Lungs, Gas Exchange & Breathing Mechanics
A complete guide to pulmonary anatomy and physiology — from airway architecture and alveolar ultrastructure through the mechanics of inspiration and expiration, alveolar gas exchange, oxygen and carbon dioxide transport, ventilation-perfusion matching, neural control of breathing, lung volumes, surfactant, and the pathophysiology of asthma, COPD, and pulmonary embolism.
Every cell in your body depends on a continuous supply of oxygen and an equally continuous removal of carbon dioxide. Pause breathing for four minutes and irreversible brain injury begins. The respiratory system exists to prevent exactly that — moving approximately 10,000 litres of air per day through a branching network of airways, exposing it to a gas-exchange surface larger than a studio apartment, and transferring oxygen into roughly five litres of blood every minute. Understanding how that system is built, how it works, what can go wrong with it, and why the physics and chemistry of breathing matter clinically is the foundation of anatomy, physiology, nursing science, and medicine at every level.
The Respiratory System — Scope, Components, and Core Functions
The respiratory system is the organ system dedicated to gas exchange between the internal environment of the body and the external atmosphere. It does not work alone — it operates in constant partnership with the cardiovascular system (which circulates oxygenated blood to tissues and returns deoxygenated blood to the lungs) and the nervous system (which regulates breathing rate and depth in response to metabolic demands and chemical signals). Together these systems constitute what physiologists call the oxygen transport cascade — the sequential steps by which oxygen moves from atmospheric air into the mitochondria of active cells.
The respiratory system is conventionally divided into two functional zones. The conducting zone encompasses all airways from the nasal passages and mouth through the pharynx, larynx, trachea, bronchi, and bronchioles down to the terminal bronchioles — these structures conduct air to the gas-exchange surfaces but perform no gas exchange themselves. Their collective dead space volume (~150 mL) represents air that is moved with each breath but does not participate in gas exchange. The respiratory zone begins at the respiratory bronchioles, which have alveolar outpouchings in their walls, and continues through alveolar ducts and alveolar sacs to the alveoli themselves — the functional units of the lung where all gas exchange occurs. The transition from conducting to respiratory zone at approximately generation 17 of airway branching marks one of the most physiologically significant boundaries in the body.
Gas Exchange — Primary Function
Delivering oxygen from atmospheric air into pulmonary capillary blood and simultaneously removing CO₂ from venous blood into alveolar air, driven entirely by partial pressure gradients across the 0.2–0.5 µm blood-air barrier. Approximately 250 mL O₂ per minute crosses this barrier at rest; up to 3,500 mL/min during maximal exercise.
Air Conditioning — the Conducting Zone
Warming inhaled air to body temperature, humidifying it to 100% relative humidity, and filtering particles through mucus-ciliary clearance before it contacts the fragile alveolar epithelium. This protects the gas-exchange surface from thermal injury, desiccation, and pathogen exposure with every breath.
pH Regulation — Acid-Base Balance
CO₂ dissolved in blood forms carbonic acid; the lungs regulate blood pH by controlling how much CO₂ is exhaled. Hyperventilation raises pH (respiratory alkalosis); hypoventilation lowers it (respiratory acidosis). The respiratory system provides the fastest compensation for metabolic acid-base disturbances — responding within minutes versus hours for the renal response.
Upper Airway Anatomy — Nose to Larynx
Air enters the respiratory tract through the nose or mouth. The nasal route is preferred under resting conditions because the nasal cavity performs critical air-conditioning functions that the oral cavity cannot replicate efficiently: the nasal turbinates (conchae) — three scroll-shaped projections of bone covered by richly vascularised mucosa — enormously increase the surface area of the nasal cavity, promoting heat exchange and humidification. Nasal mucosal blood flow is tightly regulated; vasodilation warms cold air, vasoconstriction is the basis of nasal congestion during respiratory infections.
Nasal Cavity, Pharynx, and Larynx — Architecture and Function
The nasal cavity is divided by the nasal septum into two chambers, each lined by pseudostratified ciliated columnar epithelium with goblet cells producing mucus. Two layers of mucus exist: a low-viscosity periciliary layer (sol layer) in which cilia beat freely, and an overlying viscous gel layer that traps inhaled particles. The mucociliary escalator moves this particle-laden mucus toward the pharynx at approximately 5–20 mm/min for swallowing. Olfactory epithelium occupies the roof of the nasal cavity; sinus ostia open into the nasal cavity and drain the paranasal sinuses (maxillary, ethmoid, frontal, sphenoid).
