Chapter 17 - Respiratory System: Gas Exchange and Regulation of Breathing

Pulmonary Circulation
     The cells of the body consume an average 250 ml of oxygen per minute and produce about 200 ml of carbon dioxide per minute. The ratio of the carbon dioxide produced over the oxygen consumed is called the respiratory quotient. Hence, the average respiratory quotient is 0.8
     The figure below illustrates the movements of oxygen and carbon dioxide into and out of the lungs and tissue under resting conditions. 
     The figure above illustrates how oxygen and carbon dioxide goes between alveolar air and blood across the respiratory membrane composed of type I epithelial cells of the alveolar walls, endothelial cells of capillaries and the basement membranes sandwiched between them. 
Diffusion of Gases
  Partial Pressure of Gases
     The partial pressure of a gas is the proportion of pressure contributed by an individual gas to the total pressure of a mixture of gases. Partial pressure is found by multiplying:
1. Fractional concentration of a gas in a mixture by,
2. Total pressure exerted by a gas mixture.
     The total pressure of air can be described as the sum of the major gases found in air
Pair = Pnitrogen + Poxygen + Pwater
     On a molar basis air is 79% nitrogen and 21% oxygen assuming zero humidity. Any humidity (water vapor) subtracts from the proportions of nitrogen and oxygen. 
     Carbon dioxide accounts for only 0.03% of the air molecules. 
     At zero humidity and at sea level in air:
Pnitrogen = 0.79 x 760 mm Hg = 600 mm Hg
Poxygen = 0.21 x 760 mm Hg = 160 mm Hg
Pcarbon dioxide = 0.0003 x 760 mm Hg = 0.23 mm Hg
     At 100% humidity the partial pressure of H2O is 47 mm Hg. This causes partial pressures to be:
Pnitrogen = 563 mm Hg
Poxygen = 150 mm Hg
Pcarbon dioxide = 0.21 mm Hg
  Solubility of Gases in Liquids
     Gas molecules dissolved in water have a certain partial pressure. When a liquid and gas come into contact, the concentration of gas molecules in the liquid is proportional to the partial pressure of the gas. At a given partial pressure the relative concentration of different dissolved gases will differ based on there different solubility in the liquid. For example carbon dioxide is 20 times more soluble in blood than oxygen.
     Henry's law describes this relationship with :
c =

k

P

     Where:
c = Molar concentration of gas
P = Partial pressure of gas in atmosphere
k = Henry's law constant (based on gas and temperature)
     When containers of water are exposed to 100 mm Hg of pure oxygen or carbon dioxide, overtime the gas in the air equilibrates with the gas dissolved in the liquid till they are both at 100 mm Hg. However, because carbon dioxide dissolves more readily in water, the concentration of the gas in the water is much higher for carbon dioxide than for oxygen. This becomes clear when the calculations are made:
   
Pressure at 37o C Concentration in Air Concentration in Water
Oxygen 100 mm Hg 5.2 mmole/liter 0.15 mmole/liter
Carbon dioxide 100 mm Hg 5.2 mmole/liter 3.0 mmole/liter

 

