Gas exchange in the lung

Introduction

Why do we breathe? The vital importance of breathing was clear even in ancient times, when people believed that the air we breathe, or pneumo , gives rise to the spirit. Oxygen in the air enables active cellular metabolism, enabling optimal function at the cellular level and ultimately proper functioning of all of the body’s organ systems.

Ultimately, the lungs bear two important responsibilities:

To provide oxygen to cells to enable energy release via oxidative phosphorylation;
To maintain physiologically optimal pH (alongside the kidneys) through control of carbon dioxide, a waste product of cellular metabolism, in the blood.

The lungs perform these tasks through passive gas exchange between the atmosphere and the blood, absorbing oxygen from air and releasing carbon dioxide into air. Breathing or ventilation—the mechanical function of the lung—makes effective gas exchange possible.

System structure: The distal respiratory tree and pulmonary circulation

Please refer to Chapter 13 for a more in-depth discussion of lung structure. However, it is useful to review and expand upon some of these basic tenets with attention to pulmonary gas exchange.

Recall that the trachea gives rise to large airways that progressively branch during descent into the lungs, ultimately leading to the respiratory bronchioles and alveoli that participate in gas exchange ( Fig. 14.1 ).

The large airways allow passage of air but do not perform gas exchange (i.e., they are conducting airways).
The volume occupied by the conducting airways, where gas exchange does not occur, is also known as anatomic dead space.

Fig. 14.1, The respiratory bronchioles and alveoli. A , Alveolus; AD , alveolar duct; AR , alveolar ring; AS , alveolar sac; R , respiratory bronchiole; T , terminal bronchiole.

The walls of the alveolar compartments, across which gas exchange occurs, are only about two cells thick ( Fig. 14.2 ).

The alveolar lumen is lined by type I pneumocytes, flat, thin cells that lie adjacent to the basement membrane.
Alveoli are enmeshed in extensive plexus of capillaries, whose walls are composed of flat, thin endothelial cells.
Other cells appear intermittently in the alveolar wall do not constitute the gas exchange surface, but still serve vital functions.
- Type II pneumocytes (secretion of surfactant)
- Fibroblasts (lay down basement membrane, which is composed of collagen and elastin)
- Macrophages
- Clara cells (main secretory cell type in distal conducting airways, defend against pollutants and aid in repair)

Fig. 14.2, Schematic of the structure of alveoli.

From one alveoli to the next, we would encounter the following cell types:

First alveolar space → type I pneumocyte → basement membrane → capillary endothelial cell wall → blood → opposite capillary wall → basement membrane → type I pneumocyte → second alveolar space

Pulmonary circulation, consisting of the pulmonary arteries, capillaries, and veins, is supplied by the right ventricle pumping deoxygenated blood into the pulmonary trunk.

The pulmonary trunk feeds into dual pulmonary arteries.
These each contribute to capillaries surrounding the alveoli, which participate in gas exchange.
Oxygenated blood is then carried into the pulmonary vein, which supplies the left ventricle for propulsion of oxygenated blood to the rest of the body.

However, the lungs also contain bronchial arteries, which carry oxygenated blood from systemic circulation to feed the lungs.

These primarily feed the walls of large airways, which (unlike alveoli) cannot rely on direct oxygen absorption.
Bronchial arteries arise from the thoracic aorta and posterior intercostal arteries.
However, deoxygenated bronchial blood ultimately feeds back into the pulmonary veins (see Fast Fact Box 14.1 ).

Fast Fact Box 14.1

Because of dual blood supply from the bronchial and pulmonary arteries, the lungs are more resistant to infarction.

Fig. 14.3 shows the functional units of the lung, including the two pulmonary arterial supplies.

Fig. 14.3, The functional units of the lung. A , Alveoli; AD , alveolar ducts; RB , respiratory bronchioles; TB , terminal bronchioles.

System function: Oxygenation and the clearance of carbon dioxide

Our first consideration in understanding gas exchange is the behavior of gases in general. For this, we will briefly review the principles of gases from introductory chemistry in the context of clinical medicine.

