Respiratory System Physiology

Learning Objectives

By the end of this page, you should be able to:

• Describe the structure of the upper and lower respiratory tract and relate structure to function
• Explain the mechanics of inspiration and expiration, including the role of intrapleural pressure
• Define and interpret the major lung volumes and capacities (TV, IRV, ERV, RV, FRC, VC, TLC)
• Explain how oxygen and carbon dioxide are transported in blood, including the oxygen-hemoglobin dissociation curve
• Apply the concept of ventilation-perfusion (V/Q) matching to explain regional differences in gas exchange
• Describe the neural and chemical control of breathing, including central and peripheral chemoreceptors
• Connect respiratory physiology to common clinical conditions (COPD, asthma, pneumonia, restrictive lung disease)

Quick Answer

The respiratory system moves air into and out of the lungs (ventilation) and exchanges oxygen and carbon dioxide between air and blood (gas exchange) to keep every cell in the body supplied with oxygen and free of excess CO2. Air travels from the nose or mouth through the pharynx, larynx, trachea, and a branching tree of bronchi and bronchioles before reaching the alveoli, where gas exchange actually occurs across a paper-thin membrane. Breathing itself is driven by pressure changes created by the diaphragm and intercostal muscles, while a control center in the brainstem continuously adjusts breathing rate and depth based on blood CO2, O2, and pH. For medical students, respiratory physiology is the foundation for understanding blood gases, ventilator management, and diseases ranging from asthma to ARDS.

Structure of the Respiratory System

The airway is functionally divided into a conducting zone (moves air, no gas exchange) and a respiratory zone (where gas exchange happens). Everything down to the terminal bronchioles is conducting zone — its job is to warm, humidify, and filter air, not exchange gas.

Upper Respiratory Tract

1. Nose — Contains olfactory receptors for smell; filters, warms, and humidifies incoming air via a highly vascular mucosal lining
2. Mouth — Alternative air route during exercise or nasal congestion, but bypasses the nose's filtering and humidifying function
3. Pharynx (throat) — Shared passage for food and air; divided into nasopharynx, oropharynx, and laryngopharynx
4. Larynx (voice box) — Houses the vocal cords; the epiglottis here closes over the trachea during swallowing to prevent aspiration

Lower Respiratory Tract

1. Trachea — Cartilage-ringed tube from larynx to bronchi, lined with ciliated pseudostratified columnar epithelium that sweeps mucus and trapped particles upward (the mucociliary escalator)
2. Bronchi — Right and left primary bronchi lead into each lung; the right main bronchus is shorter, wider, and more vertical, which is why aspirated objects most often lodge there
3. Bronchioles — Progressively smaller airways lacking cartilage; smooth muscle here responds to autonomic and inflammatory signals (bronchoconstriction in asthma)
4. Respiratory bronchioles — Transition zone where occasional alveoli begin to appear, marking the start of the respiratory zone
5. Alveoli — ~300 million tiny air sacs providing roughly 70 m² of surface area for gas exchange. Type I pneumocytes form the thin gas-exchange surface; type II pneumocytes secrete surfactant and can regenerate the epithelium after injury

Mechanics of Breathing

Breathing is entirely pressure-driven. Gas flows from high pressure to low pressure, so the lungs create pressure gradients by changing volume — this is Boyle's law in action (pressure and volume are inversely related at constant temperature).

Inspiration (active process)

1. The diaphragm contracts and flattens, increasing the vertical dimension of the thoracic cavity
2. External intercostal muscles contract, lifting the ribs and expanding the cavity further
3. As thoracic volume increases, intrapleural pressure becomes more negative (roughly −8 cmH2O at end-inspiration vs. −5 cmH2O at rest)
4. Alveolar pressure drops below atmospheric pressure, and air flows in until pressures equalize

Expiration (passive at rest, active in exercise or forced breathing)

1. At rest, the diaphragm and intercostals simply relax, and the elastic recoil of the lungs and chest wall returns them to resting volume
2. Alveolar pressure rises above atmospheric pressure, pushing air out
3. During forced expiration (exercise, coughing), internal intercostals and abdominal muscles contract to actively reduce thoracic volume

Intrapleural pressure is always negative relative to alveolar pressure — this negative pressure is what keeps the lungs from collapsing away from the chest wall. If air enters the pleural space (pneumothorax), this pressure gradient is lost and the lung collapses.

