Anatomy & Physiology II · In-depth topic guides

Gas Exchange and Gas Transport

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This topic covers the physical gas laws (Dalton's law of partial pressures and Henry's law of solubility) that govern gas movement, the partial pressure gradients driving external (alveolar) respiration and internal (tissue) respiration, the principle of ventilation-perfusion (V/Q) coupling and its autoregulatory mechanisms, oxygen transport by hemoglobin including the oxyhemoglobin dissociation curve, and carbon dioxide transport in its three blood forms — including the Bohr effect, Haldane effect, and the chloride shift. Clinical applications include the classification of hypoxia, carbon monoxide poisoning, hypercapnia, and cyanosis.

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15.1 Gas Laws Governing Respiration

The behavior of gases in the respiratory system is governed by two fundamental physical laws that together determine how much gas dissolves in blood and in which direction it moves.

15.1.1 Dalton's Law of Partial Pressures

Dalton's law states that in a mixture of gases, each gas exerts a partial pressure proportional to its percentage in the mixture, and the total pressure is the sum of all individual partial pressures:

P_total = P_O₂ + P_CO₂ + P_N₂ + P_H₂O

At sea level, atmospheric pressure is 760 mm Hg. Knowing the fractional concentration of each gas, partial pressures in dry atmospheric air are:

Gas	Fraction of Atmosphere	Partial Pressure (mm Hg)
Nitrogen (N₂)	~78.6%	597
Oxygen (O₂)	~20.9%	159
Carbon dioxide (CO₂)	~0.04%	0.3
Water vapor	Varies	Varies

In the body, however, inhaled air is humidified in the conducting airways before it reaches the alveoli. At body temperature (37 °C), water vapor exerts a partial pressure of 47 mm Hg, which displaces other gases. Therefore, the partial pressure of oxygen in inspired (tracheal) air is:

P_IO₂ = (760 − 47) × 0.209 = 150 mm Hg

This dilution by water vapor is why alveolar PO₂ is lower than atmospheric PO₂.

15.1.2 Henry's Law

Henry's law states that the amount of gas that dissolves in a liquid is directly proportional to the partial pressure of that gas above the liquid and its solubility coefficient:

Concentration of dissolved gas = Partial pressure × Solubility coefficient

Key implications for respiration:

A higher partial pressure drives more gas into solution — this creates the partial pressure gradient that drives gas exchange.
Carbon dioxide (CO₂) is approximately 20 times more soluble in plasma than oxygen (O₂). This means that at equal partial pressures, CO₂ dissolves far more readily.
Nitrogen (N₂) has very low solubility. It remains mostly in the gas phase and serves no metabolic role in respiration.

Table 15.1 — Relative Solubility of Respiratory Gases in Plasma (37 °C)

Gas	Solubility Coefficient (mL gas / mL plasma / mm Hg)	Relative Solubility
O₂	0.003	1.0 (reference)
CO₂	0.06	~20× more than O₂
N₂	0.0012	0.4× (less than O₂)

Clinical insight: Henry's law also explains why hyperbaric oxygen therapy works — increasing atmospheric pressure to 2–3 atmospheres raises alveolar PO₂, which dramatically increases the amount of O₂ dissolved directly in plasma, bypassing the hemoglobin limit entirely.

15.2 Partial Pressure Gradients: Atmosphere → Alveoli → Blood → Tissues

Gas exchange occurs entirely by passive diffusion down partial pressure gradients. The gradients for O₂ and CO₂ are oppositely directed, creating a countercurrent-like exchange system.

Table 15.2 — Partial Pressures (mm Hg) of O₂ and CO₂ at Key Sites

Site	PO₂ (mm Hg)	PCO₂ (mm Hg)
Atmospheric air (dry, sea level)	159	0.3
Tracheal (inspired) air (humidified)	150	0.3
Alveolar air	~104	~40
Pulmonary arterial blood (deoxygenated, entering lungs)	~40	~45
Pulmonary venous blood (oxygenated, leaving lungs)	~95	~40
Systemic arterial blood	~95	~40
Systemic venous blood (deoxygenated, returning from tissues)	~40	~45
Tissue interstitial fluid	~40	~45

Note: Pulmonary venous PO₂ (~95 mm Hg) is lower than alveolar PO₂ (~104 mm Hg) because of two factors: (1) physiological shunt — a small fraction of bronchial and coronary venous blood drains directly into the pulmonary veins or left atrium, mixing deoxygenated blood with oxygenated blood; and (2) ventilation-perfusion mismatch — some alveoli are slightly underventilated relative to their perfusion.

15.3 External Respiration: Alveolar Gas Exchange

External respiration is the diffusion of O₂ from alveoli into pulmonary capillary blood and CO₂ from pulmonary capillary blood into alveoli.

15.3.1 Partial Pressure Gradients Across the Respiratory Membrane

Gas	Direction of Diffusion	Gradient
O₂	Alveoli (PO₂ ~104) → Blood (PO₂ ~40)	~64 mm Hg gradient
CO₂	Blood (PCO₂ ~45) → Alveoli (PCO₂ ~40)	~5 mm Hg gradient

Despite the CO₂ gradient being only ~5 mm Hg (vs. ~64 mm Hg for O₂), CO₂ diffuses approximately equally rapidly because it is 20 times more soluble than O₂ (Henry's law), so a smaller gradient suffices to move the same volume of CO₂.

15.3.2 The Respiratory Membrane

The respiratory membrane (also called the alveolar-capillary membrane) is the barrier across which gases must diffuse. From the alveolar lumen to the capillary lumen, it consists of:

Alveolar epithelial cell (Type I pneumocyte)
Fused basement membranes of the alveolar epithelium and capillary endothelium
Capillary endothelial cell
A thin layer of interstitial fluid (normally minimal)

Total thickness: approximately 0.5 µm. Blood spends approximately 0.75 seconds in the pulmonary capillaries, but equilibration of PO₂ and PCO₂ occurs within 0.25 seconds — providing a generous safety margin.

