Respiratory System

Airway Anatomy

The respiratory tract divides into the conducting zone and the respiratory zone. The conducting zone (nose, pharynx, larynx, trachea, bronchi, bronchioles, terminal bronchioles) warms, humidifies, and filters air but performs no gas exchange; its volume is anatomical dead space (~150 mL). Cartilage rings keep the trachea and bronchi patent; smooth muscle in bronchioles allows bronchoconstriction and bronchodilation under autonomic control (sympathetic β₂ receptors → bronchodilation; parasympathetic muscarinic receptors → bronchoconstriction). The respiratory zone (respiratory bronchioles, alveolar ducts, alveolar sacs, alveoli) is where gas exchange occurs. Type I pneumocytes form the thin alveolar wall; Type II pneumocytes secrete pulmonary surfactant, which reduces surface tension and prevents alveolar collapse (LaPlace's law: P = 2T/r—smaller alveoli would have higher collapsing pressure without surfactant). Alveolar macrophages provide immune defense. The respiratory membrane—the fused basement membranes of the alveolar epithelium and capillary endothelium—is only ~0.5 μm thick, minimizing the diffusion distance for O₂ and CO₂.

Ventilation and Gas Exchange

Ventilation is the bulk movement of air into and out of the lungs, driven by pressure gradients. During inspiration, the diaphragm contracts and flattens, and the external intercostals lift the ribcage, expanding thoracic volume. Per Boyle's law (P₁V₁ = P₂V₂), increased volume decreases intrapleural pressure (normally ~−5 cm H₂O, dropping to ~−8 cm H₂O during inspiration), which pulls the lungs open, dropping alveolar pressure below atmospheric pressure (~−1 cm H₂O), driving air in. Expiration at rest is passive: elastic recoil of the lungs and chest wall restores resting volume. Forced expiration recruits internal intercostals and abdominal muscles. Key volumes and capacities: tidal volume (TV, ~500 mL), inspiratory reserve volume (IRV), expiratory reserve volume (ERV), residual volume (RV, ~1.2 L), vital capacity (VC = TV + IRV + ERV), total lung capacity (TLC = VC + RV). Minute ventilation (V̇E) = tidal volume × respiratory rate. Alveolar ventilation = (tidal volume − dead space) × respiratory rate—this is what actually participates in gas exchange.

Partial Pressures

Gas exchange is governed by partial pressure gradients, not concentration gradients. Dalton's law: the total pressure of a gas mixture equals the sum of the partial pressures of its components. In dry atmospheric air at sea level (760 mmHg): PO₂ = 21% × 760 ≈ 160 mmHg, PCO₂ ≈ 0.3 mmHg. As air enters the conducting airways, it becomes saturated with water vapor (PH₂O = 47 mmHg at 37°C), diluting other gases: inspired PO₂ = (760 − 47) × 0.21 ≈ 150 mmHg. In the alveoli, PO₂ drops further to ~100 mmHg because O₂ is continuously absorbed by pulmonary capillary blood while CO₂ (~40 mmHg) diffuses in. Mixed venous blood entering the pulmonary capillaries has PO₂ ~40 mmHg and PCO₂ ~46 mmHg. The alveolar-arterial (A-a) O₂ gradient is normally <15 mmHg; an elevated A-a gradient indicates a gas-exchange problem (diffusion impairment, shunt, or V/Q mismatch). Fick's law of diffusion states that gas flux is proportional to surface area × (P₁ − P₂) × solubility / (thickness × √MW)—CO₂ diffuses ~20× faster than O₂ because its solubility in aqueous solution is far higher, despite its slightly larger molecular weight.