Lung Volumes and Capacities

These are classic exam material because spirometry tracings are a favorite USMLE figure.

• Tidal volume (TV) — Air moved in a normal resting breath (~500 mL)
• Inspiratory reserve volume (IRV) — Extra air that can be inhaled beyond a normal tidal breath (~3000 mL)
• Expiratory reserve volume (ERV) — Extra air that can be forcefully exhaled after a normal tidal breath (~1100 mL)
• Residual volume (RV) — Air remaining in the lungs after maximal exhalation; cannot be measured by spirometry because it can never be exhaled (~1200 mL)
• Functional residual capacity (FRC) = ERV + RV — the lung volume at the end of a normal, passive exhalation; the point where inward lung recoil exactly balances outward chest wall recoil
• Vital capacity (VC) = TV + IRV + ERV — the maximum air that can be exhaled after a maximal inhalation
• Total lung capacity (TLC) = VC + RV — the volume in the lungs after a maximal inspiration

Any volume that includes RV (FRC, TLC) cannot be measured by simple spirometry — it requires techniques like helium dilution or body plethysmography, because spirometry only tracks air that actually moves in and out through the mouthpiece.

Gas Exchange and Diffusion

Gas exchange across the alveolar-capillary membrane depends on Fick's law: diffusion rate is proportional to surface area and the partial pressure gradient, and inversely proportional to membrane thickness. This is exactly why diseases matter mechanistically:

• Pulmonary fibrosis thickens the membrane → slows diffusion
• Emphysema destroys alveolar walls → reduces surface area
• Pulmonary edema adds fluid to the diffusion path → slows diffusion

CO2 diffuses about 20 times faster than O2 across the membrane (it is far more soluble), which is why oxygenation problems appear before ventilation (CO2) problems in most early lung disease.

Oxygen transport

Oxygen is carried in blood in two forms: dissolved in plasma (a tiny fraction, following Henry's law) and bound to hemoglobin (the overwhelming majority — about 98%). Each hemoglobin molecule binds up to four O2 molecules, and the binding is cooperative: once one O2 binds, the molecule's affinity for the next O2 increases. This cooperativity produces the sigmoid (S-shaped) oxygen-hemoglobin dissociation curve, rather than a straight line or simple hyperbola.

The Bohr effect describes how a rightward shift of the curve — caused by increased CO2, increased H+ (lower pH), increased temperature, or increased 2,3-BPG — decreases hemoglobin's affinity for O2 and promotes unloading exactly where it's needed: in metabolically active, acidic, warm tissue. Fetal hemoglobin has a left-shifted curve (higher O2 affinity) so it can pull oxygen across the placenta from maternal blood.

Carbon dioxide transport

CO2 travels in blood in three forms:

1. Dissolved CO2 (~7%)
2. Bound to hemoglobin as carbaminohemoglobin (~23%)
3. As bicarbonate (HCO3-) (~70%) — CO2 combines with water inside red blood cells via carbonic anhydrase to form carbonic acid, which dissociates into H+ and HCO3-. The HCO3- is shuttled out of the RBC into plasma in exchange for chloride (the "chloride shift")

Deoxygenated hemoglobin binds CO2 and H+ more readily than oxygenated hemoglobin — this is the Haldane effect, the CO2-transport mirror of the Bohr effect. It means that as hemoglobin drops off O2 in the tissues, it simultaneously becomes better at picking up CO2 and H+ for the return trip to the lungs.