Exchange of Oxygen and Carbon Dioxide
     Gases will diffuse down their partial pressure gradients.
  Gas Exchange in the Lungs 
     Although partial pressures of oxygen and carbon dioxide in the atmosphere are 160 mm Hg and 0.23 mm Hg, respectively, in the alveoli the pressures are 100 mm Hg for oxygen and 40 mm Hg for carbon dioxide. This is because:
1. Exchanges of gas between alveoli and capillaries.
2. Mixing of atmospheric air with air of anatomic dead spaces.
3. Saturation of alveoli air with water vapor.
     Deoxygenated blood entering the pulmonary capillaries has a PO2 of 40 mm Hg and PCO2 of 46 mm Hg. The gases diffuse down their concentration gradients and leave at the same partial pressures as the gases in the alveoli (PO2 = 100 mm Hg and PCO2 = 40 mm Hg).
     Diffusion is a very rapid process taking about 0.25 seconds or within the first 33% of the capillary length in the alveoli. The rapidness of the rate of diffusion is due to the relative thinness of the respiratory membrane.
  Gas Exchange in Respiring Tissue
     When oxygenated blood enters the tissue the PO2 is 100 mm Hg and that of PCO2 is 40 mm Hg. The tissues have a lower partial pressure of oxygen because of oxygen utilization and a higher carbon dioxide concentration because of carbon dioxide production.
     The amount of PO2 and PCO2 in the venous blood depends on the metabolic activity of the tissue with the greater activity resulting in lower PO2 and higher PCO2.
     The venous blood from all parts of the body returns to the right side of the heart and mixes. The venous blood in the right atrium is therefore called mixed venous blood. At rest, the typical values are a PO2 of 40 mm Hg and PCO2 of 46 mm Hg.
  Determinants of Alveolar PO2 and PCO2
     Alveolar PO2 and PCO2 are determined by:
1. PO2 and PCO2 of inspired air.
2. Minute alveolar ventilation.
3. Rates of oxygen consumption and carbon dioxide production.
     Normally PO2 and PCO2 of inspired air remains constant and the alveolar partial pressures depend on the last two factors. This is reflected by the fact that:
1. When alveolar ventilation increases relative to oxygen consumption alveolar PO2 increases and PCO2 decreases.
2. When alveolar ventilation decreases relative to oxygen consumption alveolar PO2 decreases and PCO2 increases.
     Normal alveolar ventilation is adjusted to meet tissue demands. This appropriate increase in ventilation is referred to as hyperpnea. Hypoventilation occurs when alveolar ventilation is insufficient to meet tissue demand. As a consequence PCO2 rises and PO2 decreases. Hyperventilation occurs when alveolar ventilation exceeds the demands of the tissue so that PO2 increases and PCO2 decreases.
Transport of Gases in Blood
  Oxygen Transport by Hemoglobin
     Approximately 1.5% of the oxygen transported in the blood is dissolved in plasma or the cytosol of red blood cells while the remaining 98.5% is bound to hemoglobin. The oxygen bound to hemoglobin is in equilibrium with the oxygen dissolved in plasma which is related to PO2. The oxygen is transported bound to the heme portions of the hemoglobin molecule. The binding of oxygen to hemoglobin depends upon the PO2 in the surrounding fluid. The higher the PO2 the greater the binding.
     Since there are four binding sites on the hemoglobin molecule the number of oxygen molecules on a hemoglobin molecule ranges from none to four. When four oxygen molecules are bound to the molecule, it is said to be 100% saturated. At 100% saturation 1 gram of hemoglobin carries 1.34 ml of oxygen.
      The math:
Hemoglobin in blood 12-17gm/dL or an average of 150 gm/L
Oxygen carrying capacity
   1.34 ml/gram x 154 grams/liter ~ 200 ml/L
Cardiac output 5 liter/minute
Blood supplies
   5 liter/minute x 200 ml O2 /L = 1000 ml O2/min.
Tissues need 250 ml O2 /min. Therefore, under resting conditions venous blood is still 75% saturated.
     Anemia is a decrease in O2 carrying capacity of the blood. With anemia, tissues may not be supplied with the oxygen they need and fatigue occurs more readily. 
  Hemoglobin Oxygen Disassociation Curve
     The curve that shows percent saturation of hemoglobin as a function of PO2 is s-shaped (sigmoidal). The s-shaped nature of the curve can be explained in the following way:
     At low partial pressures the affinity of hemoglobin for O2 is low. An increase in PO2 results in only a small increase in percent saturation.
     As the PO2 increases the hemoglobin molecule acquires at least one molecule of O2. The binding of one molecule of O2 to hemoglobin causes a conformational change in the hemoglobin that increases the affinity of the remaining subunits for oxygen. This is called positive cooperativity. The positive cooperativity causes the steep part of the curve as the PO2 goes from 15 mm Hg to 60 mm Hg. 
     From 60 mm Hg to 80 mm Hg the slope of the curve decreases because as the O2 binds to hemoglobin fewer binding sites become available. Above a PO2 of 80 mm Hg the slope of the curve becomes nearly flat. 
    At the PO2 of the systemic arteries of 100 mm Hg the hemoglobin is 98% saturated. At the PO2 of the systemic veins the hemoglobin is 75% saturated. At rest the tissue takes only about 25% of the O2 transported in the blood.
    The hemoglobin oxygen disassociation curve can shift either to the left or to the right. When the curve shifts to the right, the affinity of oxygen for hemoglobin decreases and oxygen can be more easily unloaded. When the curve shifts to the left, the affinity of oxygen for hemoglobin increases and oxygen can be more easily loaded. 
 