Gases

For both a single gaseous species and a mixed gas (such as that in atmospheric air and the alveoli), the relationships among different parameters of this gas are expressed within the ideal gas law:

PV = nRT

$PV = nRT$

where P = pressure exerted by gas, V = volume occupied by gas, n = number of moles of gas, R = empirically determined constant, and T = temperature of the gas.

In a mixture of gases, one can express the amount of a particular species of gas as the partial pressure. This same term can also be used to describe the amount of a particular species of gas that has been dissolved in the blood. The partial pressure of a given gas is related to the total pressure of the gas mixture in proportion to the mol fraction of the given gas.

P_{1} / P_{T} = n_{1} / n_{T}

$P_{1} / P_{T} = n_{1} / n_{T}$

where P ₁ = partial pressure of gas 1, P _T = total pressure, n ₁ = moles of gas 1, and n _T = total moles in gaseous mixture.

Given that n _T in a gaseous mixture is the sum of its components, this relationship implies Dalton’s law of partial pressures, or:

P_{T} = P_{1} + P_{2} + P_{3} \dots P_{n}

$P_{T} = P_{1} + P_{2} + P_{3} \dots P_{n}$

Using these relationships, we can better understand the movement of gas from blood to alveoli ( Fig. 14.4 ).

Molecules in atmospheric gas dissolve into blood in proportion to the quantity of each gas in the mixture.
The greater the partial pressure, the more molecules that will dissolve into blood. (see Fig. 14.4 A)
- High P ₁ = high efflux into blood = high blood concentration
- Low P ₁ = low efflux into blood = low blood concentration
Net dissolution of a given gas continues until equilibrium is achieved between influx and efflux (see Fig. 14.4 B) (see Clinical Correlation Box 14.1 ).

Fig. 14.4, Equilibrium vapor pressure. A, The large amount of free gas and small amount of dissolved gas means more molecules randomly move into solution than come out. The amount of dissolved gas increases, which in turn increases the number of molecules coming out of solution. B, The amount of free gas depletes and the amount of dissolved gas increases until the rates of gas-liquid crossover become the same in both directions.

Clinical Correlation Box 14.1

What happens when you submit an arterial blood gas (ABG)?

The sensors in blood gas analyzers yield readings in partial pressure, yet they do not measure partial pressure directly. Instead, the sample is exposed to O ₂ and pH-sensitive electrodes covered in a permeable membrane. These electrodes then read out the number of millivolts in proportion to the quantity of O ₂ and CO ₂ in solution. This millivolt reading is then converted to an equilibrium partial pressure using a reference measurement.

The reference measurements are derived from electrode sampling of blood from a tonometer with a known equilibrium partial pressure of O ₂ or CO _2.

Acquire millivolt reading for known PCO ₂ and PCO ₂
Correlation forms basis for linear conversion from millivolts → equilibrium partial pressure for a patient sample
Recalibration must occur with sufficient frequency (i.e., every personnel shift) to ensure accuracy

By using this convention to describe the amount of blood gas, we can readily predict the direction of change of blood oxygen content when systemic venous blood (the same as pulmonary arterial blood), for example, is exposed to alveolar air.

The venous blood would be at equilibrium at 40 mm Hg partial pressure of oxygen (PO ₂ ).
On exposure, a higher alveolar PO ₂ (P _A O ₂ ) will drive more oxygen into solution until a new equilibrium is reached (e.g., 100 mm Hg), with the blood and the alveolar air at the same PO ₂ .
The equilibrium PO ₂ is higher than blood’s initial PO ₂ and lower than alveolar air’s initial PO ₂ ( Fig. 14.5 ).

For a list of the most physiologically significant partial pressures, please refer to Table 14.1 .

TABLE 14.1

Important Partial Pressures With Typical Values

Partial Pressure	Symbol	Normal Value (mm Hg)
Alveolar partial pressure of oxygen	P _A O ₂	100–105
Alveolar partial pressure of carbon dioxide	P _A CO ₂	40
Arterial partial pressure of oxygen = PO ₂ in pulmonary vein	P _a O ₂	95–100
Arterial partial pressure of carbon dioxide = PCO ₂ in pulmonary vein	P _a CO ₂	40
Inspired partial pressure of oxygen	P _I O ₂	149 ^a
Inspired partial pressure of carbon dioxide	P _I CO ₂	0.3 (negligible)
Venous partial pressure of oxygen = PO ₂ in pulmonary artery	P _V O ₂	40
Venous partial pressure of carbon dioxide = PO ₂ in pulmonary artery	P _V CO ₂	45

a Assuming (BT)PS, that is, saturated pressure because it is inside the body.

