Physiology of the Lung
The lung functions as a sophisticated gas exchange organ where oxygen is transferred from inspired air into the bloodstream while carbon dioxide is removed, with this process critically dependent on ventilation-perfusion matching, alveolar-capillary diffusion, and integrated cardiovascular-respiratory coupling.
Core Gas Exchange Mechanisms
The lung operates through four integrated processes 1:
- Pulmonary ventilation - movement of air into and out of the lungs
- Pulmonary diffusion - exchange of O₂ and CO₂ between alveoli and blood
- Gas transport - carriage of O₂ and CO₂ in the bloodstream
- Capillary gas exchange - transfer between capillary blood and tissues
Oxygen Transport Cascade
Oxygen moves through a dramatic pressure gradient from inspired air to tissues. Mixed venous blood enters the pulmonary artery with a PO₂ of approximately 6 kPa (45 mmHg), rises to 16 kPa (120 mmHg) by the end of the pulmonary capillary, but equilibrates to about 13 kPa (100 mmHg) in larger pulmonary veins due to ventilation-perfusion mismatch 2.
The inspired air PO₂ is 21 kPa, while alveolar PO₂ reaches 16 kPa 2. This gradient drives diffusion across the alveolar-capillary membrane.
Oxygen is carried in blood primarily bound to hemoglobin, not dissolved in plasma. The dissolved component is negligible, making hemoglobin saturation (SO₂) the critical determinant of oxygen content 2. Normal arterial saturation ranges from 95-98% in healthy adults at sea level 2.
Carbon Dioxide Elimination
The CO₂ gradient is much more gradual than oxygen. Carbon dioxide tension falls from approximately 7 kPa (52 mmHg) in venous blood and pulmonary artery to about 5 kPa (37 mmHg) in pulmonary veins and arterial circulation 2. This smaller gradient reflects CO₂'s higher solubility and the larger tissue capacitance for carbon dioxide compared to oxygen 3.
Ventilation-Perfusion (V/Q) Matching
The lung maximizes gas exchange efficiency through active matching of ventilation to perfusion via hypoxic pulmonary vasoconstriction (HPV). This mechanism is unique to pulmonary circulation—all other vascular beds dilate in response to hypoxia 2.
Regional Distribution
In the upright position, both ventilation and perfusion are greatest at the lung bases 2:
- Ventilation is highest basally because the lung is most compressed at the base due to its weight and lower intrapleural pressure, causing greater expansion on inspiration
- Perfusion is greatest at the base due to relatively low perfusion pressure in the pulmonary circulation
Hypoxic Pulmonary Vasoconstriction
In poorly ventilated lung areas, precapillary pulmonary arterioles constrict when sensing low alveolar PO₂ (PAO₂), typically at a threshold around 8 kPa (60 mmHg) 2. This redirects blood flow to well-ventilated regions.
A critical caveat: Deoxygenated blood from poorly ventilated units cannot be fully compensated by mixing with blood from well-ventilated units because the PaO₂-oxygen content relationship is non-linear 2. Once hemoglobin is fully saturated at 100%, increasing PO₂ further adds minimal oxygen content (only dissolved oxygen).
Ventilatory Control
Chemoreceptor Regulation
Peripheral chemoreceptors in the carotid body sense PaO₂ (not oxygen content or saturation) and drive ventilation when PaO₂ falls 2. This design prevents excessive ventilation in response to anemia, which would be ineffective since the problem is carrying capacity, not oxygen availability.
The carotid body can distinguish PaO₂ from oxygen content because its extremely high oxygen delivery-to-consumption ratio means tissue PO₂ reflects arterial PO₂ even during anemic hypoxia 2.
Ventilatory Response to Exercise
The ventilatory equation quantifies the relationship 3:
V'E = [863 × V'CO₂] / [PACO₂ × (1 - VD/VT)]
Where:
- V'E = minute ventilation
- V'CO₂ = carbon dioxide output
- PACO₂ = alveolar CO₂ tension (≈ arterial PCO₂)
- VD/VT = dead space fraction of tidal volume
Lung disease typically increases both resting ventilation and ventilatory requirements during exercise 3. In COPD, high V/Q areas may receive 50% of alveolar ventilation but only 5% of cardiac output, forcing the bulk of CO₂ elimination through poorly ventilated regions and retarding CO₂ kinetics 3.
Cardiovascular Integration
During exercise, oxygen uptake increases primarily through cardiac output augmentation (up to 6-fold increase) and redistribution of blood flow from non-active tissues to skeletal muscles 1. Concomitantly, pulmonary blood flow increases through both elevated cardiac output and pulmonary vasodilation. Greater oxygen extraction at the tissue level widens the arteriovenous oxygen difference.
Pathophysiological Considerations
Hypoxemia Mechanisms
The principal cause of hypoxemia in disease states is intrapulmonary shunting—persistent perfusion of atelectatic or fluid-filled alveoli 4. In ARDS, shunting may exceed 25% of cardiac output (normal <5%) 4. This form of hypoxemia is relatively refractory to oxygen therapy because non-ventilated units cannot participate in gas exchange regardless of inspired oxygen concentration.
Compliance and Work of Breathing
Lung compliance (change in volume per change in transpulmonary pressure) decreases dramatically in acute lung injury 4. Static inflation pressure for typical tidal volumes may exceed 25 cmH₂O, implying compliance <20 mL/cmH₂O—less than one-fourth of normal 4. This reflects reduced aerated lung volume from alveolar edema and surfactant dysfunction, not necessarily changes in intrinsic tissue elasticity.
Pulmonary Hypertension
Increased pulmonary artery pressure commonly occurs in ARDS, initially from hypoxic vasoconstriction, thromboxane and endothelin release, and intravascular platelet thrombi 4. Late pulmonary hypertension reflects fibrotic obliteration of the vascular bed and carries worse prognosis 4.