  Factors Affecting Affinity of Hemoglobin for O2
     Factors that affect the affinity of hemoglobin for oxygen include:
1. Temperature
   A higher temperature cause a decrease in affinity. In more active tissue with a higher temperature O2 unloads more easily.
2. pH
   Hydrogen ion increases (pH decreases) in more active tissue. This decreases the affinity of hemoglobin by the Bohr effect which can be expressed in this equation
Hb + O2 --> Hb-O2 + H+
<--

In more active tissue pH decreases and O2 is more easily unloaded.

3. PCO2
   CO2 binds reversibly with Hb to form carbaminohemoglobin a molecule which has a lesser affinity for O2 . This decrease in the affinity of Hb for oxygen in the presence of CO2 is called the carbamino effect.
   These first three factors work together to promote O2 unloading in respiring tissues and O2 loading in the lungs.
4. 2,3 - Diphosphoglycerate
   2,3 -DPG is produced from an intermediate compound in glycolysis and decreases the affinity of hemoglobin for oxygen. At low oxygen levels an enzyme catalyzes the synthesis of 2,3-DPG. Hence, 2,3-DPG concentration increases, the affinity of Hb for oxygen decreases. This is helpful for unloading oxygen during anemia and at high altitudes. At high oxygen levels, oxyhemoglobin inhibits the enzyme that synthesizes 2,3-DPG and 2,3-DPG levels decrease.
Carbon Dioxide Transport in Blood
     The carbon dioxide in the blood exists as
Dissolved as carbon dioxide  : 5-6%
Carbaminohemoglobin : 5-8%
Dissolved as HCO3 - : 86-90%
  Role of Carbonic Anhydrase in Carbon Dioxide Transport
     Carbonic anhydrase catalyzes the reaction that converts CO2 and H2O to carbonic acid. Carbonic acid reversibly disassociates to H+ + bicarbonate. The equation is:
CO2 + H2O --> H2CO3 --> H+ + HCO3-
<-- <--
Hence, an increase in PCO2 makes the blood more acidic while a decrease in PCO2 does the opposite. This reaction is important in the transport and exchange of CO2 and plays an important role in maintaining acid-base balance
  CO2 Exchange and Transport in Systemic Capillaries and Veins
     Respiring cells produce CO2 at the rate of 200 ml/minute. As CO2 increases in the tissues it goes down its concentration gradient into the plasma and into the erythrocyte. 
     Most of the CO2 is converted to bicarbonate and H+ by carbonic anhydrase in the erythrocytes. This conversion of CO2 maintains a pressure gradient favoring diffusion of CO2 from the tissue into the blood. As bicarbonate levels in the erythrocyte increase, bicarbonate ions are transported out of the erythrocyte in exchange for Cl- . This coupled exchange of HCO3-  for Clis referred to as the chloride shift. The H+ left behind in the erythrocyte is buffered by binding to hemoglobin.
     In the lungs, the pressure gradient favors the diffusion of CO2 from the blood into the alveoli. The decrease in CO2 causes bicarbonate in the erythrocyte to bind with H+ to form carbonic acid which in turn is converted into CO2 and H2O by carbonic anhydrase. While bicarbonate in the erythrocyte decreases more bicarbonate is brought into the erythrocyte in exchange for Cl- .
  Effect of Oxygen on Carbon Dioxide Transport 
     The PO2 affects the ability of the blood to carry CO2. The binding of O2 to hemoglobin decreases the affinity of Hb for CO2. Conversely, a decrease in PO2 increases the binding of CO2 to hemoglobin. This phenomenon is called the Haldane Effect. 
     Study the figure below to understand the combined effects of PO2 and PCO2 on CO2 and O2 loading and unloading.
 