Ventilation

During periods of rest (i.e., in between breaths or while holding one’s breath), the composition of air within the gas-exchanging portion of the lung (the alveolar gas) will remain dynamic.

Peripheral tissues continuously absorb O ₂ from systemic blood and offload CO ₂ .
Blood returning to the lung from the body tissues is thus O ₂ -poor and CO ₂ -rich.
If ventilation is not occurring, this blood continuously absorbs O ₂ from the alveolar gas and deposits CO ₂ in return via simple diffusion.
Therefore O ₂ levels in alveolar gas are continuously going down while CO ₂ levels are going up.

Ventilation can thus be seen as an effort to keep alveolar gas O ₂ -rich and CO ₂ -poor by blowing off gas low in O ₂ and high in CO ₂ and replacing it with atmospheric gas, which has the opposite proportions. This maintains the alveolar gas to blood gas gradients necessary to promote continued clearance of CO ₂ and absorption of O ₂ .

Before inhalation, the lung volume is at functional residency capacity (FRC) as described in Chapter 13 . Inspiration adds the tidal volume (V _T ) to the preexisting volume at FRC ( Fig. 14.6 )

The tidal volume is composed of two components, V _A and V _D .
- 2/3 of V _T is added to the expanded alveoli, and is called V _A .
- 1/3 of V _T is added to the expanded dead space, and is called V _D .
- V _A + V _D = V _T
V _A mixes with the preexisting FRC volume.
- PO ₂ rises above FRC levels but drops below that of atmospheric air.
- PCO ₂ drops below FRC levels but rises above that of atmospheric air (~0).

Fig. 14.6, The addition of tidal volume to the conducting airways and alveoli. Two-thirds of the tidal volume is added to the gas-exchanging alveolar space and one-third to the anatomic dead space, assuming all alveoli are open and participating in gas exchange. For simplicity, the alveolar space is represented by one large schematic alveolus in one lung. A, At functional residual capacity (FRC): before the addition of a tidal volume V T . B, At FRC + V T after the addition of a tidal volume V T . All partial pressures are measured in mm Hg.

With expiration, the same tidal volume is blown off and the new V _A (with higher CO ₂ , lower O ₂ composition) leaves the alveoli. Now, there is a better gradient for O ₂ absorption and CO ₂ clearance in the alveoli ( Fig. 14.7 ).

Fig. 14.7, Gas exchange throughout the breathing cycle. A, At functional residual capacity (FRC), preinspiration, the alveolus filled with end expiratory alveolar air. B, At FRC + tidal volume (V T ), after inspiration, the added volume of inspired, fresh atmospheric air. C, At FRC + V T , end expiratory alveolar air mixing with inspired fresh air. D, Back to FRC, after expiration. E, At FRC, after gas exchange has again created end expiratory alveolar air. All partial pressures are measured in mm Hg.

This paradigm leads to two important tenets:

With decreasing respiratory rate, alveolar gas at FRC will have more time to accumulate CO ₂ and lose O ₂ → ↑P _A CO ₂ and ↓ P _A O ₂ .
With decreasing tidal volume, less V _A will be added to FRC with constant CO ₂ production → ↑ P _A CO ₂ and ↓ P _A O ₂ .

Stated another way, V _A and f (the frequency of breathing in breaths per minute) have an inverse relationship with the amount of alveolar CO ₂ (P _A CO ₂ ), and a direct relationship with the amount of alveolar O ₂ (P _A O ₂ ). Thus the partial pressures of O ₂ and CO ₂ in alveolar gas are a function of the net size of the addition of V _A to alveolar gas per unit time, ${\dot{V}}_{A}$ ${\dot{V}}_{A}$ . Note the dot notation that stands for the first derivative. It indicates that this is a flow rate—a change in volume over time. V _A is the alveolar volume (units in mL) while dot V _A is the alveolar ventilation flow rate (units in mL/min). This ventilation rate can be expressed as the magnitude of V _A multiplied by the frequency of V _A ’s addition to alveolar gas. In other words,

{\dot{V}}_{A} = V_{A} f

${\dot{V}}_{A} = V_{A} f$

where V _A = the portion of the tidal volume added to alveolar gas, f = the frequency of breathing in breaths per minute, and ${\dot{V}}_{A}$ ${\dot{V}}_{A}$ is the alveolar ventilation.