The pharynx is divided into the nasopharynx (behind the nasal cavity, where the Eustachian tubes open), oropharynx (behind the mouth), and laryngopharynx (behind the larynx). The pharynx serves both respiratory and digestive tracts — during swallowing, the epiglottis folds over the laryngeal inlet to prevent aspiration of food, and the nasopharynx is sealed by elevation of the soft palate.
The larynx has three functions: airway protection (closing the glottis to prevent aspiration during swallowing), phonation (vibration of the vocal cords to produce sound), and airflow regulation. The laryngeal skeleton consists of nine cartilages (thyroid, cricoid, epiglottis, paired arytenoids, corniculate, and cuneiform), connected by membranes and moved by intrinsic laryngeal muscles. The vocal cords (true vocal folds) are fibromuscular structures whose tension and separation are controlled by the recurrent laryngeal nerve (a branch of the vagus). Damage to this nerve — from thyroid surgery, neck dissection, or a left-sided thoracic mass compressing it — causes hoarseness or complete aphonia.
Subglottic airways begin immediately below the vocal cords. The cricoid cartilage, the only complete cartilaginous ring in the airway, is the narrowest part of the upper airway in children — explaining why subglottic oedema (croup) disproportionately reduces airflow in paediatric patients compared to adults.
Lower Airways — Trachea, Bronchi, and Bronchioles
Below the larynx, the lower airway begins with the trachea and branches progressively until reaching the alveoli. This branching system — the tracheobronchial tree — is one of the body's most elegant engineering solutions: it must deliver equal airflow to every alveolus, minimize resistance to airflow, maintain structural patency against the pressures generated during breathing and coughing, and progressively change its epithelial lining, wall structure, and mechanical properties from a rigid conducting tube to the gossamer-thin alveolar membrane.
Lung Anatomy — Lobes, Pleura, Vasculature, and Innervation
The lungs are paired organs occupying the thoracic cavity on either side of the mediastinum, enclosed within the pleural membranes. The right lung has three lobes (upper, middle, lower) separated by the oblique and horizontal fissures; the left lung has two lobes (upper and lower) separated by the oblique fissure, with the cardiac notch accommodating the heart creating the lingula — a tongue-shaped projection of the upper lobe. The left lung is approximately 10% smaller than the right. As documented by the National Heart, Lung, and Blood Institute's reference resource on how the lungs work, the right lung divides into three lobes while the left contains two, with the left lung slightly smaller due to cardiac positioning.
The Pleural Membrane System
Each lung is enclosed within a double-layered serous membrane: the visceral pleura (covering the lung surface, including fissures between lobes) and the parietal pleura (lining the inner thoracic wall, diaphragm, and mediastinum). The pleural cavity between them contains 5–15 mL of serous fluid that reduces friction during breathing. Critically, the pleural pressure is subatmospheric (~−5 cmH₂O at rest, more negative during inspiration) — this negative pressure maintains lung inflation by counteracting the lung's natural tendency to recoil inward. Pneumothorax (air in the pleural space) removes the negative pressure gradient and causes lung collapse. Tension pneumothorax, where air accumulates under pressure, shifts the mediastinum and can be rapidly fatal if untreated.
Blood Supply for Gas Exchange
The pulmonary circulation carries the entire cardiac output from the right ventricle through the pulmonary artery (the only artery in the body carrying deoxygenated blood) to the alveolar capillary network and back to the left atrium via four pulmonary veins. It is a low-pressure system (pulmonary artery systolic pressure ~25 mmHg, compared to systemic ~120 mmHg) with thin-walled, distensible vessels. The bronchial circulation (from the aorta) separately supplies oxygenated blood to airway walls and lung parenchyma. This dual circulation means bronchial tissue remains viable even when pulmonary artery flow is interrupted — relevant in pulmonary embolism, where bronchial perfusion prevents immediate infarction in many cases.