15.3.3 Factors Affecting Alveolar Gas Exchange

Three primary factors influence the efficiency of gas exchange:

1. Partial Pressure Gradients (↑ gradient → ↑ exchange rate)

High altitude → ↓ atmospheric PO₂ → ↓ alveolar PO₂ → ↓ O₂ gradient → ↓ O₂ loading.
Hyperventilation → ↓ alveolar PCO₂ → ↑ CO₂ gradient → ↑ CO₂ unloading.

2. Respiratory Membrane Thickness (↑ thickness → ↓ exchange rate)

Pulmonary edema (fluid in the interstitium) increases the diffusion distance, slowing gas exchange. Seen in left-sided heart failure.
Pulmonary fibrosis (scarring/thickening of the alveolar walls) also increases membrane thickness.
Pneumonia causes inflammatory exudate and consolidation, thickening the membrane locally.

3. Surface Area (↓ surface area → ↓ exchange rate)

Emphysema: destruction of alveolar walls and septa → fewer, larger air spaces → dramatically reduced surface area for gas exchange.
Lung resection (surgical removal of lung tissue) reduces total surface area.
The normal adult lung has a total alveolar surface area of approximately 70–100 m² — roughly the size of a tennis court.

15.4 Ventilation-Perfusion (V/Q) Coupling

For efficient gas exchange, ventilation (airflow to alveoli) and perfusion (blood flow to pulmonary capillaries) must be matched. The V/Q ratio is the ratio of alveolar ventilation (V̇_A) to pulmonary capillary blood flow (Q̇):

Optimal V/Q ratio ≈ 0.8 (ventilation ~4.2 L/min ÷ perfusion ~5 L/min)

15.4.1 V/Q Mismatch

Condition	V/Q Ratio	Mechanism	Consequence
Shunt (perfusion without ventilation)	V/Q < 0.8 (low)	Alveolus perfused but poorly ventilated (e.g., mucus plug, atelectasis)	Blood bypasses gas exchange → ↓ arterial PO₂
Dead space (ventilation without perfusion)	V/Q > 0.8 (high)	Alveolus ventilated but poorly perfused (e.g., pulmonary embolism)	Wasted ventilation → no gas exchange

15.4.2 Autoregulation of V/Q Matching

The lungs use local autoregulatory mechanisms to redirect airflow and blood flow toward well-matched units:

1. Response to Low Alveolar PO₂ (Hypoxic Pulmonary Vasoconstriction):

When an alveolus is poorly ventilated, its local PO₂ drops.
In response, the adjacent pulmonary arterioles vasoconstrict. This is the opposite of the systemic circulation (where hypoxia → vasodilation).
Purpose: divert blood away from poorly ventilated regions toward well-ventilated regions where it can become oxygenated.

2. Response to High Alveolar PCO₂ (Bronchodilation):

When an alveolus has high PCO₂, the local bronchioles dilate.
Purpose: increase airflow to regions that need to eliminate CO₂.

3. Response to Low Alveolar PCO₂ (Bronchoconstriction):

When an alveolus has low PCO₂ (well-ventilated but not metabolically active), local bronchioles constrict.
Purpose: redirect airflow toward regions where CO₂ is being produced and gas exchange is needed.

15.5 Internal Respiration: Tissue Gas Exchange

Internal respiration is the diffusion of O₂ from systemic capillary blood into tissue cells and CO₂ from tissue cells into capillary blood.

Gas	Direction of Diffusion	Gradient
O₂	Systemic capillary blood (PO₂ ~95) → Tissue interstitial fluid (PO₂ ~40)	~55 mm Hg gradient
CO₂	Tissue cells (PCO₂ ~45) → Systemic capillary blood (PCO₂ ~40)	~5 mm Hg gradient

Oxygen diffuses out of the capillary and into metabolically active cells, where it is used in aerobic respiration to produce ATP. CO₂, the metabolic waste product, diffuses in the opposite direction to be transported to the lungs for elimination.

15.6 Oxygen Transport in the Blood

Oxygen is transported in the blood in two forms:

Form	Percentage	Mechanism
Bound to hemoglobin (Hb)	~98.5%	O₂ reversibly binds to the heme iron (Fe²⁺) of hemoglobin
Dissolved in plasma	~1.5%	Free O₂ dissolved in plasma per Henry's law

Although dissolved O₂ constitutes only ~1.5%, it is this dissolved fraction that determines PO₂ — and PO₂ is what drives O₂ binding to hemoglobin and diffusion into tissues.

15.6.1 Hemoglobin Structure and O₂ Binding

Hemoglobin is a tetrameric protein composed of:

2 alpha (α) globin chains + 2 beta (β) globin chains (adult hemoglobin A, HbA)
Each globin chain wraps around a heme group, and each heme contains one ferrous iron (Fe²⁺) atom.
Each Fe²⁺ atom can reversibly bind one O₂ molecule.
Therefore, one hemoglobin molecule can carry up to 4 O₂ molecules.

When fully loaded with four O₂ molecules, hemoglobin is called oxyhemoglobin (HbO₂). When O₂ is released, it becomes deoxyhemoglobin (HHb) or reduced hemoglobin.

15.6.2 Cooperative Binding

Hemoglobin exhibits cooperative binding (also called positive cooperativity):

The binding of the first O₂ molecule is relatively difficult (low affinity) because the hemoglobin molecule is in its tense (T) state (deoxy conformation).
Binding of the first O₂ molecule induces a conformational change that makes the second and third O₂ molecules bind more easily.
The hemoglobin transitions to the relaxed (R) state (oxy conformation), which has high O₂ affinity.
This sigmoidal (S-shaped) binding curve is the hallmark of cooperativity — hemoglobin's affinity increases as more O₂ is bound.

Contrast with myoglobin: Myoglobin, with a single heme group, cannot display cooperativity and has a hyperbolic (non-sigmoidal) dissociation curve, giving it a higher affinity for O₂ at low PO₂ — ideal for extracting O₂ from hemoglobin in muscle tissue.

15.6.3 Oxygen Saturation (SaO₂ / SpO₂)

Hemoglobin saturation is the percentage of heme binding sites occupied by O₂:

SaO₂ (%) = (O₂ bound to Hb / Total O₂-binding capacity of Hb) × 100

100% saturation = all four heme sites occupied on every Hb molecule (rarely achieved at normal PO₂).
Normal arterial saturation (SaO₂): 95–100%.
Normal venous saturation (SvO₂): approximately 75% (at rest), reflecting tissue O₂ extraction.