Oxygen and Carbon Dioxide Transport

Oxygen is transported in blood in two forms: ~98% bound to hemoglobin (Hb) inside erythrocytes, ~2% dissolved in plasma. Each Hb tetramer can bind up to four O₂ molecules; O₂ content = (Hb concentration × 1.34 mL O₂/g Hb × % saturation) + dissolved O₂ (0.003 mL O₂/dL/mmHg PO₂). CO₂ is transported in three forms: ~70% as bicarbonate (HCO₃⁻), ~23% as carbaminohemoglobin (CO₂ bound to Hb's N-terminal amino groups), and ~7% dissolved. In systemic capillaries, CO₂ diffuses into RBCs, where carbonic anhydrase catalyzes CO₂ + H₂O → H₂CO₃ → H⁺ + HCO₃⁻. HCO₃⁻ exits via the chloride-bicarbonate exchanger (Band 3 protein) in exchange for Cl⁻—this is the chloride shift. In the lungs, the reactions reverse: HCO₃⁻ re-enters RBCs (reverse chloride shift), carbonic anhydrase converts HCO₃⁻ + H⁺ → CO₂ + H₂O, and CO₂ diffuses into the alveolus. The Haldane effect: deoxygenated Hb has a higher affinity for CO₂ and H⁺ than oxygenated Hb, facilitating CO₂ pickup in tissues and CO₂ release in lungs.

Hemoglobin Binding

The O₂-hemoglobin dissociation curve is sigmoidal, reflecting cooperative binding: binding of the first O₂ to deoxyhemoglobin (T-state, low affinity) induces a conformational shift that increases affinity at remaining sites (R-state, high affinity). This cooperativity makes Hb an exquisitely sensitive O₂ buffer—it loads O₂ efficiently in the lungs (high PO₂, ~97% saturation) and unloads it steeply in tissues (PO₂ ~25–40 mmHg, where the curve's slope is greatest). The curve's position is modulated by four factors, summarized by the Bohr effect: increased CO₂, decreased pH, increased temperature, and increased 2,3-bisphosphoglycerate (2,3-BPG) all shift the curve RIGHT (decreased affinity → enhanced O₂ unloading in tissues). The Bohr effect is adaptive: metabolically active tissues produce CO₂ and H⁺ (lactic acid), which shift the curve right locally, promoting O₂ delivery exactly where it's most needed. Fetal hemoglobin (HbF, α₂γ₂) has lower 2,3-BPG binding and thus a higher O₂ affinity than adult Hb (HbA, α₂β₂)—the left-shifted curve ensures O₂ transfer from maternal to fetal blood across the placenta. Carbon monoxide (CO) shifts the curve left and reduces O₂ content: CO binds Hb ~200× more tightly than O₂, occupying binding sites and increasing affinity at remaining sites, so Hb holds onto O₂ too tightly and fails to release it in tissues.

Acid-Base Compensation

The respiratory system is the body's rapid-response acid-base regulator. The key equilibrium is: CO₂ + H₂O ⇌ H₂CO₃ ⇌ H⁺ + HCO₃⁻. Because CO₂ is volatile and exhaled, respiratory control of PCO₂ provides minute-to-minute pH adjustment. When blood pH falls (acidosis), central and peripheral chemoreceptors (carotid and aortic bodies) detect the increased [H⁺] and stimulate the medullary respiratory centers to increase ventilation (hyperventilation), blowing off CO₂ and shifting the equilibrium left—this is respiratory compensation for metabolic acidosis and occurs within minutes. Conversely, when pH rises (alkalosis), ventilation decreases (hypoventilation), retaining CO₂—respiratory compensation for metabolic alkalosis. In the other direction, the kidneys provide slower (hours to days) metabolic compensation: respiratory acidosis (elevated PCO₂ from hypoventilation or COPD) prompts renal retention of HCO₃⁻ and excretion of H⁺; respiratory alkalosis (decreased PCO₂ from hyperventilation or high altitude) prompts renal excretion of HCO₃⁻. The Henderson-Hasselbalch equation: pH = 6.1 + log([HCO₃⁻] / (0.03 × PCO₂)). Normal values: pH 7.35–7.45, PCO₂ 35–45 mmHg, [HCO₃⁻] 22–26 mEq/L.