Lung Fluid Balance and Immune Surveillance
An extensive pulmonary lymphatic network drains approximately 20 mL/hour of interstitial fluid from the lung parenchyma toward hilar and mediastinal lymph nodes. Lymphatic drainage prevents interstitial and alveolar oedema by removing fluid filtered from capillaries. When lymphatic drainage is overwhelmed — by left heart failure raising pulmonary capillary pressure, by hypoalbuminaemia reducing plasma oncotic pressure, or by direct lymphatic obstruction — pulmonary oedema develops, filling alveoli with fluid and causing life-threatening hypoxaemia. Pulmonary lymph nodes are also the first site of cancer metastasis from primary lung tumours and the site of lymph node stations used in lung cancer staging.
Autonomic Control of Airway Calibre
Pulmonary innervation is predominantly autonomic. Parasympathetic fibres (preganglionic in the vagus nerve, postganglionic in airway walls) release acetylcholine onto M₃ muscarinic receptors on airway smooth muscle, causing bronchoconstriction and mucus secretion. Sympathetic stimulation activates β₂ adrenoceptors on airway smooth muscle causing bronchodilation — the therapeutic basis of beta-2 agonist bronchodilators. Non-adrenergic non-cholinergic (NANC) pathways release VIP (vasodilatory/bronchodilatory) and substance P (bronchoconstrictor) from airway nerve terminals, contributing to airway tone regulation. Sensory afferents (stretch receptors, rapidly adapting receptors, C-fibres/J-receptors) provide feedback to the respiratory centres and trigger cough, bronchospasm, and mucus secretion in response to irritants.
Alveolar Structure — the Gas-Exchange Unit
The alveolus is the fundamental anatomical and functional unit of the respiratory system. An adult's lungs contain approximately 300–500 million alveoli — polyhedral air sacs with a mean diameter of approximately 200–300 µm — that collectively provide a gas-exchange surface area estimated at 50–100 m². This extraordinary surface area, compressed into the volume of a pair of lungs, is achieved through the fractal branching of the alveolar ducts and the thin shared walls (alveolar septa) between adjacent alveoli. According to StatPearls' reference on lung histology, the adult lung contains roughly 300 million alveoli providing approximately 80 square metres of gas-exchange surface.
Pneumocytes — Gas Exchange
Flat, squamous epithelial cells covering ~95% of the alveolar surface. Extremely thin (0.1–0.3 µm). Their primary function is creating the thin component of the blood-air barrier. Cannot divide — replaced by type II pneumocytes after injury. Critical for passive O₂/CO₂ diffusion.
Pneumocytes — Surfactant Secretion
Cuboidal cells covering ~5% of surface but ~60% of cell numbers. Synthesise and secrete pulmonary surfactant stored in lamellar bodies. Also serve as progenitor cells replacing both type I and type II pneumocytes after injury. Critical in RDS (premature lungs) and ARDS pathology.
Alveolar — Immune Defence
Resident phagocytes ("dust cells") patrolling the alveolar surface. Engulf inhaled particles, pathogens, cellular debris, and surfactant components. Activated macrophages release pro-inflammatory cytokines initiating the alveolar inflammatory response. Long-lived; accumulate in coal miners' lungs producing black nodules (coal worker's pneumoconiosis).
Interalveolar Connections
Small openings (2–10 µm) between adjacent alveoli in shared septa, allowing collateral ventilation. When one airway is obstructed, pores of Kohn allow air to reach downstream alveoli through neighbouring units, preventing atelectasis. Poorly developed in neonates; gradually form during childhood.
Diffusion Membrane
The composite membrane gas must cross: alveolar epithelium (type I pneumocyte) + fused basement membranes + capillary endothelium. Total thickness 0.2–0.5 µm under thin portions; increases to ~2 µm at thicker regions. Diffusion rate inversely proportional to thickness (Fick's law) — pulmonary oedema thickens it, impairing O₂ more than CO₂.
Structural Framework
The shared wall between adjacent alveoli, containing capillaries, type I and II pneumocytes, fibroblasts, elastin and collagen fibres (providing recoil and structural support), and macrophages. Emphysema destroys septal walls, coalescing alveoli into enlarged air spaces with reduced surface area and loss of elastic recoil — the anatomical basis of air trapping and barrel chest.