Pulse oximetry estimates saturation non-invasively by measuring light absorption and is reported as SpO₂.

15.7 The Oxyhemoglobin Dissociation Curve

The oxyhemoglobin dissociation curve plots hemoglobin saturation (%) against PO₂ (mm Hg) and has a characteristic sigmoid (S) shape reflecting cooperative binding.

Region of Curve	PO₂ Range	Shape	Functional Significance
Flat upper portion (loading zone)	PO₂ 60–100 mm Hg	Nearly horizontal	At alveolar PO₂ (~104 mm Hg), Hb is ~98–100% saturated. Even if alveolar PO₂ drops moderately (e.g., mild hypoventilation, altitude), saturation stays high — safety margin for O₂ loading.
Steep lower portion (unloading zone)	PO₂ 10–40 mm Hg	Very steep	In tissue capillary PO₂ range (~40 to ~15 mm Hg), a small drop in PO₂ causes a large release of O₂ — facilitates O₂ unloading at metabolically active tissues.

Key PO₂ Points on the Curve:

PO₂ (mm Hg)	Approximate Saturation	Anatomic/Clinical Significance
100	98–100%	Normal arterial blood
60	90%	Critical threshold: below this, saturation falls steeply
40	75%	Normal venous PO₂ at rest
27	50%	P₅₀ — the PO₂ at which Hb is 50% saturated (normal adult HbA)

15.7.1 The P₅₀ Value

P₅₀ is the PO₂ at which hemoglobin is 50% saturated. For normal adult hemoglobin (HbA) at pH 7.4 and 37 °C, P₅₀ ≈ 27 mm Hg. The P₅₀ is a convenient index of hemoglobin's O₂ affinity:

↑ P₅₀ = decreased affinity (curve shifts right → O₂ unloading is enhanced).
↓ P₅₀ = increased affinity (curve shifts left → O₂ loading is enhanced, but unloading is impaired).

15.8 Factors Shifting the Oxyhemoglobin Dissociation Curve

15.8.1 Right Shift (↓ Affinity = ↑ O₂ Unloading)

A right shift decreases hemoglobin's affinity for O₂, meaning that at any given PO₂, less O₂ is bound — effectively, O₂ is more readily released to tissues. This is beneficial during exercise when active muscles need more O₂.

Factors causing a right shift:

Factor	Direction of Change	Mechanism
↑ Temperature	Right shift	Higher temperature weakens the Hb–O₂ bond, favoring the T state
↑ PCO₂	Right shift	CO₂ binds to Hb, promoting T state (part of the Bohr effect)
↓ pH (↑ [H⁺])	Right shift	H⁺ binds to Hb, stabilizing the T state — the Bohr effect
↑ 2,3-BPG (2,3-bisphosphoglycerate)	Right shift	2,3-BPG binds to the central cavity of deoxyhemoglobin, stabilizing the T state; produced by RBCs during glycolysis; elevated in chronic hypoxia, anemia, high altitude, and pregnancy

Mnemonic — "CADET, face RIGHT!": CO₂ ↑, Acid (H⁺) ↑, 2,3-DPG (BPG) ↑, Exercise (temperature ↑) → Right shift.

15.8.2 Left Shift (↑ Affinity = ↓ O₂ Unloading)

A left shift increases hemoglobin's affinity for O₂, meaning that at any given PO₂, more O₂ is bound — loading is enhanced, but O₂ is held more tightly and released less readily to tissues.

Factors causing a left shift:

Factor	Direction of Change	Mechanism
↓ Temperature	Left shift	Cooler blood increases Hb–O₂ bond stability
↓ PCO₂	Left shift	Lower CO₂ levels favor the R state
↑ pH (↓ [H⁺]) (alkalosis)	Left shift	Less H⁺ to stabilize the T state
Fetal hemoglobin (HbF)	Left shift (relative to HbA)	HbF (α₂γ₂) binds 2,3-BPG less avidly → higher baseline O₂ affinity → facilitates O₂ transfer from maternal blood (HbA) to fetal blood (HbF) across the placenta

15.8.3 The Bohr Effect

The Bohr effect describes the influence of pH and PCO₂ on hemoglobin's oxygen affinity:

In metabolically active tissues: ↑ CO₂ production → ↑ carbonic acid formation → ↑ H⁺ (↓ pH) → right shift → enhanced O₂ unloading (exactly where O₂ is needed).
In the lungs: CO₂ is exhaled → ↓ PCO₂ → ↑ pH → left shift → enhanced O₂ loading (exactly where O₂ should be picked up).

The Bohr effect is a form of negative feedback that automatically matches O₂ delivery to metabolic demand.

Table 15.3 — Summary: Bohr Effect

Location	pH	PCO₂	Hb–O₂ Affinity	Curve Shift	O₂ Effect
Lungs	↑ (more alkaline)	↓	↑ Increased	Left	Enhanced O₂ loading
Tissues	↓ (more acidic)	↑	↓ Decreased	Right	Enhanced O₂ unloading

15.9 Carbon Dioxide Transport in the Blood

CO₂ is transported from tissues to the lungs in three forms:

Table 15.4 — Forms of CO₂ Transport in Blood

Form	Percentage of Total CO₂	Description
Bicarbonate (HCO₃⁻)	~70%	CO₂ converted to carbonic acid, then dissociates to HCO₃⁻ and H⁺; transported in plasma
Carbaminohemoglobin	~20%	CO₂ bound to the amino groups of hemoglobin (and to a lesser extent, other plasma proteins)
Dissolved CO₂	7–10%	Free CO₂ dissolved in plasma (per Henry's law)

15.9.1 Bicarbonate Formation and the Chloride Shift (Tissue Level)

In systemic tissue capillaries, where PCO₂ is high:

CO₂ diffuses into RBCs from the tissues.
Inside the RBC, carbonic anhydrase catalyzes a critical reaction: CO₂ + H₂O ⇌ H₂CO₃ ⇌ H⁺ + HCO₃⁻ This reaction is reversible and proceeds in both directions depending on PCO₂.
The HCO₃⁻ produced accumulates inside the RBC and diffuses out into the plasma down its concentration gradient via a Band 3 (AE1) anion exchanger.
To maintain electrical neutrality, Cl⁻ moves into the RBC in exchange — this is the chloride shift (or Hamburger phenomenon).
The H⁺ produced is buffered by hemoglobin (which binds H⁺, reducing intracellular acidity and also promoting O₂ unloading via the Bohr effect).