Central Regulation of Ventilation
     To ensure that the rate of respiration is adequate to meet the body's metabolic needs it is essential to control minute alveolar respiration to keep the partial pressures of the key gases, oxygen and carbon dioxide, at the appropriate levels. The pattern of ventilation is initiated and modified within the central nervous system.
  Neural Control of Breathing by Motor Neurons
     During quiet breathing the breathing cycle consists in the contraction of the inspiratory muscles followed by relaxation of the same muscle during expiration. During more active breathing the expiratory muscles contract during the expiration phase. This is reflected by the activity of the motor neurons innervating the respective muscles.
  Generation of Breathing Rhythm in the Brainstem
     Respiratory control regions are present in the medulla and pons of the brainstem. There are two general classes of neurons located here:
Inspiratory neurons which generate action potentials during inspiration.
Expiratory neurons which generate action potentials during expiration.
  Respiratory Centers of the Medulla
     Two respiratory centers in the medulla include:
1.  Dorsal Respiratory Group contains primarily inspiratory neurons. The inspiratory neurons show a ramp increase in activity during inspiration followed by an abrupt termination.
2. Ventral Respiratory Group contains two regions of expiratory neurons and one region of inspiratory neurons. When the respiratory drive increases, as during exercise, the inspiratory neurons contribute to enhanced inspiration and the expiratory neurons stimulate the muscles that increase the force of expiration.
  Respiratory Center of Pons
     This center contains both inspiratory and expiratory neurons and mixed neurons that control both inspiratory and expiratory neurons. This center may facilitate the transition between inspiration and expiration.
  Central Pattern Generator 
     The central pattern generator is a network of neurons that generates a regular, repeating pattern of neural activity called the respiratory rhythm.
  Model of Respiratory Control During Quiet Breathing 
     The figure above shows a simplified model to describe how the breathing rhythm is generated by the central pattern generator and modified by other centers of the central nervous system. Note that the central control region resides in the medulla but other portions of the brain including the pons, cerebral cortex, cerebellum, limbic system, hypothalamus and medullary cardiovascular areas provide input that can modify this rhythm.  
  Peripheral Input to Respiratory Centers
     The central pattern generator is reflexively controlled by various types of receptors that include: 
1. Chemoreceptors  - Peripheral (in systemic arteries) and central (in brain) monitor conditions in arterial blood and in cerebrospinal fluid. Regulate ventilation under resting conditions. 
2. Pulmonary stretch receptors in smooth muscles of airways. 
3. Irritant receptors lining the respiratory tract.
4. Proprioceptors in muscles and joints.
Control of Ventilation by Chemoreceptors
     Peripheral chemoreceptors are located in the carotid bodies near the carotid sinus. These are specialized cells in direct contact with arterial blood that communicate with afferent neurons that project to the respiratory control regions. These cells respond to changes in arterial PO2, PCO2 or pH. The primary stimulus for chemoreceptors is pH. The main cause of decreases in pH is an increase in PCO2. Peripheral chemoreceptors also respond to arterial PO2 but only when arterial PO2 drops below 60 mm Hg. This is an extreme drop that usually does not occur.
     Central chemoreceptors are neurons in the medulla that respond directly to changes in hydrogen ion concentration in the cerebrospinal fluid. H ions do not cross the blood-brain barrier but carbon dioxide does. Carbon dioxide is converted to H ion and bicarbonate ion by carbonic anhydrase in the CSF.
  Chemoreceptor Reflexes 