Breathing Mechanics — Inspiration, Expiration, and Pressure Changes
Breathing is a mechanical pump. Air moves into and out of the lungs because of pressure gradients created by changes in thoracic volume — and thoracic volume changes because of skeletal muscle contraction. The relationship governing this is Boyle's Law: at constant temperature, pressure and volume are inversely proportional. When inspiratory muscles increase thoracic volume, intrapulmonary pressure falls below atmospheric and air flows in. When muscles relax, elastic recoil decreases thoracic volume, intrapulmonary pressure rises above atmospheric, and air flows out.
Diaphragm Contracts — Primary Inspiratory Muscle
The diaphragm — a dome-shaped musculotendinous sheet separating the thoracic and abdominal cavities — is the primary respiratory muscle, responsible for approximately 70–80% of resting tidal ventilation. When it contracts, the dome descends 1–2 cm during quiet breathing and up to 10 cm during maximal inspiration, directly increasing thoracic volume in the vertical dimension. The diaphragm is innervated by the phrenic nerve (C3, C4, C5 nerve roots — "C3, 4, 5 keeps the diaphragm alive"). High cervical spinal cord injury above C3 abolishes diaphragm function entirely, requiring permanent ventilatory support.
External Intercostals Contract — Lateral Thoracic Expansion
The external intercostal muscles run obliquely downward and forward between adjacent ribs. When they contract, they elevate the ribs in a "bucket-handle" motion, swinging the ribs outward and upward to increase thoracic volume in the lateral and anteroposterior dimensions. This contributes approximately 20–30% of resting tidal volume and becomes increasingly important during exercise and respiratory distress when larger tidal volumes are needed. Rib movement during breathing can be assessed clinically — absent or paradoxical rib movement indicates significant respiratory compromise.
Intrapulmonary Pressure Falls Below Atmospheric
As thoracic volume increases, intrapulmonary pressure (the pressure within the airways and alveoli) falls by approximately 1–2 cmH₂O below atmospheric pressure (101,325 Pa ≈ 760 mmHg at sea level). This pressure gradient is small but sufficient to drive airflow into the lungs along the pressure gradient. Simultaneously, intrapleural pressure becomes more negative (from approximately −5 cmH₂O to −8 cmH₂O), further expanding the lungs against the recoil pressure of their elastic tissue. The transmural pressure (intrapulmonary minus intrapleural) — also called transpulmonary pressure — is the distending pressure that holds the lungs open.
Passive Expiration — Elastic Recoil Drives Airflow Out
Quiet expiration is entirely passive — no muscle contraction is required. When the diaphragm and external intercostals relax, the stretched elastic tissue of the lungs (elastin fibres in alveolar walls and alveolar surface tension) generates a recoil force that decreases thoracic volume, raises intrapulmonary pressure above atmospheric, and drives air out. Lung compliance — the volume increase per unit pressure increase (C = ΔV/ΔP) — quantifies the ease of lung inflation. Normal lung compliance is approximately 200 mL/cmH₂O. Reduced compliance (stiff lungs) occurs in pulmonary fibrosis, pulmonary oedema, and ARDS — requiring greater inspiratory effort. Increased compliance with reduced elastic recoil occurs in emphysema — passive expiration is impaired and air trapping develops.
Active Expiration — Forced Breathing and Exercise
During exercise, hyperventilation, or forced manoeuvres (FVC testing, coughing, sneezing), expiration becomes active. The internal intercostal muscles pull ribs downward and inward; the abdominal muscles (rectus abdominis, external and internal obliques, transversus abdominis) contract to push the diaphragm upward. These muscles generate the high intrathoracic pressures needed for effective coughing (up to 300 cmH₂O) and produce the sharp increase in expiratory flow rates measurable during spirometry. Respiratory accessory muscles — sternocleidomastoid, scalene muscles — assist inspiration in respiratory distress, their visible contraction ("use of accessory muscles") being an important clinical sign of significant respiratory compromise.
Lung Volumes and Capacities — Spirometry and What the Numbers Mean
Quantifying how much air the lungs can hold, how much is moved per breath, and how quickly it can be exhaled is the domain of spirometry — one of the most commonly performed clinical investigations in pulmonary medicine. Lung volumes provide the physiological framework for interpreting spirometric data and understanding the distinction between obstructive and restrictive ventilatory patterns.
