Physiology Note - Physiology of Gas Exchange

 

 Principles of Gas Exchange

Contributed by Shivali Sandal, Mandi

Principles of Gas Exchange

Gas exchange is the core function of the respiratory system: delivering oxygen to tissues and removing carbon dioxide. It occurs in two settings:

1.  External respiration — alveoli ↔ pulmonary capillaries.

2.  Internal respiration — systemic capillaries ↔ tissues.

The process is entirely passive, driven by pressure gradients, requiring no energy.

1. Anatomy and site of gas exchange

The lungs are designed to maximise efficiency. The lungs contain nearly 300 million alveoli, providing a vast surface area of ~70 m² in adults¹. Each alveolus is enveloped by a dense pulmonary capillary network, forming the alveolo-capillary (respiratory) membrane, the site of gas exchange. Normally, it is just 0.5–1 µm, allowing rapid diffusion.

The transit time of blood in alveolar capillaries under normal conditions is around 0.75 -1 seconds, though as little as 0.25 s is sufficient for complete oxygen equilibration.

 At rest, ~250 mL O₂ enters blood and ~200 mL CO₂ leaves per minute.

Key features:

Type I pneumocytes: thin squamous cells that form the diffusion surface.

Type II pneumocytes: secrete surfactant, reducing surface tension and preventing alveolar collapse.

 

        Figure 1. Alveolar Capillary Unit    Image courtesy: Laniece, Alexandra. (2018). Alveoli-on-a-chip

 

2. Determinants of gas exchange

·   Surface area of the alveolo-capillary membrane.

·   Partial pressure gradients of gases.

·   Matching of ventilation (V) and perfusion (Q).

 

3.     Fundamental laws of gas diffusion:

3a. Dalton’s Law of Partial Pressures → Each gas exerts its own pressure in a mixture, and diffusion occurs down these partial pressure gradients.

Example: Alveolar PO₂ ≈ 100 mmHg vs venous PO₂ ≈ 40 mmHg → oxygen enters blood.

3b. Diffusion Through Gases – Graham’s Law→ Diffusion rate is inversely proportional to the square root of molar mass. Smaller/lighter gases diffuse faster.

3c. Diffusion Through Liquids – Henry’s Law→ Gas dissolved in liquid = partial pressure × solubility. CO₂ is ~20× more soluble than O₂ → despite a smaller gradient, it diffuses faster.

   3d. Overall Gas Transfer – Fick’s Law

 

V → rate of diffusion of the gas

(P_A - Pₐ) → partial pressure gradient between alveolus (P_A) and blood (P_a) drives diffusion.

A (surface area) → for diffusion.

T (thickness)→ the alveolo-capillary barrier is extremely thin (~0.5 µm), minimizing diffusion distance.

D (diffusion coefficient) → depends on solubility and molecular weight.

Clinical Relevance: Together, these laws explain why O₂ uptake is gradient-dependent, while CO₂ clearance is solubility-dependent.

 

4.     The Oxygen Cascade

The oxygen cascade² describes the progressive fall in oxygen tension from the atmosphere (~159 mmHg at sea level) → alveoli (~100 mmHg) → arterial blood (~95 mmHg) → tissues (~40 mmHg) → mitochondria (~1–2 mmHg). This gradient ensures oxygen always flows “downhill” to where it’s needed for energy production- the mitochondria for cellular respiration.

5.     External vs. Internal Respiration

5a. External Respiration (Alveoli ↔ Blood)

When venous blood (PO₂ ~40mm Hg, PCO₂ ~45mm Hg) reaches pulmonary capillaries, it encounters alveolar gas (PO₂ ~100, PCO₂ ~40).

O₂ diffusion: Rapid diffusion across a ~60 mmHg gradient raises PaO₂ to ~100 mmHg (slightly lower, ~95, from physiological shunt). In the capillary, the oxygen binds to haemoglobin. Bound oxygen doesn’t exert a partial pressure.