Pulmonary Circulation

The pulmonary circulation is a low-pressure, low-resistance system. The pulmonary artery carries deoxygenated blood from the right ventricle to the lungs at a mean pressure of ~15 mmHg (versus ~95 mmHg in the systemic circulation). Pulmonary capillaries form a dense network around alveoli, and the entire cardiac output (~5 L/min) passes through them. Unlike systemic capillaries, pulmonary capillaries respond to hypoxia with vasoconstriction (hypoxic pulmonary vasoconstriction), not vasodilation—this is an adaptive mechanism that diverts blood flow away from poorly ventilated alveoli toward well-ventilated regions, optimizing ventilation-perfusion (V/Q) matching. Ideal V/Q = ~0.8 (alveolar ventilation ~4 L/min, cardiac output ~5 L/min). V/Q mismatch is the most common cause of hypoxemia: shunt (V/Q = 0, perfused but not ventilated—e.g., pneumonia, atelectasis) and dead space (V/Q = ∞, ventilated but not perfused—e.g., pulmonary embolism). The pulmonary veins return oxygenated blood to the left atrium. Pulmonary capillary wedge pressure (measured via Swan-Ganz catheter) reflects left atrial pressure and is used clinically to distinguish cardiogenic from non-cardiogenic pulmonary edema.

How it works

The respiratory system can be understood as a linked chain of pressure gradients and binding equilibria. Breathing creates a negative intrapleural pressure that draws air down a pressure gradient into the alveoli. There, O₂ diffuses down its partial pressure gradient (~100 → 40 mmHg) across a membrane only 0.5 μm thick, while CO₂ diffuses the opposite way (~46 → 40 mmHg). Once in the blood, O₂ binds cooperatively to hemoglobin—a molecular oxygen sponge that saturates at high PO₂ and unloads at low PO₂, with the curve tuned by local CO₂, pH, temperature, and 2,3-BPG. CO₂ is carried primarily as bicarbonate, with carbonic anhydrase catalyzing the interconversion in RBCs. Every breath simultaneously brings in O₂ and blows off CO₂, which is also an acid; so breathing rate directly controls blood pH through the CO₂-HCO₃⁻ buffer system. The pulmonary circulation, a low-pressure loop accepting the entire cardiac output, actively matches perfusion to ventilation via hypoxic vasoconstriction. Every variable—pressure, volume, flow, saturation, pH—is coupled; change one, and the entire system shifts to compensate.

How it works

The respiratory system can be understood as a linked chain of pressure gradients and binding equilibria. Breathing creates a negative intrapleural pressure that draws air down a pressure gradient into the alveoli. There, O₂ diffuses down its partial pressure gradient (~100 → 40 mmHg) across a membrane only 0.5 μm thick, while CO₂ diffuses the opposite way (~46 → 40 mmHg). Once in the blood, O₂ binds cooperatively to hemoglobin—a molecular oxygen sponge that saturates at high PO₂ and unloads at low PO₂, with the curve tuned by local CO₂, pH, temperature, and 2,3-BPG. CO₂ is carried primarily as bicarbonate, with carbonic anhydrase catalyzing the interconversion in RBCs. Every breath simultaneously brings in O₂ and blows off CO₂, which is also an acid; so breathing rate directly controls blood pH through the CO₂-HCO₃⁻ buffer system. The pulmonary circulation, a low-pressure loop accepting the entire cardiac output, actively matches perfusion to ventilation via hypoxic vasoconstriction. Every variable—pressure, volume, flow, saturation, pH—is coupled; change one, and the entire system shifts to compensate.

Comparisons

• C/P (Gas laws): Boyle's law governs ventilation; Dalton's law determines partial pressures; Henry's law describes dissolved gas content; Fick's law governs diffusion across the respiratory membrane.
• C/P (Acid-base): Henderson-Hasselbalch equation directly ties PCO₂ to pH; respiratory compensation for metabolic disturbances; distinguish acute vs. chronic compensation by the degree of change.
• B/B (Hemoglobin biochemistry): Cooperative binding (T to R state transition), Bohr effect (pH/CO₂ shifts), 2,3-BPG modulation, HbF vs. HbA affinity, CO poisoning mechanism.
• B/B (Enzymes): Carbonic anhydrase kinetics in RBCs; chloride-bicarbonate exchange; passages may test inhibition of carbonic anhydrase (acetazolamide).
• B/B (Autonomic control): Sympathetic β₂ → bronchodilation; parasympathetic → bronchoconstriction; central vs. peripheral chemoreceptors regulating respiratory rate.
• P/S (Altitude physiology): Hypoxic ventilatory response, acclimatization, chronic mountain sickness, and the increase in 2,3-BPG and erythropoietin with altitude.