LUNG VOLUMES (cannot be subdivided): Tidal Volume (TV) ~500 mL Volume per normal resting breath Inspiratory Reserve (IRV) ~3,000 mL Extra volume after normal inspiration Expiratory Reserve (ERV) ~1,100 mL Extra volume expelled after normal expiration Residual Volume (RV) ~1,200 mL Volume remaining after maximal expiration Cannot be measured by spirometry LUNG CAPACITIES (combinations of volumes): Total Lung Capacity (TLC) ~5,800 mL = TV + IRV + ERV + RV Vital Capacity (VC) ~4,600 mL = TV + IRV + ERV (maximal breath) Inspiratory Capacity (IC) ~3,500 mL = TV + IRV Functional Residual Cap (FRC) ~2,300 mL = ERV + RV (equilibrium lung volume) KEY SPIROMETRIC MEASUREMENTS: FEV₁ Forced Expiratory Volume in 1 second ~3,200 mL typical male FVC Forced Vital Capacity ~4,000 mL typical male FEV₁/FVC ratio ~0.80 normal < 0.70 = obstructive pattern (asthma, COPD) ≥ 0.70 with reduced FVC = restrictive pattern (fibrosis) PEFR Peak Expiratory Flow Rate ~500–700 L/min male; used in asthma monitoring DLCO Diffusing Capacity for CO Gas transfer factor; reduced in emphysema, fibrosis, anaemia
Gas Exchange at the Blood-Air Barrier — Fick's Law and Partial Pressures
Gas exchange at the alveolus is governed by Fick's Law of Diffusion: the rate of diffusion of a gas across a membrane is directly proportional to the surface area (A) and the partial pressure gradient (ΔP), and inversely proportional to membrane thickness (T) and the square root of the gas's molecular weight. Mathematically: V̇gas = D × A × ΔP / T, where D is the diffusion coefficient (inversely related to molecular weight and directly related to solubility). For the respiratory system, this means maximizing surface area (achieved through ~300–500 million alveoli), minimizing membrane thickness (achieved through type I pneumocyte architecture), and maintaining large partial pressure gradients (achieved through continuous ventilation refreshing alveolar gas and pulmonary circulation removing dissolved gases from capillary blood).
The blood-air barrier is one of the thinnest biological membranes in the body — at 0.2 µm in its thinnest regions, it is roughly 500 times thinner than a sheet of standard office paper, yet it separates the liquid blood compartment from the gas-phase alveolar air with complete structural integrity under the pressure changes of every breath.
Reflecting the remarkable engineering of alveolar ultrastructure as characterised in pulmonary anatomy literature
Gas exchange is effectively complete within the first third of the transit time of a red blood cell through the alveolar capillary — approximately 0.25 seconds out of a total 0.75-second transit time at rest. This large reserve means gas exchange remains adequate during exercise even as cardiac output triples and transit time shortens.
Principle underlying the diffusion reserve and its clinical significance in disease states that reduce the safety margin
| Location | PO₂ (mmHg) | PCO₂ (mmHg) | SaO₂ / CaO₂ | Clinical Significance |
|---|---|---|---|---|
| Atmospheric air | 159 | 0.3 | — | FiO₂ = 0.21 (21% O₂). Falls with altitude: at 5,500 m PO₂ ≈ 80 mmHg, causing mountain sickness |
| Alveolar air (PAO₂) | 100 | 40 | — | Reduced by hypoventilation (↑PCO₂ displaces O₂), V/Q mismatch, shunt. PAO₂ calculated by alveolar gas equation |
| Pulmonary artery (deoxygenated) | 40 | 45 | 75% / ~15 mL/dL | Mixed venous blood — reflects whole-body O₂ extraction. SvO₂ <65% indicates increased O₂ extraction or reduced O₂ delivery |
| Pulmonary vein (oxygenated) | 100 | 40 | ~98% / ~19.5 mL/dL | After alveolar gas exchange. Slight drop to PaO₂ 95 mmHg in systemic arterial blood due to physiological shunt |
| Systemic arterial blood | 95 | 40 | ~97% / ~19–20 mL/dL | Normal ABG values. PaO₂ <60 mmHg defines significant hypoxaemia (SaO₂ ~90%) — threshold for O₂ therapy in COPD |
| Tissue capillaries | 40 | 45 | ~75% | O₂ extracted by tissues. In sepsis or cardiogenic shock, extraction increases further as delivery falls — SvO₂ may fall to 30–50% |
Oxygen Transport — Haemoglobin, the Dissociation Curve, and the Bohr Effect
Dissolving sufficient oxygen in plasma to meet tissue demands would require a blood volume approximately 70 times larger than we actually have. Haemoglobin solves this problem by providing a reversible, high-capacity oxygen carrier that increases the oxygen content of blood from approximately 0.3 mL/dL (dissolved in plasma) to approximately 20 mL/dL (combined with haemoglobin). This 70-fold enhancement is the foundation of vertebrate oxygen transport. Normal blood haemoglobin concentration is 120–170 g/L; each gram of haemoglobin fully saturated carries 1.34 mL O₂ (the Hüfner constant), giving a maximum oxygen-carrying capacity of approximately 20 mL O₂ per 100 mL blood.