In the plasma, HCO₃⁻ travels to the lungs as the major transport form of CO₂. Note that most of the reaction occurs in the RBC because carbonic anhydrase is located there; the reaction would be far too slow in plasma alone.

15.9.2 Reverse Chloride Shift (Lung Level)

In the pulmonary capillaries, where PCO₂ is low:

CO₂ diffuses out of the blood into the alveoli.
The low PCO₂ drives the carbonic anhydrase reaction to the left: H⁺ + HCO₃⁻ → H₂CO₃ → CO₂ + H₂O
HCO₃⁻ moves into the RBC from the plasma, and Cl⁻ moves out of the RBC — the reverse chloride shift.
The regenerated CO₂ diffuses into the alveoli for exhalation.

15.9.3 Carbaminohemoglobin Formation

CO₂ can bind directly to the amino-terminal groups of the globin chains of hemoglobin to form carbaminohemoglobin:

Hb-NH₂ + CO₂ ⇌ Hb-NH-COO⁻ + H⁺

This reaction does not require an enzyme and occurs rapidly.
Deoxygenated hemoglobin (HHb) binds CO₂ more readily than oxyhemoglobin (HbO₂) — this is the Haldane effect.

15.9.4 The Haldane Effect

The Haldane effect describes the influence of oxygenation on CO₂ transport:

Deoxygenated hemoglobin has a higher affinity for CO₂ and H⁺ than oxyhemoglobin.
In tissues, where O₂ is being unloaded from hemoglobin, the resulting deoxyhemoglobin binds more CO₂ (forming carbaminohemoglobin) and more H⁺ (buffering the protons from carbonic acid dissociation) → facilitates CO₂ loading.
In the lungs, as hemoglobin binds O₂ and becomes oxyhemoglobin, its affinity for CO₂ and H⁺ decreases → facilitates CO₂ unloading.

Table 15.5 — Bohr Effect vs. Haldane Effect

Feature	Bohr Effect	Haldane Effect
What is affected	O₂ binding to hemoglobin	CO₂ binding to hemoglobin
Agent	CO₂ / H⁺ (pH)	O₂
Mechanism	↑ CO₂ / ↓ pH → ↓ Hb–O₂ affinity (right shift) → more O₂ released	↑ O₂ → ↓ Hb–CO₂ affinity → more CO₂ released
Location of benefit	Tissues (enhanced O₂ unloading)	Lungs (enhanced CO₂ unloading)
Reciprocal	Bohr: CO₂/H⁺ → affects O₂ binding	Haldane: O₂ → affects CO₂/H⁺ binding

Together, the Bohr and Haldane effects create a reciprocal coupling between O₂ unloading and CO₂ loading in the tissues, and O₂ loading and CO₂ unloading in the lungs — a beautifully coordinated system.

15.10 Clinical Considerations and Disorders of Gas Exchange

15.10.1 Types of Hypoxia

Hypoxia is inadequate O₂ delivery to tissues. It is classified by etiology:

Table 15.6 — Four Types of Hypoxia

Type	Primary Defect	PO₂ of Arterial Blood	O₂ Content	Example Causes
Hypoxic hypoxia	Low arterial PO₂	↓	↓	High altitude, hypoventilation, V/Q mismatch, diffusion impairment (pulmonary edema, fibrosis)
Anemic hypoxia	Low functional hemoglobin	Normal	↓	Anemia (↓ RBCs), CO poisoning (Hb blocked), methemoglobinemia (Fe²⁺ oxidized to Fe³⁺)
Ischemic (stagnant) hypoxia	Low blood flow / cardiac output	Normal	Normal (but flow ↓)	Heart failure, circulatory shock, arterial occlusion, embolism
Histotoxic hypoxia	Cells cannot use delivered O₂	Normal	Normal	Cyanide poisoning (blocks cytochrome c oxidase in ETC)

15.10.2 Carbon Monoxide (CO) Poisoning

Carbon monoxide is a colorless, odorless gas that competes with O₂ for hemoglobin binding:

CO has approximately 200–250 times the affinity of O₂ for the Fe²⁺ in hemoglobin.
Even at low partial pressures, CO displaces O₂ from hemoglobin, forming carboxyhemoglobin (HbCO).
HbCO cannot carry O₂ and also causes a left shift of the dissociation curve for any remaining HbO₂ — O₂ is held more tightly and released less readily to tissues.
Classic sign: "cherry red" skin color (carboxyhemoglobin is bright red). Do not confuse with cyanosis (bluish from deoxyhemoglobin).
Treatment: 100% O₂ or hyperbaric oxygen therapy to displace CO and directly dissolve O₂ in plasma.

15.10.3 Hypercapnia

Hypercapnia is elevated arterial PCO₂ (>45 mm Hg), usually caused by hypoventilation (e.g., COPD, respiratory depression, neuromuscular disorders). Consequences include:

Respiratory acidosis (↑ PCO₂ → ↑ H₂CO₃ → ↑ H⁺ → ↓ pH).
Cerebral vasodilation → increased intracranial pressure → headache, confusion, eventual coma (CO₂ narcosis).
Stimulates central and peripheral chemoreceptors to increase ventilation (unless chemoreceptor drive is blunted, as in chronic COPD).

15.10.4 Cyanosis

Cyanosis is a bluish discoloration of the skin and mucous membranes caused by increased deoxyhemoglobin in capillary blood:

Central cyanosis: bluish lips, tongue, oral mucosa — reflects low arterial O₂ saturation (e.g., hypoxic hypoxia or right-to-left cardiac shunt). Requires approximately 5 g/dL of deoxygenated hemoglobin in arterial blood.
Peripheral cyanosis: bluish fingers/toes — reflects sluggish blood flow and increased O₂ extraction in peripheral tissues (e.g., cold exposure, heart failure, shock). Arterial saturation may be normal.

