Gas Exchange

Since human cells are primarily reliant on aerobic metabolism, it is of vital importance to efficiently obtain oxygen from the environment and bring it to the tissues while excreting the byproduct of cellular respiration (CO2). Respiration involves both the respiratory and circulatory systems. There are 4 processes that supply the body with O2 and dispose of CO2. The respiratory system is involved in pulmonary ventilation and external respiration, while the circulatory system is responsible for transport and internal respiration. Pulmonary ventilation (breathing) represents movement of air into and out of the lungs. External respiration, or gas exchange, is represented by the O2 and CO2 exchange between the lungs and the blood.

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Anatomy of the Respiratory System Involved in Gas Exchange

Gas exchange occurs at the level of the alveoli in the lungs and capillaries of the pulmonary circulation.

  • Respiratory unit:
    • Smallest functioning unit in the lungs
    • Composed of a respiratory bronchiole, alveolar ducts, atria, and alveoli
  • Vascular beds: 
    • Capillaries fill space between alveoli.
    • Very little distance between blood in capillaries and air in alveoli 
  • Pulmonary membrane: 
    • Area of interface between capillaries and alveoli
    • Averages 0.6 micrometers in thickness
    • Layers of pulmonary membrane (inside alveoli → capillaries):
      • Fluid layer coating inside of alveolus (contains surfactant to break surface tension)
      • Alveolar epithelium
      • Epithelial basement membrane
      • Interstitium
      • Capillary basement membrane 
      • Capillary endothelial membrane

Physics of Gas Exchange

Physical properies of gases

During gas exchange, O₂ and CO₂ must cross the pulmonary membrane. This process is driven by multiple complex forces determined by the physical properties of these gases. 

  • Concentration: O₂ and CO₂ will flow from areas of high concentration to those of low concentration.
  • Difference in partial pressure of gas in air in alveoli and of gas dissolved in blood:
    • Partial pressure of gas in alveoli: 
      • The air pressure in a fixed container is proportional to the concentration of molecules of air forced into that container.
      • Atmospheric air is composed of O₂, nitrogen, and carbon dioxide. The rate of diffusion of each gas is proportional to the pressure exerted by that gas alone, called partial pressure.
      • Example: Atmospheric air is 760 mm Hg and is 21% O₂. The partial pressure of O₂ (PO₂) in the alveoli is 760 x 0.21 = 160 mm Hg.
    • Partial pressure of gas dissolved in blood:
      • Gas dissolved in liquid exerts partial pressure determined both by its concentration and a constant known as solubility coefficient.
      • Example: partial pressure of O₂ dissolved in blood = concentration O₂/solubility coefficient of O₂ = 0.025 mm Hg
    • Gas flows from areas of high partial pressure to those of low partial pressure.

Forces driving the rate of exchange of O₂ and CO₂

The rate of gas exchange is determined by the efficiency of the exchange across the pulmonary membrane and the speed at which it can be brought there from the air (for O₂) or from the body (for CO₂).

  • O₂:
    • The diffusion of O₂ into blood from alveoli is extremely efficient.
    • Even ↑ speed at which O₂ brought to alveoli (ventilation) cannot improve diffusion of O₂ across pulmonary membrane
    • The only factor that can affect diffusion is modification of the partial pressure of O₂ in breathed air (e.g., breathing pure O₂ or breathing at high elevations).
  • CO₂:
    • Diffusion is slower.
    • The speed of ventilation is directly proportional to the speed of diffusion across the pulmonary membrane and of removal from the body.
  • Clinical correlation:
    • The O₂ saturation of blood is determined by the partial pressure of O₂ breathed by the patient.
    • The CO₂ saturation of blood is determined by the speed of ventilation (breathing).

Gas Transport

O₂ and CO₂ must be transported through the bloodstream to reach sites of gas exchange.

O₂ transport

  • There are:
    • 0.295 mL of O₂ per dL of arterial blood
    • 0.124 mL of O₂ per dL of venous blood
  • 1.5% of O₂: dissolved in plasma.
  • 98.5% of O₂: loosely bound to each iron atom of Hb in RBCs.
  • Hb: 
    • Has 4 binding sites for O
    • Affinity of Hb for O₂ ↑ with amount of O bound to it
  • O saturation:
    • Percentage of Hb bound to O₂:
      • In arterial blood, Hb has O₂ saturation close to 99%.
      • In venous blood, Hb has O₂ saturation of around 75%.
      • Allows for reserve of O₂ to be preserved in blood
  • Hb loading and unloading:
    • Loading and unloading of O₂ are facilitated by changes in the shape of Hb.
      • As O₂ binds, Hb affinity for O₂ ↑
      • As O₂ is released, Hb affinity for O₂ ↓
    • Rate of loading and unloading of O₂ is regulated by:
      • PO₂ (↓ O₂ levels allow for O₂ to dissociate from Hb more easily)
      • ↑ Temperature will ↓ Hb affinity for O₂
      • ↓ Blood Ph will ↓ Hb affinity for O₂
      • ↑ PCO₂  will ↓ affinity of Hb for O₂
      • ↑ Concentration of bisphosphoglycerate (BPG) will ↓ affinity of Hb for O₂

CO₂ transport

  • 7%–10% of CO₂: dissolved in plasma
  • 20% of CO₂: bound to Hb (carbaminohemoglobin)
  • The remaining 70% is bicarbonate (HCO3); CO₂ is converted into HCO3 by carbonic anhydrase inside RBCs.

Ventilation/Perfusion (V/Q) Coupling

Ventilation and perfusion are the mechanisms that transport O₂ and CO₂ between the pulmonary membrane and the body’s tissues.