Ventilation-Perfusion (V/Q) Matching

Efficient gas exchange requires that ventilation (air reaching alveoli) and perfusion (blood reaching alveolar capillaries) are matched. In an upright lung, both ventilation and perfusion are greater at the base than the apex due to gravity, but perfusion increases more steeply, so:

• Apex of the lung: V/Q ratio is high (~3) — relatively over-ventilated compared to blood flow
• Base of the lung: V/Q ratio is low (~0.6) — relatively over-perfused compared to ventilation
• Overall average V/Q ratio: approximately 0.8

The lung has a built-in correction mechanism: hypoxic pulmonary vasoconstriction. When alveolar oxygen is low in a region (poor ventilation), the local pulmonary arterioles constrict, redirecting blood flow toward better-ventilated regions of the lung. This is the opposite of what systemic arterioles do in hypoxia (they dilate) — a distinction that is a favorite exam trap.

Extreme mismatches define two important physiologic concepts:

• Dead space (V/Q → infinity): ventilation without perfusion, as in a pulmonary embolism
• Shunt (V/Q → 0): perfusion without ventilation, as in a mucus-plugged airway or ARDS; shunt physiology does not improve much with supplemental oxygen because the blood never contacts ventilated alveoli

Control of Breathing

Breathing is normally an unconscious, rhythmic process generated by neurons in the medulla (the dorsal and ventral respiratory groups), with the pons fine-tuning the rhythm. But the actual minute-to-minute adjustments come from chemoreceptors:

• Central chemoreceptors (in the medulla) — the dominant driver of breathing under normal conditions. They don't sense CO2 directly; they sense the H+ that CO2 generates after crossing the blood-brain barrier and being hydrated to carbonic acid in the CSF. This makes them exquisitely sensitive to even small changes in arterial CO2.
• Peripheral chemoreceptors (carotid and aortic bodies) — sense arterial PO2, PCO2, and pH directly in the blood. They respond significantly to O2 only when PO2 falls quite low (below ~60 mmHg), because hemoglobin stays highly saturated until that point.

In healthy individuals, CO2 (via central chemoreceptors) is by far the primary drive to breathe. In chronic CO2 retainers (severe COPD), the central chemoreceptors can become desensitized to chronically elevated CO2, and peripheral chemoreceptor-driven hypoxic drive becomes relatively more important — the physiological rationale (though a more nuanced one than the old teaching) behind cautious oxygen titration in these patients.

Clinical Relevance

Respiratory Diseases

1. COPD (emphysema and chronic bronchitis) — Airflow limitation from airway inflammation and, in emphysema, destruction of alveolar walls and loss of elastic recoil, which lowers the driving pressure for expiration and traps air (increasing FRC and RV)
2. Asthma — Reversible bronchoconstriction and airway inflammation causing episodic obstruction; obstructive pattern with a reduced FEV1/FVC ratio that improves with bronchodilators
3. Pneumonia — Alveolar inflammation and fluid filling (consolidation) that creates a shunt-like physiology, since fluid-filled alveoli cannot be ventilated even though they remain perfused
4. Restrictive lung disease (e.g., pulmonary fibrosis) — Reduced lung compliance lowers all lung volumes (TLC, VC, FRC) but preserves or increases the FEV1/FVC ratio, distinguishing it from obstructive disease

Diagnostic Techniques

1. Spirometry — Measures FEV1 and FVC to distinguish obstructive (low FEV1/FVC) from restrictive (normal or high FEV1/FVC, low FVC) disease
2. Arterial blood gas (ABG) — Directly measures PaO2, PaCO2, and pH to assess oxygenation, ventilation, and acid-base status
3. Chest X-ray / CT — Structural imaging for infiltrates, masses, effusions, and fibrosis
4. DLCO (diffusing capacity) — Assesses the alveolar-capillary membrane's ability to transfer gas; reduced in fibrosis and emphysema, but characteristically normal in asthma and chronic bronchitis