Important: Anemic patients may be severely hypoxic without visible cyanosis because they lack sufficient hemoglobin to reach the 5 g/dL deoxyhemoglobin threshold. Conversely, polycythemic patients may appear cyanotic even with adequate oxygenation due to their high total hemoglobin.

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The same idea, in plain words

Explain it like I’m 10

Gas Laws: Dalton and Henry

Picture a jar filled with different colored marbles — red for oxygen, blue for nitrogen, green for CO₂. Dalton's law says each color pushes on the jar wall with its own pressure, and the total pressure is all of them added up. Now imagine shaking those marbles into a glass of water. Henry's law says the more marbles you shake in and the more "dissolvable" those marbles are, the more end up in the water. CO₂ dissolves like sugar cubes — easily, about 20 times better than oxygen — which is why CO₂ doesn't need as big a pressure push to move into and out of blood.

How Oxygen Gets From Air to Blood (External Respiration)

Think of two rooms separated by a thin screen door: one room (the alveolus) has lots of oxygen, the other (the blood) has very little. Oxygen rushes through the screen door from the crowded room to the empty one — that's diffusion. The bigger the difference between the rooms (the partial pressure gradient), the faster the flow. The screen door is the respiratory membrane — if it gets swollen and thick (like in pneumonia or fluid in the lungs), it's harder for oxygen to get through. If you reduce the size of the door (like in emphysema, where lung walls break down), less oxygen can pass.

V/Q Coupling: Matching Air and Blood

Imagine a factory with air vents and conveyor belts. Every workstation (alveolus) needs both a working air vent (ventilation) and a moving conveyor belt (perfusion). If a vent is clogged, the smart factory's valves automatically send the conveyor belt (blood) to a workstation with a working vent — that's hypoxic pulmonary vasoconstriction. If a conveyor belt breaks, extra air is redirected elsewhere. The factory constantly adjusts so air and blood meet up: the perfect balance is called V/Q matching.

Oxygen's Taxi: Hemoglobin

Your blood has tiny four-seat taxis called hemoglobin. Each taxi can carry up to four oxygen passengers. When the taxi is full, it's called oxyhemoglobin; when it drops off the passengers, it's deoxyhemoglobin. The cool thing is that once the first passenger hops in, the taxi doors open wider and the next passengers jump in more easily — that's cooperative binding.

The Oxygen Drop-Off Curve

Imagine you're driving an oxygen delivery truck. At high oxygen pressure (in the lungs), the truck is nearly full — that's the flat top of the curve. But when you enter a busy neighborhood (working muscles) where oxygen pressure is low, the truck starts dropping off packages quickly — that's the steep part of the curve. Things that shift the drop-off to happen faster and easier (right shift) are: exercise heat (↑ temperature), CO₂ buildup (↑ PCO₂), and acidity (↓ pH — the Bohr effect). These all scream "the tissue is working hard — dump more oxygen NOW!" The opposite (left shift) happens in the lungs where it's cool, CO₂ is low, and pH is high — oxygen stays in the taxi because it's about to be loaded with more.

CO₂ Transport and the Chloride Shift

CO₂ is the body's exhaust gas. It travels in three ways: most of it (70%) turns into bicarbonate — like carbonated water bubbles. Inside the red blood cell, a speedy enzyme called carbonic anhydrase converts CO₂ plus water into bicarbonate and acid. The bicarbonate sneaks out of the cell, and to keep the electrical balance fair, chloride ions swap places and go in — that's the chloride shift, like swapping seats at a concert so everyone stays balanced.

The Bohr and Haldane Effects: A Perfect Swap

Think of Bohr and Haldane as a buddy system. In the muscle neighborhood, oxygen gets dropped off (hemoglobin releases O₂). Once empty-handed, hemoglobin grabs onto CO₂ and acid, giving them a ride to the lungs — that's the Haldane effect: empty hemoglobin is stickier for CO₂. In the lungs, when hemoglobin picks up fresh O₂, it drops off the CO₂ passengers. And the acid/CO₂ that built up in the tissues also makes hemoglobin let go of O₂ more easily — that's the Bohr effect. It's like hemoglobin has a rule: "when I'm getting rid of oxygen, I'll pick up CO₂; when I'm loading oxygen, I'll drop off CO₂."

Carbon Monoxide: The Silent Hijacker

Carbon monoxide (CO) is like an invisible enemy that sneaks onto the taxi (hemoglobin) and locks all the doors. It sticks over 200 times harder than oxygen, so even a tiny amount blocks oxygen from getting a seat. The skin can even turn "cherry red" instead of blue — a dangerous clue doctors look for.

Types of Hypoxia (Not Enough Oxygen to Tissues)

Not all "oxygen shortage" problems are the same:

Hypoxic hypoxia: there's not enough oxygen in the air or it can't get into your blood (high altitude, lung disease).
Anemic hypoxia: there's plenty of oxygen in the air, but not enough working taxis (anemia, CO poisoning).
Ischemic hypoxia: the taxis are fine, but the delivery roads are blocked (heart failure, shock, clot).
Histotoxic hypoxia: oxygen arrives just fine, but the cells' oxygen-using machinery is broken (cyanide poisoning).