Hüfner's Constant — mL O₂ carried per gram of fully saturated haemoglobin
This physical constant determines the maximum oxygen-carrying capacity of blood from any measured haemoglobin concentration. A patient with haemoglobin of 150 g/L at 97% saturation carries approximately 150 × 1.34 × 0.97 = 195 mL O₂/L blood. Anaemia (low haemoglobin) reduces this carrying capacity proportionally — which is why moderate anaemia causes fatigue and dyspnoea on exertion, and why transfusion thresholds in critical care are based on oxygen delivery calculations rather than haemoglobin concentration alone.
The oxygen-haemoglobin dissociation curve describes the sigmoidal relationship between PO₂ and haemoglobin oxygen saturation. The sigmoidal shape arises from the cooperative binding of oxygen to haemoglobin's four subunits — exactly the allosteric behaviour described for regulatory proteins. Binding of each O₂ molecule changes the conformation of the haemoglobin tetramer, increasing the affinity of the remaining subunits for subsequent O₂ molecules (the T-state to R-state transition first described by Max Perutz). The physiological consequence is a flat upper portion of the curve (loading plateau at pulmonary PO₂ ≈ 100 mmHg, where haemoglobin is nearly fully saturated despite significant variation in alveolar PO₂) and a steep lower portion (unloading slope at tissue PO₂ ≈ 40 mmHg, where large amounts of O₂ are released with small changes in PO₂).
The position of the oxygen-haemoglobin dissociation curve is not fixed — it shifts in response to physiological conditions, optimising O₂ loading at the lungs and O₂ unloading at tissues. The Bohr effect describes the rightward shift of the curve (reduced O₂ affinity, enhanced O₂ release at any given PO₂) caused by increased PCO₂, decreased pH, increased temperature, and increased 2,3-diphosphoglycerate (2,3-DPG). These are precisely the conditions present in actively metabolising tissues — high CO₂, low pH, high temperature, elevated 2,3-DPG in red blood cells adapting to chronic hypoxia. The Bohr effect thus constitutes an elegant feedback mechanism ensuring that haemoglobin releases more oxygen exactly where it is most needed.
Conversely, the leftward shift (increased O₂ affinity, reduced unloading) at the lungs — where CO₂ is low, pH is higher, and temperature is cooler than in exercising muscle — ensures efficient O₂ loading. Carbon monoxide (CO) causes a pathological left shift: CO binds haemoglobin 240 times more avidly than O₂, and CO-haemoglobin (carboxyhaemoglobin) shifts the curve leftward, impairing O₂ unloading in tissues — explaining why CO poisoning causes cellular hypoxia despite apparently normal PaO₂.
Carbon Dioxide Transport — Three Forms and the Chloride Shift
Carbon dioxide produced by cellular metabolism (approximately 200 mL/min at rest) is transported from tissues to the lungs in three forms: approximately 7–10% dissolved in plasma as CO₂; approximately 20–25% as carbaminohaemoglobin (CO₂ bound directly to the amino groups of haemoglobin and plasma proteins); and approximately 70% as bicarbonate ions (HCO₃⁻) dissolved in plasma. The bicarbonate route is quantitatively dominant and involves the enzyme carbonic anhydrase, one of the most efficient biological catalysts known (turnover number ~600,000 reactions per second).