From the above relationships come the definitions of hyperventilation and hypoventilation.

Hyperventilation (P _A CO ₂ < 38 mm Hg) refers to elimination of CO ₂ exceeding its rate of production, leading to a decreased P _a CO ₂ in the blood (hypocapnia; P _a CO ₂ < 38 mm Hg).
- An increased breathing frequency is known as tachypnea, and is not synonymous with hyperventilation.
Hypoventilation (P _A CO ₂ > 42 mm Hg), similarly, is not simply a decreased rate of breathing but a decrease in alveolar ventilation relative to CO ₂ production. When the elimination of CO ₂ is less than its production rate, the consequence is an increased P _a CO ₂ (hypercapnia; P _a CO ₂ > 42 mm Hg).

The alveolar ventilation equation

The relationship between alveolar ventilation and P _A CO ₂ , described earlier, can be stated mathematically in the alveolar ventilation equation:

{\dot{V}}_{A} = ({\dot{V}}_{c o_{2}} / P_{A} C O_{2}) (K)

${\dot{V}}_{A} = ({\dot{V}}_{c o_{2}} / P_{A} C O_{2}) (K)$

where ${\dot{V}}_{{CO}_{2}}$ ${\dot{V}}_{{CO}_{2}}$ is the rate of CO ₂ production and K is a constant that includes conversion from standard temperature (22° C) to body temperature (37° C).

${\dot{V}}_{{CO}_{2}}$ ${\dot{V}}_{{CO}_{2}}$ represents the mass of CO ₂ being produced in the peripheral tissues in accordance with the cells’ production and its diffusion into the blood.

Unless the metabolic rate in the tissues changes, ${\dot{V}}_{{CO}_{2}}$ ${\dot{V}}_{{CO}_{2}}$ remains constant.

Instead of representing an anatomic lung volume, ${\dot{V}}_{{CO}_{2}}$ ${\dot{V}}_{{CO}_{2}}$ is the volume per time that would be occupied by the mass of CO ₂ produced if this CO ₂ were at standard temperature (295.15K) and pressure (760 mm Hg) in dry (PH ₂ O = 0 mm Hg) air.

As ${\dot{V}}_{A}$ ${\dot{V}}_{A}$ goes up and dilutes this constant amount of CO ₂ production in the alveolar gas, the alveolar partial pressure of CO ₂ (P _A CO ₂ ) goes down.

One might at first think that the same sort of equation could be written for the relationship between ${\dot{V}}_{A}$ ${\dot{V}}_{A}$ and P _A O ₂ , but it cannot because the relationship between ${\dot{V}}_{A}$ ${\dot{V}}_{A}$ and P _A CO ₂ is linear, but the relationship between ${\dot{V}}_{A}$ ${\dot{V}}_{A}$ and P _A O ₂ is not linear over the entire physiologic range. Although increased ${\dot{V}}_{A}$ ${\dot{V}}_{A}$ will increase P _A O ₂ , it does not do so in a linear relationship because unlike CO ₂ , there is a significant amount of O ₂ in the inspired air.

Diffusion

The average distance between blood and alveolar air in the lung is less than 1.5 µm, which ensures that simple diffusion is possible. In the healthy lung, blood equilibrates with respect to O ₂ and CO ₂ after traveling about one-third of the length of the pulmonary capillary. The equation that describes the determining factors for diffusion rate is Fick’s law:

{\dot{V}}_{G} = (P_{A} − P_{C}) (A) (S) / (T) (MW)

${\dot{V}}_{G} = (P_{A} − P_{C}) (A) (S) / (T) (MW)$

where ${\dot{V}}_{G}$ ${\dot{V}}_{G}$ = volume of gas transferred across the membrane per unit time, P _A = partial pressure of the gas in the alveolus, P _C = partial pressure of the gas in the capillary, A = area of membrane of transfer, S = solubility of the gas in blood, T = thickness of membrane, and MW = molecular weight of the gas.