Key takeaways

Question: At sea level (atmospheric pressure = 760 mm Hg), humidified inspired air has a water vapor pressure of 47 mm Hg. What is the partial pressure of inspired oxygen (P_IO₂) given that oxygen constitutes approximately 20.9% of dry atmospheric air?
ELI-10: Imagine a jar of mixed candies with some water poured in. The water takes up space (water vapor pressure), so the candies have less room. Before water, oxygen candy had 159 spots out of 760. After water takes 47 spots, oxygen only gets a share of the remaining 713 — which works out to about 150.
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Question: Carbon dioxide (CO₂) is approximately 20 times more soluble in plasma than oxygen (O₂). This means that at the same partial pressure gradient, CO₂:
ELI-10: Think of O₂ as a big, clunky beach ball trying to squeeze through a door, while CO₂ is like water — it just slides right through. Because CO₂ dissolves so easily (like sugar in hot tea), it doesn't need a big push to move from one side to the other. Even a gentle nudge is enough.
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Question: Which of the following correctly states the partial pressure gradients that drive external respiration (alveolar gas exchange)?
ELI-10: External respiration is like two lines at a ticket booth — oxygen is waiting to get into the concert (blood), so it moves from the crowded outside (alveoli) into the venue. Meanwhile, CO₂ is trying to leave after the show, so it moves in the opposite direction — from inside (blood) out to the exit (alveoli). Each moves where it's less crowded for itself.
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Question: All of the following conditions impair alveolar gas exchange by increasing the thickness of the respiratory membrane EXCEPT:
ELI-10: Emphysema is like knocking down walls in a house to make fewer, bigger rooms — you have less total wall space (surface area) for oxygen to pass through. The remaining walls aren't thicker, there are just fewer of them. Pulmonary edema, fibrosis, and pneumonia are like putting extra layers of wallpaper on the walls — the walls get thicker and oxygen has a harder time getting through.
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Question: A patient aspirates a peanut fragment that lodges in the right main bronchus, blocking airflow to the right lung. Which local autoregulatory response would occur in the affected lung tissue?
ELI-10: Imagine an apartment building where one floor has broken air conditioning. Instead of sending more people to that hot floor, the building manager reroutes everyone to the floors with working AC. The lungs do the same thing — if an air sac can't get fresh air, the blood vessels around it squeeze shut and send blood somewhere it can actually pick up oxygen.
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Question: A pulmonary embolism occludes blood flow to a region of the lung while ventilation to that region remains normal. What is the V/Q ratio in the affected region, and what term describes this condition?
ELI-10: Think of a vending machine (alveolus) that has a plugged coin slot (blocked blood vessel from an embolism). Air still goes into the machine when you open the door (ventilation), but no money (blood) gets exchanged. The machine is just taking up space without doing business — that's "dead space." A shunt is the opposite: the coin slot works but the machine door is jammed shut.
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Question: During a 5K race, a runner's leg muscles generate significant heat, produce large amounts of CO₂, and cause a local decrease in pH. What happens to the oxyhemoglobin dissociation curve, and what is the physiological benefit?
ELI-10: When a muscle is working hard, it's like a party that's getting hot and sweaty. The muscle screams, "It's hot in here! There's too much CO₂! Everything's getting acidic!" Hemoglobin hears these SOS signals and responds by letting go of its oxygen passengers more easily — "If it's this crazy in there, you clearly need this oxygen more than I do!" That's the Bohr effect in action.
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Question: Fetal hemoglobin (HbF) has a higher affinity for oxygen than adult hemoglobin (HbA) because:
ELI-10: Think of HbF as having "stickier hands" for oxygen than mom's hemoglobin (HbA). The reason is that a helper molecule called 2,3-BPG normally makes adult hemoglobin let go of oxygen — it's like a crowbar prying oxygen loose. But fetal hemoglobin is shaped differently so the crowbar doesn't fit as well. This means fetal hemoglobin hangs on tighter, pulling oxygen away from mom's blood and delivering it to the baby.
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Question: Which of the following correctly lists the three forms of carbon dioxide transport in blood, from highest to lowest percentage?
ELI-10: CO₂ takes three different buses to get from your muscles to your lungs. The biggest bus — like a double-decker city bus — is the bicarbonate bus (70 out of every 100 CO₂ molecules). A medium-sized minibus is the carbaminohemoglobin bus (20 out of 100). And a tiny car is the dissolved CO₂ (only about 10 out of 100). Most passengers take the big bus.
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Question: As CO₂ enters a red blood cell in a tissue capillary and is converted to bicarbonate (HCO₃⁻) by carbonic anhydrase, bicarbonate moves out of the RBC into the plasma. To maintain electrical neutrality, which ion moves into the RBC?
ELI-10: Imagine the red blood cell is a crowded elevator. Bicarbonate (a negatively charged person) wants to get off. To keep the elevator balanced (not too positively charged on the inside), a chloride (another negatively charged person) has to step on at exactly the same time, swapping spots. If they didn't swap, the elevator's "charge balance" would be thrown off — like having too many positive charges stuck inside.
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Question: A family of four is found unconscious in their home during winter. The emergency physician notes that all patients have bright cherry-red skin despite low pulse oximeter readings. Which mechanism best explains the pulse oximetry findings and skin color?
ELI-10: CO is like a cheater in a game of musical chairs. It sneaks into the seat (hemoglobin) 200 times faster than oxygen, kicks oxygen out, and locks the chair. Worse, the chair now looks bright cherry red instead of the usual darker color, so the pulse oximeter — which only checks chair color, not who's sitting in it — gets fooled and thinks everything is fine. Doctors need a special machine called a co-oximeter to catch the cheater.
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Question: The Haldane effect describes how oxygenation of hemoglobin affects CO₂ transport. All of the following are consequences of the Haldane effect EXCEPT:
ELI-10: The Haldane effect is like hemoglobin having mood swings. When hemoglobin is carrying oxygen (happy/loaded), it doesn't want to carry CO₂ — "I'm full, no more passengers!" But when it drops off oxygen in the tissues (empty-handed), it gets generous and says, "Sure, hop in, CO₂!" Back in the lungs, when it gets oxygen again, it kicks CO₂ out. Option D is wrong because low pH actually makes hemoglobin let go of oxygen more easily, not grab it tighter — that's the Bohr effect talking, not the Haldane.
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Question: A 55-year-old man with a history of heavy smoking presents with shortness of breath and a bluish tinge to his lips. Arterial blood gas analysis shows: PaO₂ = 55 mm Hg (normal: 80–100), hemoglobin = 15 g/dL (normal), cardiac output = normal. Which type of hypoxia does this patient most likely have?
ELI-10: This is a "not enough oxygen getting into the blood in the first place" problem — the lungs aren't doing their job. If the problem were with the taxis (anemic), the hemoglobin would be low. If the roads were blocked (ischemic), the heart wouldn't be pumping well. If the factories were broken (histotoxic), the oxygen numbers would look fine but cells couldn't use it. But here, the oxygen level in the blood is simply too low — that's hypoxic hypoxia: bad air-in, bad lungs.
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Question: A mountaineer acclimatizes over several weeks at high altitude. Which of the following adaptive changes in oxygen transport would be expected?
ELI-10: When you live at high altitude where the air is thin, your body's red blood cells start making more of a helper molecule called 2,3-BPG. Think of 2,3-BPG as a tiny crowbar that pries oxygen off hemoglobin. The lungs have a harder time loading oxygen at altitude, so you compensate by making sure that whatever oxygen does get picked up is delivered to tissues more easily. It's like a delivery service that's getting fewer packages but making absolutely sure every single package gets dropped off — no holding back.
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Check yourself

14 review questions from the chapter. Try each one, then open the answer.