     Changes in PCO2 are primary stimuli for changes in ventilation under normal conditions. Both central and peripheral chemoreceptors are sensitive to changes in pH but the central chemoreceptors are not exposed to H+ from sources other than  CO2 because of the blood-brain barrier. Only the peripheral receptors are sensitive to O2 when it drops below 60 mm Hg. Activation of chemoreceptors cause an increase in ventilation. The figure below shows this reflex operating during hyperventilation and hypoventilation.
Local Regulation of Ventilation and Perfusion
  Ventilation-Perfusion Ratio 
     In the normal lung, the rate of air flow to the alveoli (ventilation, VA) is matched to the rate of blood flow (perfusion, QA). The relationship between these two rates is expressed by the ventilation-perfusion ratio or, VA/QA. The ventilation-perfusion ratio is approximately equal to 1 in the normal lung. 
     In lung diseases that cause obstruction of airways such as emphysema and bronchitis, the airflow to certain alveoli decreases and the blood flow in the capillaries of these alveoli will have less gas exchange. The blood leaving these capillaries will then have a lower PO2 and a higher PCO2 and a ventilation-perfusion ratio of less than 1
     When pulmonary capillaries are blocked, blood flow to the alveoli decreases and the capillaries less affected by the blockage and still flowing through the alveoli will have a greater gas exchange. As a result the blood and air in these alveoli will have a higher PO2 and a lower PCO2. The ventilation-perfusion ratio will be greater than 1
  Local Control of Ventilation and Perfusion
     In order to maintain a ventilation perfusion ratio of 1, changes in the partial pressure of gases in the alveoli and tissues affect contractile activity of bronchiolar smooth muscle that adjust the diameter of the passageway, and also the smooth muscle  in the arterioles that affect the blood flow. 
     Oxygen acts primarily on pulmonary arterioles with a low PO2 causing vasoconstriction with decreased flow and carbon dioxide acts primarily on the bronchioles with a high PCO2 causing bronchodilation and increased ventilation. Therefore, when V/Q is high the increase in PO2 causes vasodilation and the decrease in PCO2 causes bronchoconstriction and the ratio returns towards 1. When V/Q is low the decrease in PO2 causes vasoconstriction and the increase in PCO2 causes bronchodilation. Note that the effect of oxygen and carbon dioxide on pulmonary arterioles is the opposite of the effects of these gases on systemic arterioles. 
The Respiratory System in Acid-Base Homeostasis
  Acid-Base Disturbances in Blood
     Changes in the pH of the body has serious consequences because it changes the shape of protein molecules. Arterial pH affects the pH of body tissues hence it is necessary to regulate blood pH within narrow limits around the normal of 7.4. If the pH drops below 7.35 it is said to be in a condition of acidosis. If the pH increases to greater than 7.45 it is said to be in a condition of alkalosis. Severe acidosis causes depression of CNS activity and leads to coma. Severe alkalosis causes the nervous system to become overly excitable and causes uncontrollable muscle seizures and convulsions.
  Role of Respiratory System in Acid-Base Balance
   Hemoglobin as a Buffer
     Hemoglobin can bind or release hydrogen ions. Deoxyhemoglobin has a greater affinity for H ions than oxyhemoglobin as described by the Bohr effect. In the tissues:
HbO2 > O2 + Hb Hb + H+ > HbH
This serves as a buffer for the increase in H ion resulting from CO2.
In the lungs:
HbH > H+ + Hb Hb + O2 > HbO2
  Bicarbonate Ions as a Buffer
     When H+ increases in the blood it combines with HCO3- to form CO2. When CO2 increases this reaction goes in reverse to form bicarbonate and the hydrogen ion.
   The relationship between CO2 and acidity is described by the Henderson-Hasselbach equation:
pH = 6.1 +

log

[HCO3]
[CO2]
To maintain a pH of 7.4 the ratio of bicarbonate to carbon dioxide should remain at 20:1. The lungs can regulate the concentration of CO2.
     Respiratory disturbances that change [CO2] can result in acid-base imbalance:
Respiratory acidosis is an increase in blood acidity due to increased CO2.
Respiratory alkalosis is a decrease in blood acidity due to decreased CO2.