Common confusions

• Conflating minute ventilation with alveolar ventilation. Dead space (~150 mL) does NOT participate in gas exchange. A patient breathing rapidly but shallowly may have normal minute ventilation but inadequate alveolar ventilation because each breath mostly moves dead space air.
• Misidentifying which side of the O₂-hemoglobin curve corresponds to which condition. RIGHT shift = decreased affinity = enhanced unloading (exercising muscle, acidosis, high temperature, high 2,3-BPG). LEFT shift = increased affinity = impaired unloading (HbF, CO poisoning, alkalosis, hypothermia).
• Forgetting water vapor pressure in alveolar gas calculations. Inspired PO₂ is NOT 160 mmHg—it's (760 − 47) × 0.21 ≈ 150 mmHg because air is humidified in the airways. MCAT questions love this adjustment.
• Assuming CO₂ transport is just 'dissolved in blood.' Only ~7% is dissolved; the vast majority is bicarbonate. Carbonic anhydrase is essential—inhibition (e.g., acetazolamide) impairs CO₂ transport and causes a metabolic acidosis.
• Reversing the chloride shift direction. In systemic capillaries: HCO₃⁻ exits RBC, Cl⁻ enters (chloride shift IN). In pulmonary capillaries: HCO₃⁻ enters RBC, Cl⁻ exits (reverse chloride shift). Hb's buffering of H⁺ drives the entire process.
• Confusing the Bohr effect with the Haldane effect. Bohr: CO₂/H⁺ decrease Hb-O₂ affinity (right shift). Haldane: deoxygenation of Hb increases its affinity for CO₂ and H⁺. They are complementary, reciprocal effects.
• Assuming pulmonary vessels vasodilate with hypoxia like systemic vessels. Pulmonary circulation uniquely vasoconstricts in response to alveolar hypoxia—this redirects blood to better-ventilated regions. Systemic hypoxia → vasodilation; pulmonary hypoxia → vasoconstriction.

Quick review

• Conducting zone (nose → terminal bronchioles): no gas exchange, anatomical dead space ~150 mL. Respiratory zone: respiratory bronchioles → alveoli.
• Type II pneumocytes secrete surfactant → reduces surface tension → prevents alveolar collapse (LaPlace: P = 2T/r).
• Boyle's law: inspiration = ↑ thoracic volume → ↓ pressure → air flows in. Expiration at rest is passive elastic recoil.
• Alveolar PO₂ ≈ 100 mmHg; venous PO₂ ≈ 40 mmHg. Alveolar PCO₂ ≈ 40 mmHg; venous PCO₂ ≈ 46 mmHg.
• Fick's law: gas diffusion ∝ (area × ΔP × solubility) / (thickness × √MW). CO₂ diffuses ~20× faster than O₂ despite higher MW.
• O₂ transport: ~98% Hb-bound, ~2% dissolved. CO₂ transport: ~70% HCO₃⁻, ~23% carbamino-Hb, ~7% dissolved.
• O₂-Hb curve: sigmoidal (cooperative binding). RIGHT shift (↓ affinity): ↑ CO₂, ↓ pH, ↑ temp, ↑ 2,3-BPG (Bohr effect). LEFT shift: HbF, CO, alkalosis.
• Carbonic anhydrase in RBC: CO₂ + H₂O ⇌ H₂CO₃ ⇌ H⁺ + HCO₃⁻. Chloride shift: HCO₃⁻ out, Cl⁻ in (systemic); reverse in lungs.
• Respiratory compensation: hyperventilate → ↓ PCO₂ → ↑ pH (compensates metabolic acidosis). Hypoventilate → ↑ PCO₂ → ↓ pH (compensates metabolic alkalosis).
• Pulmonary circulation: low pressure (~15 mmHg mean), hypoxic vasoconstriction (opposite of systemic), V/Q matching.
• pH 7.35–7.45, PCO₂ 35–45 mmHg, HCO₃⁻ 22–26 mEq/L. Henderson-Hasselbalch: pH = 6.1 + log([HCO₃⁻] / 0.03 × PCO₂).
• A-a gradient > 15 mmHg indicates gas-exchange problem (shunt, diffusion defect, or V/Q mismatch—not pure hypoventilation).