A. 159 mm Hg B. 150 mm Hg C. 104 mm Hg D. 100 mm Hg
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B. 150 mm Hg Why It's the Answer: Dalton's law requires subtracting water vapor pressure first: P_IO₂ = (760 − 47) × 0.209 ≈ 150 mm Hg. Option A (159 mm Hg) is the PO₂ of dry atmospheric air (760 × 0.209) without accounting for humidification. Option C (104 mm Hg) is the PO₂ in the alveoli after gas mixing, not inspired air. Option D (100 mm Hg) is the approximate PO₂ of systemic arterial blood.
A. Diffuses 20 times more slowly than O₂ B. Requires a larger partial pressure gradient to move across the respiratory membrane C. Diffuses about 20 times more rapidly than O₂ at an equal pressure gradient D. Cannot be carried in the dissolved form unlike O₂
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C. Diffuses about 20 times more rapidly than O₂ at an equal pressure gradient Why It's the Answer: Per Henry's law, dissolved gas concentration = partial pressure × solubility coefficient. Since CO₂'s solubility coefficient is ~20× that of O₂, at equal partial pressure gradients the same physical gradient drives much more CO₂ across the membrane. This is why CO₂ can be exchanged efficiently even though its partial pressure gradient (~5 mm Hg) is much smaller than O₂'s (~64 mm Hg). Options A, B, and D are incorrect — gas diffusion is faster with higher solubility, CO₂ needs a smaller gradient, and CO₂ is carried in dissolved form (7–10%).
A. PO₂ gradient: blood (40 mm Hg) → alveoli (104 mm Hg); PCO₂ gradient: alveoli (40 mm Hg) → blood (45 mm Hg) B. PO₂ gradient: alveoli (104 mm Hg) → blood (40 mm Hg); PCO₂ gradient: blood (45 mm Hg) → alveoli (40 mm Hg) C. PO₂ gradient: alveoli (40 mm Hg) → blood (104 mm Hg); PCO₂ gradient: blood (40 mm Hg) → alveoli (45 mm Hg) D. Both O₂ and CO₂ move from blood into the alveoli because all gases follow the same pressure gradient
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B. PO₂ gradient: alveoli (104 mm Hg) → blood (40 mm Hg); PCO₂ gradient: blood (45 mm Hg) → alveoli (40 mm Hg) Why It's the Answer: In external respiration, O₂ diffuses from the alveolus into the blood down its partial pressure gradient (104 → 40 mm Hg), and CO₂ diffuses from the blood into the alveolus down its gradient (45 → 40 mm Hg). Option A reverses the directions. Option C uses incorrect values — alveolar PO₂ is ~104, not 40. Option D is wrong because each gas follows its own partial pressure gradient independently.
A. Pulmonary edema from left-sided heart failure B. Pulmonary fibrosis (scarring of alveolar walls) C. Emphysema with destruction of alveolar septa D. Pneumonia with inflammatory exudate in the alveoli
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C. Emphysema with destruction of alveolar septa Why It's the Answer: Emphysema impairs gas exchange by reducing the surface area (destruction of alveolar walls and septa creates fewer, larger air spaces), not by increasing membrane thickness. Options A (pulmonary edema), B (pulmonary fibrosis), and D (pneumonic exudate) all increase the diffusion distance by adding fluid, scar tissue, or inflammatory material to the respiratory membrane.
A. Bronchoconstriction in the blocked region to redirect air B. Pulmonary vasodilation in the blocked region to increase blood flow C. Pulmonary vasoconstriction in the blocked region to divert blood toward ventilated alveoli D. Decreased ventilation to the left lung to match the blocked right lung
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C. Pulmonary vasoconstriction in the blocked region to divert blood toward ventilated alveoli Why It's the Answer: When an alveolus is poorly ventilated (↓ alveolar PO₂), the local pulmonary arterioles undergo hypoxic pulmonary vasoconstriction — this is the opposite of the systemic response to hypoxia. The purpose is to shunt blood away from the poorly ventilated region toward well-ventilated alveoli where it can actually become oxygenated, improving the V/Q match. Bronchoconstriction (A) would further reduce airflow. Vasodilation (B) would worsen the V/Q mismatch by sending even more blood to a region that cannot oxygenate it. Option D is not a local autoregulatory mechanism.
A. V/Q < 0.8; shunt B. V/Q > 0.8; dead space ventilation C. V/Q = 0.8; normal matching D. V/Q = 0; anatomical shunt
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B. V/Q > 0.8; dead space ventilation Why It's the Answer: When perfusion is blocked by a pulmonary embolism but ventilation continues, the V/Q ratio is greater than 0.8 (high V/Q) because ventilation is present with little or no perfusion. This is called dead space ventilation — air is moving in and out of alveoli but no gas exchange occurs because there is no blood flow. A shunt (A) is the opposite: perfusion without ventilation (V/Q < 0.8). Option C describes ideal matching. Option D would mean zero ventilation with perfusion present.
A. Left shift; oxygen is held more tightly so it is conserved for vital organs B. Right shift; oxygen is released more readily to the active muscles (Bohr effect) C. No shift; the curve position is fixed regardless of local conditions D. Upward shift; hemoglobin's maximum oxygen capacity increases
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B. Right shift; oxygen is released more readily to the active muscles (Bohr effect) Why It's the Answer: ↑ temperature, ↑ PCO₂, and ↓ pH (↑ H⁺) all cause a right shift of the oxyhemoglobin dissociation curve, which is the Bohr effect. This decreases hemoglobin's oxygen affinity so that O₂ is unloaded more readily at any given PO₂ — precisely what working muscles need. Option A describes a left shift, which would impair O₂ delivery. Option C is wrong — the curve is dynamic. Option D is wrong — maximum O₂ capacity (g/dL of Hb) does not change; the curve shifts right or left, not up or down.