  • For gas exchange to be efficient, ventilation and perfusion must be perfectly matched.
  • Changes in metabolic needs or disease states can effect ventilation or perfusion independently.
  • Mechanisms exist to keep ventilation and perfusion balanced.


Perfusion is the flow of blood to pulmonary vasculature.

  • Pulmonary perfusion = cardiac output
  • During heavy exercise, metabolic need for O₂ ↑ and more CO₂ must be removed
  • Cardiac output and pulmonary blood flow ↑ to satisfy demand through 2 mechanisms: 
    • Recruitment: when pulmonary arterial pressure ↑, collapsed vessels open
    • Distension: when pulmonary arterial pressure ↑, arterial vessels that were conducting blood at full capacity widen
  • Lung volume and blood flow:
    • At ↑ lung volumes, capillaries are compressed, producing ↑ vascular resistance (compression effect)
    • At ↓ lung volumes, capillaries are also compressed, ↑ vascular resistance
    • Vasodilation effect on blood flow: Negative pleural pressure exerted on alveoli being transferred to blood vessels causes vasodilation.


  • Changes in PO₂ in alveoli → changes in diameter of arterioles affecting perfusion:
    • PO₂ induces vasoconstriction
    • PO₂ induces vasodilation
    • Promotes redistribution of blood flow to alveoli with greater PO₂
  • When PO₂ ↓ in all alveoli, there is chemoreflex vasoconstriction
  • Changes in PCO₂ → changes in diameters of bronchioles:
    • If alveolar CO₂ is ↑, bronchioles dilate
    • If alveolar CO₂ is ↓, bronchioles constrict
  • Gravity and blood flow:
    • Gravity ↓ flow of blood toward apex and ↑ toward base

Hypoxemia and Hypercapnia

There are 2 important PO₂ differences (gradients):

  • Alveolar–arterial (A-a): difference in PO₂ between the alveoli and systemic arterial blood
  • Arteriovenous (AV): difference in PO₂ between venous and arterial blood
Pressures of O₂ and CO₂ Respiratory gas exchange

Arterial-venous (a-v) difference in PO2 between venous and arterial blood:
Pressures of O2 and CO2 in the alveoli and systemic circulation before and after gas exchange.

Image by Lecturio. License: CC BY-NC-SA 4.0

Tissue hypoxia

  • Low O availability to the tissues
  • Hypoxia is sensed by the kidneys, stimulating RBC synthesis through the release of EPO.


  • Low PO₂ in the blood
  • Can be caused by:
    • Hypoventilation 
    • Reduced (< 21%) inspired fraction of O₂
    • Diffusional impairment: inadequate diffusion of gases into the capillaries
    • Right-to-left shunt: communication between pulmonary arterial and venous circulations allowing deoxygenated blood to partially skip gas exchange
    • V/Q inequality
Diagram Hypoxemia Respiratory Gas exchange

Diagram of a RIGHT-TO-LEFT shunt:
See the communication that allows blood to skip gas exchange and lower the arterial pressure of O2.

Image by Lecturio. License: CC BY-NC-SA 4.0


  • Arterial PCO₂ greater than 40 mm Hg
  • This process can occur due to:
    • Decreased alveolar ventilation
    • Severe V/Q inequality
    • Increased CO₂ production without ventilatory compensation
  • Alveolar ventilation and PaCO₂ are inversely related.

Clinical Correlation

  • Anemia: a decrease in RBCs in circulation. Anemia causes a decrease in the amount of available O as the overall amount of Hb is diminished. Etiologies can be grouped with those that feature a failure to produce sufficient RBCs (iron deficiency, bone marrow dysplasia, and neoplasia) and those that feature increased destruction of RBCs (autoimmune, infectious, genetic). Common symptoms of anemia include pallor of the mucous membranes and easy fatigability. Pulse oximetry remains normal, as the percentage saturation of each hemoglobin molecule does not vary. The diagnosis of anemia is confirmed with blood tests that indicate a decrease in RBCs. Treatment is directed at fixing the underlying pathology causing anemia.
  • Polycythemia: an increase in RBCs in circulation. Polycythemia causes an increase in the amount of available O₂ as the overall amount of Hb is increased. Etiologies vary from nonpathological (high-altitude habituation, perinatal adjustment period) to serious disease processes (neoplasia, polycythemia vera). Polycythemia patients typically have a ruddy complexion, and they can present with excessive clotting and its consequences. The diagnosis is confirmed by blood cell counts, and treatment varies by etiology.
  • Carbon monoxide (CO) poisoning: breathing CO decreases the amount of available O₂ in a patient’s circulation by occupying binding sites of Hb meant for O₂ with greater affinity. Pulse oximetry often reports normal, even elevated saturations, as all binding sites of hemoglobin are occupied. Patients often report having a headache and a decreased level of consciousness. Carbon monoxide poisoning can be lethal if the patient is not removed from the source of CO.
  • Pulmonary edema: presence of fluid instead of air in alveoli. The presence of additional fluid impedes proper gas exchange, greatly decreasing available surface area. Pulmonary edema has various etiologies, including cardiac failure and sepsis. Patients present with shortness of breath and often have audible rales on exam. Pulse oximetry is often low in these patients. Treatment aims to remove the causes of excess fluid buildup.


  1. Hall, JE, & Hall, ME. (2021). Guyton and Hall textbook of medical physiology (14th ed.). Elsevier.
  2. Powers KA, Dhamoon AS. (2021). Physiology, pulmonary ventilation, and perfusion. StatPearls. Treasure Island (FL): StatPearls Publishing.
  3.  Biga, LM, Dawson, S, Harwell A, Hopkins, R, et al. Anatomy and physiology. Retrieved April 26, 2021, from

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