs Hb CO2 Hb + CO2 Cl– Alveoli HCO3– HCO3– in H+ ions get pulled off of plasma Hb H H+ + Hb Hb  Gas Transport: Transport of CO2 in the Blood VENOUS BLOOD CO2 Dissolved CO2 (7%) Cellular respiration Red blood cell CO2 + Hb Hb CO2 (23%) Cl– Tissue in peripheral tissues 70% HCO3– in CA HCO3– CO2 + H2O H2CO3 Plasma H+ + Hb Hb H Capillary endothelium Cell membrane Transport to lungs in venous and pulmonary circulation Dissolved CO2 Dissolved CO2 CO2 Lungs Hb CO2 Hb + CO2 Cl– Alveoli HCO3- and H+ react to HCO3– HCO3– H2CO3 in form H2CO3 plasma Hb H H+ + Hb  Gas Transport: Transport of CO2 in the Blood VENOUS BLOOD CO2 Dissolved CO2 (7%) Cellular respiration Red blood cell CO2 + Hb Hb CO2 (23%) Cl– Tissue in peripheral tissues 70% CA HCO3– HCO3– in CO2 + H2O H2CO3 plasma H+ + Hb Hb H Capillary endothelium Cell membrane Transport to lungs in venous and pulmonary circulation Dissolved CO2 Dissolved CO2 CO2 Lungs Hb CO2 Hb + CO2 Cl– Alveoli CA HCO3– HCO3– H2CO3 H2O + CO2 in plasma Hb H H+ + Hb CA converts H2CO3 back into H2O and CO2  Gas Transport: Transport of CO2 in the Blood VENOUS BLOOD CO2 Dissolved CO2 (7%) Cellular respiration Red blood cell CO2 + Hb Hb CO2 (23%) Cl– Tissue in peripheral tissues 70% CA HCO3– HCO3– in CO2 + H2O H2CO3 Plasma H+ + Hb Hb H Capillary endothelium Cell membrane Transport to lungs in venous and pulmonary circulation Dissolved CO2 Dissolved CO2 CO2 Lungs Hb CO2 Hb + CO2 Cl– Alveoli CA HCO3– HCO3– H2CO3 H2O + CO2 in plasma Hb H H+ + Hb CO2 diffuses down pressure gradient into alveolar air Regulation of Lung Ventilation Breathing is a rhythmic process; however, the respiratory rhythm is not inherent in the muscles used for respiration (unlike the heart). The respiratory rhythm is set and regulated by neural centers in the CNS.  Regulation of Lung Ventilation During normal quiet breathing, the respiratory centers in the medulla oblongata work independently of inputs from higher brain centers. So, normal quiet breathing is subconscious. However, during normal quiet breathing the rate and depth of breathing are regulated by inputs to medullary respiratory centers from receptors called chemoreceptors.  Regulation of Lung Ventilation Respiratory centers in medulla called the dorsal and ventral respiratory groups, control the inspiratory muscles and expiratory muscles. Although there is some overlap, the inspiratory muscles (diaphragm and external intercostal muscles) are regulated primarily by neurons in the DRG, and the expiratory muscles (internal intercostal muscles and abdominal muscles) are regulated primarily by neurons in the VRG. The DRG and VRG are interconnected with each other. The normal rhythmic pattern of breathing arises from a network of spontaneously discharging neurons (respiratory pacemaker neurons) that is located in the VRG. During normal quiet breathing the neurons of the VRG are not active, except for the respiratory pacemaker neurons that send increasing excitatory signals to the neurons in the DRG that in turn excite the motor neurons of the inspiratory muscles resulting in contraction of these muscles and so inspiration occurs. During normal quiet breathing expiration is the result of the elastic recoil of the diaphragm and external intercostal muscles and lung tissue returning the volume of the thoracic cavity and lungs to their pre-inspiratory volume.  Regulation of Lung Ventilation There are also respiratory centers in the pons that receive inputs from higher brain centers and the DRG. The pontine respiratory centers modulate the activity of the medullary respiratory centers to help coordinate a smooth respiratory rhythm. The activity pattern of this neural network is subject to modulation by inputs from: Chemoreceptors. Higher brain centers provide voluntary control as well as regulation of breathing in response to emotions (ex. increased rate and depth of breathing related to emotional upsets).  Regulation of Lung Ventilation: Chemoreceptors During normal quiet breathing, input to the medullary respiratory centers from chemoreceptors regulates the rhythmic activity of these neural centers to help maintain blood gas homeostasis. There are two sets of chemoreceptors: 1) Peripheral chemoreceptors located in the aortic and carotid bodies monitor the pH (H+ concentration), PCO2 , and PO2 in the arterial blood. These receptors are most sensitive to pH and PCO2, and relatively insensitive to PO2. 2) Central chemoreceptors located on the surface of the medulla oblongata and monitor the H+ concentration and PCO2 in the cerebrospinal fluid (CSF).  Regulation of Lung Ventilation: Homeostatic Regulation of Blood Gases During normal quiet breathing a feedback loop exists that regulates lung ventilaton to maintain homeostatic regulation of PCO2, pH, and PO2. When the PCO2 increases and/or pH This will serve to decrease the removal decreases from normal levels in the of CO2 from the blood through the lungs, arterial blood and CSF and bring the PCO2 and pH back towards normal. The chemoreceptors will increase their signal rate to the medullary Which in response will decrease lung respiratory centers ventilation by decreasing the rate and depth of breathing. Which in response will increase lung ventilation by increasing the rate and The chemoreceptors will decrease their depth of breathing. signal rate to the medullary respiratory centers This will serve to increase the removal of CO2 from the blood When the PCO2 decreases and/or pH through the lungs, and bring the PCO2 increases from normal levels in the and pH back towards normal. arterial blood and CSF.