CO₂ diffusion: Despite a ~5 mmHg gradient, high solubility ensures equilibration at PaCO₂ ~40 mmHg.

Because diffusion is rapid, equilibration occurs within one-third of capillary transit time — leaving a safety margin even during exercise.

5b. Internal Respiration (Blood ↔ Tissues)

At the tissue level, the gradients reverse:

•    PO₂ in blood ~100 mmHg vs tissue PO₂ ~40 mmHg → oxygen leaves hemoglobin and diffuses into cells.

•    PCO₂ in tissue ~45 mmHg vs blood ~40 mmHg → carbon dioxide diffuses into blood.

Venous blood returning to the heart contains PaO₂ ~40 and PaCO₂ ~45, completing the cycle.

Figure 2: Partial Pressure of gases in blood

 6. Perfusion- vs Diffusion-Limited Gas Transfer

Perfusion-limited: Gas equilibrates with alveolar partial pressure within normal capillary transit time. Uptake depends on blood flow (e.g., O₂ under normal conditions, CO₂).

Diffusion-limited: Gas fails to equilibrate before blood leaves the capillary. Uptake depends on membrane properties (e.g., CO, O₂ in fibrosis or exercise).

 

7. Ventilation–Perfusion (V/Q) Matching

For gas exchange to be efficient, alveolar ventilation (V) must match pulmonary perfusion (Q).

•    Normal overall V/Q ≈ 0.8–1.0.

•    Regional differences:

Apex: V> Q → high V/Q → wasted ventilation (↑PO₂, ↓PCO₂)

Base of lung: Q>V→ low V/Q→ wasted perfusion (↓PO₂, ↑PCO₂).

8. Transport of Gases in Blood

Once gases cross the alveolo-capillary membrane, their efficient transport in blood is essential for delivery to tissues and removal of waste.

8a. Oxygen transport

·       ~98–99% bound to hemoglobin (oxyhemoglobin), ~1–2% dissolved in plasma

·       Oxygen content of arterial blood (CaO₂):

             CaO2=(1.34×Hb×SaO2)+(0.003×PaO2) ~20ml O₂/100ml of blood

·       Oxyhemoglobin dissociation curve shifts with pH, temperature, CO₂ (Bohr effect)

Figure 3. Oxyhemoglobin dissociation curve and factors that results in a shift to right or left

8b. Carbon Dioxide

·       ~70% carried as bicarbonate ions (HCO₃⁻).

·       ~20–25% bound to hemoglobin (carbaminohemoglobin).

·       ~5–10% dissolved in plasma.

 

9. Clinical Relevance

Gas exchange principles explain the pathophysiology of many respiratory diseases³:

•    Emphysema → alveolar destruction → loss of surface area → hypoxemia.

•    Fibrosis → thickened diffusion membrane → diffusion-limited O₂ uptake.

•    Pulmonary edema/ARDS → fluid-filled alveoli → impaired O₂ diffusion.

•    Pulmonary embolism → blocked perfusion → dead space ventilation (high V/Q).

•    Asthma/bronchoconstriction → impaired ventilation → low V/Q mismatch.

•    Right-to-left shunt → blood bypasses alveoli → hypoxemia refractory to O₂ therapy.

•    High altitude → reduced barometric pressure →lower alveolar PO₂ → hypoxemia despite normal lungs.

 

References :

1. Wagner PD. The Physiological Basis of Pulmonary Gas Exchange: Implications for the Clinical Interpretation of Arterial Blood Gases. Eur Respir J. 2015;45(1):227-43.
2. Petersson J, Glenny RW. Gas exchange in the lung. Semin Respir Crit Care Med. 2023;44(5):555-68. doi:10.1055/s-0043-1770060.
3. Weinberger SE, Cockrill BA, Mandel J. Approach to the patient with disease of the respiratory system. In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J, editors. Harrison’s Principles of Internal Medicine. 19th ed. New York: McGraw-Hill; 2015. p. 456-65.