Because O ₂ and CO ₂ both have a rapid diffusion rate and equilibrate early in the capillary, they display perfusion-limited gas exchange, wherein the amount of O ₂ and CO ₂ gas exchange is limited by alveolar perfusion.

No matter how fast the diffusion time, if less blood is delivered per time to the alveolar capillary, less CO ₂ will cross over into alveolar air and less O ₂ will cross over into blood.
This is because only a certain amount of these gases can be dissolved into the blood plasma, or bound to hemoglobin (or buffered by HCO ₃ ⁻ , as in the case of CO ₂ ).
Thus increasing perfusion rate ensures that new blood is present that can undergo immediate gas exchange (see Fast Fact Box 14.2 . Also Genetics Box 14.1 , Pharmacology Box 14.1 , and Development Box 14.1 ).

Fast Fact Box 14.2

The fact that O ₂ exchange is perfusion-limited means increases in heart rate will increase oxygenation.

GENETICS BOX 14.1

Patients with cystic fibrosis (CF) have mutations in the CFTR gene that encodes a transmembrane Cl ⁻ channel. The movement of Cl ⁻ helps regulate the water content of respiratory tract mucus. Without normal Cl ⁻ transport, patients produce tenacious, abnormally viscous mucus. In the lungs, this mucus impairs gas exchange and obstructs airways, causing respiratory distress with dyspnea, coughing, and wheezing. It is hoped that the CRISPR gene editing technology will allow for the safe correction of mutated CFTR genes and cure of CF.

PHARMACOLOGY BOX 14.1

Antibiotics (particularly inhaled antibiotics that combat alveolar bacteria while limiting systemic effects) are useful in treating respiratory bacterial infections in patients with cystic fibrosis (CF). Inhaled β-2-adrenergic agonists, such as albuterol, can help acute symptoms. Airway mucus can be made less viscous with inhaled DNAse I (dornase α), an endonuclease that digests neutrophil DNA. Depending on the specific CF transmembrane conductance regulator (CFTR) mutation, CF patients can benefit from Ivacaftor, a small molecule that augments the function of the Cl ⁻ channel in patients with selected “gating” mutations. It can be combined with Lumacaftor or Tezacaftor, agents that improve mutant CFTR protein folding.

DEVELOPMENT BOX 14.1

With chronic mucus hypersecretion, airflow obstruction, and repeated respiratory infections, cystic fibrosis (CF) patients progressively develop airway damage with scarring and distortion of the normal architecture called “bronchiectasis.” This impairs clearance of mucus and fluid from the airways, and leads to chronic cough and mucus hypersecretion. Patients also produce hyperviscous mucus in the gastrointestinal tract, and patients frequently have mucus obstructing their pancreatic ducts, leading to damage to this endocrine and exocrine organ and leading to diabetes and malabsorption. In affected males, accumulation of mucus in the vas deferens leads to infertility.

The exchange of other more slowly diffusing molecules, like carbon monoxide (CO), is known as diffusion-limited gas exchange.

Blood may need to travel the whole length of the capillary before equilibrating.
Thus higher rate of blood flow will actually decrease gas exchange for these substances as blood would spend less time in the capillary before being swept downstream (see Clinical Correlation Box 14.2 ).

Clinical Correlation Box 14.2

When the pulmonary intravascular pressure rises owing to increased pulmonary venous pressure (as happens in congestive heart failure), blood vessel recruitment and distention do not occur and fluid seeps easily from the lung membranes into the low-pressure alveolar spaces causing pulmonary edema. Because there is more blood flow to the dependent lung, the pulmonary edema tends to collect at the lung bases.

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Introduction

System structure: The distal respiratory tree and pulmonary circulation

System function: Oxygenation and the clearance of carbon dioxide

Gases

Ventilation

The alveolar ventilation equation

Diffusion

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Appendix 5

Appendix 4

Appendix 3

Appendix 2