Key Terms

Term	Definition	Related Concept
Tidal volume (TV)	Volume of air moved in a normal resting breath (~500 mL)	Minute ventilation, spirometry
Functional residual capacity (FRC)	Lung volume at the end of a passive exhalation (ERV + RV)	Elastic recoil balance, cannot be measured by spirometry alone
Compliance	Change in lung volume per unit change in pressure; a measure of how easily the lung stretches	Surfactant, restrictive lung disease
Surfactant	Phospholipid secreted by type II pneumocytes that reduces alveolar surface tension	Laplace's law, neonatal respiratory distress syndrome
Bohr effect	Rightward shift of the O2-hemoglobin curve with increased CO2, H+, temperature, or 2,3-BPG, favoring O2 unloading	Oxygen transport, tissue hypoxia
Haldane effect	Deoxygenated hemoglobin carries more CO2 and H+ than oxygenated hemoglobin	Carbon dioxide transport, chloride shift
V/Q ratio	Ratio of alveolar ventilation to pulmonary capillary perfusion; ideal near 1, average ~0.8	Dead space, shunt
Hypoxic pulmonary vasoconstriction	Local pulmonary arteriolar constriction in response to alveolar hypoxia, redirecting blood to better-ventilated regions	V/Q matching, pulmonary hypertension
Central chemoreceptors	Medullary receptors sensing CSF H+ (from CO2), the dominant driver of resting ventilation	Control of breathing, CO2 retention
Peripheral chemoreceptors	Carotid and aortic body receptors sensing arterial PO2, PCO2, and pH	Hypoxic drive, COPD
Dead space	Ventilated but non-perfused lung region (V/Q → infinity)	Pulmonary embolism
Shunt	Perfused but non-ventilated lung region (V/Q → 0)	ARDS, mucus plugging

Common Mistakes

Misconception: Expiration at rest is an active muscular process, just like inspiration.

Why it's wrong: Students often assume breathing out requires the same kind of active muscle contraction as breathing in, since inspiration clearly involves diaphragm and intercostal contraction.

Correct understanding: Quiet expiration at rest is passive — it results purely from elastic recoil of the lungs and chest wall once inspiratory muscles relax. Active expiration (internal intercostals, abdominal muscles) only occurs during exercise, forced breathing, or in obstructive disease where recoil alone isn't enough.

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Misconception: Oxygen is transported in the blood mainly dissolved in plasma.

Why it's wrong: This confuses how gases like CO2 behave with how O2 actually behaves; O2 has poor solubility in plasma compared to how much the body needs delivered to tissue every minute.

Correct understanding: About 98% of O2 in blood is bound to hemoglobin, and only about 1.5% is dissolved in plasma. This is precisely why anemia (low hemoglobin) can severely impair oxygen delivery even when PaO2 (dissolved O2, what pulse oximetry and ABGs reflect indirectly) looks normal.

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Misconception: Giving a COPD patient with hypoxic drive too much oxygen makes them stop breathing because oxygen is somehow "toxic" to their drive to breathe.

Why it's wrong: This oversimplifies a more nuanced mechanism and can lead to inappropriate withholding of needed oxygen in a hypoxic patient.

Correct understanding: In chronic CO2 retainers, correcting hypoxemia too aggressively can worsen V/Q mismatch (by reversing protective hypoxic pulmonary vasoconstriction) and shift the oxygen-hemoglobin curve, releasing CO2 that was buffered on hemoglobin (Haldane effect) — both raise PaCO2. It is not simply "removing the drive to breathe." Oxygen should still be given to a hypoxic patient — just titrated and monitored carefully.

Comparison and Connections

Feature	Obstructive Lung Disease (e.g., COPD, asthma)	Restrictive Lung Disease (e.g., pulmonary fibrosis)
Primary problem	Difficulty exhaling air (airway narrowing)	Difficulty expanding lungs (reduced compliance)
FEV1/FVC ratio	Decreased (<70%)	Normal or increased
TLC	Increased (air trapping)	Decreased
FRC and RV	Increased	Decreased
DLCO	Normal in asthma/bronchitis; low in emphysema	Decreased
Classic exam clue	Barrel chest, prolonged expiration, wheeze	Fine bibasilar crackles, clubbing

Practice Questions

Recall

1. Name the two lung volumes that together make up functional residual capacity (FRC). Answer guidance: Expiratory reserve volume (ERV) and residual volume (RV).