A. HbF has more heme groups per molecule than HbA B. HbF binds 2,3-BPG less avidly, shifting the dissociation curve to the left relative to HbA C. HbF is found in higher concentration in fetal blood than HbA is in adult blood D. HbF has iron in the Fe³⁺ state, which binds O₂ more tightly
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B. HbF binds 2,3-BPG less avidly, shifting the dissociation curve to the left relative to HbA Why It's the Answer: HbF (α₂γ₂) has gamma (γ) globin chains instead of beta (β) chains. The γ chains bind 2,3-BPG less effectively, which means 2,3-BPG cannot stabilize the T (deoxy) state as well → the R (oxy) state is more favored → higher O₂ affinity (left shift). This facilitates O₂ transfer from maternal HbA to fetal HbF across the placenta. HbF and HbA both have four heme groups (A is wrong). Higher concentration (C) does not affect per-molecule affinity. HbF uses Fe²⁺, not Fe³⁺ (D).
A. Dissolved CO₂ > carbaminohemoglobin > bicarbonate B. Carbaminohemoglobin > bicarbonate > dissolved CO₂ C. Bicarbonate > carbaminohemoglobin > dissolved CO₂ D. Bicarbonate > dissolved CO₂ > carbaminohemoglobin
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C. Bicarbonate > carbaminohemoglobin > dissolved CO₂ Why It's the Answer: Approximately 70% of CO₂ is transported as bicarbonate (HCO₃⁻), 20% as carbaminohemoglobin (CO₂ bound to hemoglobin's amino groups), and 7–10% as dissolved CO₂ in plasma.
A. Na⁺ B. K⁺ C. Cl⁻ D. Ca²⁺
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C. Cl⁻ Why It's the Answer: The chloride shift (Hamburger phenomenon) is the exchange of HCO₃⁻ (out) for Cl⁻ (in) across the RBC membrane via the Band 3 (AE1) anion exchanger. This maintains electroneutrality as negatively charged bicarbonate leaves the cell. Na⁺, K⁺, and Ca²⁺ are cations and do not mediate this specific electroneutral exchange.
A. CO poisoning causes metabolic acidosis, which dilates cutaneous vessels causing redness B. CO binds hemoglobin with ~200× the affinity of oxygen, forming bright-red carboxyhemoglobin, while pulse oximetry cannot distinguish HbCO from HbO₂ C. CO directly stimulates erythropoietin release, increasing RBC production and causing a ruddy complexion D. CO binds to cytochrome oxidase, preventing cellular O₂ utilization and causing venous blood to remain oxygenated
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B. CO binds hemoglobin with ~200× the affinity of oxygen, forming bright-red carboxyhemoglobin, while pulse oximetry cannot distinguish HbCO from HbO₂ Why It's the Answer: Carbon monoxide has ~200–250× higher affinity for hemoglobin than O₂, forming carboxyhemoglobin (HbCO) which is bright cherry-red (not the bluish deoxyhemoglobin of cyanosis). Standard pulse oximeters use only two wavelengths of light and cannot distinguish HbCO from HbO₂, so they may report falsely high/normal SpO₂ despite severe tissue hypoxia. A co-oximeter (multi-wavelength) is needed to measure HbCO. Option A is incorrect — metabolic acidosis does not cause cherry-red color. Option C is a chronic adaptation, not an acute CO effect. Option D describes histotoxic hypoxia (e.g., cyanide), not CO poisoning.
A. Deoxygenated hemoglobin has a higher affinity for CO₂ than oxyhemoglobin B. In the tissues, O₂ unloading promotes CO₂ loading onto hemoglobin C. In the lungs, O₂ loading onto hemoglobin promotes CO₂ release D. Deoxygenated hemoglobin binds O₂ more readily at low pH
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D. Deoxygenated hemoglobin binds O₂ more readily at low pH Why It's the Answer: Option D actually describes the opposite of what happens at low pH — the Bohr effect states that low pH (↑ H⁺) decreases hemoglobin's O₂ affinity (right shift), causing O₂ to be released more readily, not bound more readily. All other options correctly describe the Haldane effect: deoxygenated Hb has higher CO₂ affinity (A), O₂ unloading in tissues promotes CO₂ loading (B), and O₂ loading in lungs promotes CO₂ release (C).
A. Anemic hypoxia B. Ischemic (stagnant) hypoxia C. Hypoxic hypoxia D. Histotoxic hypoxia
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C. Hypoxic hypoxia Why It's the Answer: Hypoxic hypoxia is characterized by low arterial PO₂ (PaO₂ is 55 mm Hg, well below normal). His normal hemoglobin rules out anemic hypoxia (A). His normal cardiac output rules out ischemic hypoxia (B). His history of smoking with low PaO₂ points to lung pathology (likely COPD with diffusion impairment or V/Q mismatch). Histotoxic hypoxia (D) would present with normal PaO₂ but impaired cellular usage (cyanide, etc.).
A. Decreased 2,3-BPG production, causing a left shift of the oxyhemoglobin dissociation curve B. Increased 2,3-BPG production, causing a right shift of the oxyhemoglobin dissociation curve C. Conversion of adult hemoglobin (HbA) to fetal hemoglobin (HbF) D. Decreased erythropoietin secretion to conserve energy at altitude
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B. Increased 2,3-BPG production, causing a right shift of the oxyhemoglobin dissociation curve Why It's the Answer: At high altitude, chronic hypoxia stimulates RBC glycolysis to produce more 2,3-BPG. Elevated 2,3-BPG binds deoxyhemoglobin, stabilizing the T (low-affinity) state, causing a right shift of the dissociation curve. This decreases O₂ affinity so that O₂ is unloaded more readily in tissues — compensating for the reduced O₂ loading in the lungs to maintain tissue O₂ delivery. Decreased 2,3-BPG (A) would be detrimental. HbF conversion (C) does not occur. EPO secretion increases, not decreases (D), to stimulate erythropoiesis and increase total O₂-carrying capacity.