2. What percentage of oxygen in arterial blood is carried bound to hemoglobin versus dissolved in plasma? Answer guidance: About 98% bound to hemoglobin, about 1.5-2% dissolved in plasma.

Understanding

3. Explain why intrapleural pressure must remain negative relative to alveolar pressure throughout the breathing cycle. Answer guidance: Negative intrapleural pressure opposes the lung's natural tendency to collapse inward and the chest wall's tendency to spring outward, keeping the lung adherent to the chest wall. If this negative pressure is lost (e.g., pneumothorax), the lung collapses because nothing counteracts its elastic recoil.

4. Explain how the Bohr effect helps match oxygen delivery to tissue metabolic demand. Answer guidance: Actively metabolizing tissue produces more CO2 and H+ and generates heat, all of which shift the O2-hemoglobin curve right, lowering hemoglobin's O2 affinity precisely in the tissue that needs more oxygen unloaded — a self-adjusting, local mechanism.

Application

5. A patient with a large pulmonary embolism has a normal respiratory rate but low PaO2. Which V/Q abnormality best explains this, and why doesn't increased ventilation fully compensate? Answer guidance: The embolism blocks perfusion to a ventilated region, creating dead space (V/Q → infinity) in that region. Other, well-perfused alveoli cannot over-oxygenate blood enough to compensate because hemoglobin is already near-maximally saturated in normal alveoli (flat part of the O2-Hb curve), so blood from underperfused regions can't be "made up for" by extra ventilation elsewhere.

6. A patient at high altitude develops increased ventilation and, over days, an increased red blood cell count. Explain the chemoreceptor pathway driving the acute ventilatory change and why the RBC change takes longer. Answer guidance: Acutely, low PaO2 is sensed by peripheral chemoreceptors (carotid/aortic bodies), which increase ventilation once PO2 falls below about 60 mmHg. The RBC increase (polycythemia) results from erythropoietin release from the kidney in response to sustained hypoxia, but producing new red blood cells takes days to weeks — a slower compensatory mechanism than the immediate neural response.

Analysis

7. Compare the mechanism and time-course of the Bohr effect versus the Haldane effect, and explain how they work together during a single circulation of blood through the body. Answer guidance: The Bohr effect (CO2/H+/temperature shifting the O2 curve right) promotes O2 unloading in tissue capillaries. The Haldane effect (deoxygenated Hb binding CO2 and H+ better) simultaneously promotes CO2 uptake at the same location. Both occur together as blood passes through tissue capillaries: as Hb releases O2, it becomes a better CO2/H+ carrier, and the reverse happens in the lungs — Hb picks up O2, becomes less able to hold CO2/H+, and releases them for exhalation.

8. A patient with emphysema has an increased TLC and RV but reduced DLCO, while an asthma patient has increased TLC and RV with normal DLCO. Explain the physiological basis for this difference. Answer guidance: Both are obstructive diseases with air trapping (increased TLC/RV) from expiratory airflow limitation. But emphysema destroys alveolar walls and pulmonary capillaries, directly reducing the surface area available for diffusion (lower DLCO). Asthma causes bronchoconstriction and inflammation of the airways without destroying the alveolar-capillary membrane itself, so diffusing capacity remains normal.

FAQ

Why does the oxygen-hemoglobin dissociation curve have an S-shape instead of a straight line?

The S-shape reflects cooperative binding: hemoglobin has four O2-binding sites, and binding of the first O2 molecule changes the protein's conformation (from the tense/T state to the relaxed/R state), making it easier for subsequent O2 molecules to bind. This creates a curve that is relatively flat at high PO2 (so Hb stays well-saturated even if lung function drops somewhat) and steep at the PO2 range found in tissues (so small drops in tissue PO2 cause large amounts of O2 to unload) — a design well matched to both loading in the lungs and unloading in tissue.

Why is the right main bronchus the more common site for aspirated foreign objects?

The right main bronchus is wider, shorter, and more vertically oriented (more in line with the trachea) than the left, which is narrower and more angled because it must route around the heart. Gravity and airflow geometry both favor objects and aspirated material traveling into the right lung.

What actually happens to lung volumes in COPD versus restrictive lung disease, and why does that matter clinically?

In COPD, loss of elastic recoil and airway narrowing trap air, increasing FRC, RV, and TLC — patients breathe at a higher, less efficient lung volume (hyperinflation). In restrictive disease, stiff, non-compliant lungs cannot expand normally, so all volumes including TLC are reduced. This is why spirometry (which measures FEV1/FVC plus, with additional testing, TLC) is the key test distinguishing the two patterns and guides completely different management approaches.

How does the body know how much to breathe if it can't directly measure blood oxygen most of the time?

Under normal conditions, the body doesn't rely primarily on oxygen sensing at all — central chemoreceptors in the medulla respond to small changes in CSF H+ generated from CO2, making CO2 (via pH) the dominant, minute-to-minute regulator of ventilation. Oxygen sensing via peripheral chemoreceptors only becomes the dominant drive when PO2 drops quite low, such as at high altitude or in severe lung disease.

Why doesn't giving 100% oxygen fix hypoxemia caused by a shunt?

In a shunt, blood passes through unventilated alveoli (e.g., filled with fluid or collapsed) and never contacts fresh air at all, so raising the oxygen concentration of air reaching ventilated alveoli does nothing for the shunted blood. Only some of the blood ever gets exposed to the higher oxygen level, which is why PaO2 improves only partially with supplemental oxygen in shunt physiology — a key clue tested on exams to distinguish shunt from other causes of hypoxemia like hypoventilation or diffusion impairment (both of which do respond to supplemental oxygen).

Quick Revision

• Conducting zone (nose to terminal bronchioles) moves air only; respiratory zone (respiratory bronchioles to alveoli) is where gas exchange occurs
• Inspiration is always active (diaphragm + external intercostals); expiration is passive at rest, active during exertion
• Intrapleural pressure is always negative relative to alveolar pressure — this keeps the lung inflated against the chest wall
• FRC = ERV + RV; TLC = VC + RV; RV and any capacity including RV cannot be measured by spirometry alone
• ~98% of O2 in blood is bound to hemoglobin; CO2 is carried mostly (~70%) as bicarbonate
• Bohr effect: CO2/H+/temperature/2,3-BPG shift the O2-Hb curve right, promoting O2 unloading in tissues
• Haldane effect: deoxygenated hemoglobin carries CO2 and H+ better than oxygenated hemoglobin
• Normal average V/Q ratio is ~0.8; apex of lung has high V/Q, base has low V/Q
• Hypoxic pulmonary vasoconstriction redirects blood away from poorly ventilated alveoli — opposite of systemic vessel response to hypoxia
• Central chemoreceptors (medulla, respond to CSF H+ from CO2) drive normal breathing; peripheral chemoreceptors respond to O2 only when PO2 falls below ~60 mmHg
• Obstructive disease = low FEV1/FVC, increased TLC/RV; restrictive disease = normal/high FEV1/FVC, decreased TLC
• Shunt physiology (perfusion without ventilation) does not correct fully with supplemental oxygen, unlike hypoventilation or diffusion impairment

Related Topics

Prerequisites: Introduction to Physiology, basic cell biology, respiratory anatomy (thoracic cage, airway histology)

Related Topics: Acid-Base Physiology (bicarbonate buffer system), Cardiovascular System Physiology (pulmonary circulation, cardiac output coupling), Renal Physiology (compensatory response to respiratory acid-base disturbances)

Next Topics: Cardiovascular System Physiology, Renal Physiology, Acid-Base Balance

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This page is for educational purposes. Always verify with current clinical guidelines.