CO₂ to Bicarbonate — the Carbonic Anhydrase Reaction
Inside red blood cells, dissolved CO₂ is rapidly hydrated to carbonic acid (H₂CO₃) by carbonic anhydrase: CO₂ + H₂O ⇌ H₂CO₃ ⇌ H⁺ + HCO₃⁻. The carbonic acid immediately dissociates, releasing a proton (H⁺) and bicarbonate (HCO₃⁻). The H⁺ is buffered by deoxyhaemoglobin (which is a better H⁺ acceptor than oxyhaemoglobin — the Haldane effect), minimising the fall in red blood cell pH. HCO₃⁻ exits the red blood cell via the chloride-bicarbonate exchanger (Band 3 protein, anion exchanger 1/AE1) in exchange for Cl⁻ — the chloride shift — carrying the bulk of CO₂ in plasma as bicarbonate. This entire sequence operates in reverse at the alveolar capillaries: bicarbonate re-enters red blood cells, carbonic anhydrase regenerates CO₂, and CO₂ diffuses across the blood-air barrier into alveolar air for exhalation.
CO₂ and Blood pH — the Respiratory Role in Acid-Base Balance
Dissolved CO₂ is in equilibrium with carbonic acid and hence bicarbonate: CO₂ + H₂O ⇌ H₂CO₃ ⇌ H⁺ + HCO₃⁻. This equilibrium, described by the Henderson-Hasselbalch equation (pH = 6.1 + log[HCO₃⁻] / 0.03 × PCO₂), means that blood pH is determined by the ratio of bicarbonate (metabolic component, regulated by the kidneys) to PCO₂ (respiratory component, regulated by the lungs). Respiratory acidosis (hypoventilation → ↑PCO₂ → ↓pH) and respiratory alkalosis (hyperventilation → ↓PCO₂ → ↑pH) are clinical acid-base disturbances diagnosed and managed through the understanding of this relationship. The normal arterial values are: pH 7.35–7.45, PCO₂ 35–45 mmHg, HCO₃⁻ 22–26 mmol/L — their simultaneous measurement in an arterial blood gas (ABG) guides clinical management of respiratory failure, metabolic disorders, and critical illness.
Ventilation-Perfusion Matching — the Efficiency Engine of the Lung
For the lung to perform gas exchange efficiently, the distribution of ventilation (airflow) and perfusion (blood flow) must be matched — alveoli that receive airflow must also receive blood flow. The ventilation-perfusion (V/Q) ratio is the key measure of this matching. In a perfectly homogeneous lung, all alveoli would have an identical V/Q ratio of approximately 0.8 (reflecting slightly greater perfusion than ventilation). In reality, the lung is not homogeneous — both ventilation and perfusion are gravity-dependent, and their regional distribution changes with body position, disease, and respiratory effort.
Regional V/Q variation in an upright lung (schematic) — ventilation and perfusion both increase toward the base, but perfusion increases more steeply
V/Q mismatch is the most common cause of hypoxaemia in clinical practice. When alveoli are well-perfused but poorly ventilated (low V/Q — pneumonia, atelectasis, pulmonary oedema), blood passes through the pulmonary circulation without being adequately oxygenated — this is intrapulmonary shunting. When alveoli are well-ventilated but poorly perfused (high V/Q — pulmonary embolism, pulmonary hypertension), ventilation is wasted on non-perfused alveoli — this is alveolar dead space. The body's primary compensatory response to low V/Q regions is hypoxic pulmonary vasoconstriction (HPV) — local hypoxia causes pulmonary arterioles to constrict, diverting blood flow from poorly ventilated to better-ventilated regions, thereby optimising the overall V/Q distribution. HPV is inhibited by many anaesthetic agents, explaining why V/Q mismatch and hypoxaemia are common during general anaesthesia. As detailed in the StatPearls reference on pulmonary ventilation and perfusion, V/Q mismatch is the dominant cause of impaired gas exchange across virtually all major lung diseases.
Pulmonary Surfactant — Preventing Alveolar Collapse and Reducing Work of Breathing
Without pulmonary surfactant, every breath would require the respiratory muscles to overcome an enormous surface tension force — the alveolar air-liquid interface would behave like pure water, whose surface tension (~72 mN/m) would make the lungs nearly impossible to inflate and cause progressive alveolar collapse. Surfactant reduces this surface tension to near zero at end-expiration, dramatically reducing the work of breathing and preventing the alveolar collapse that would otherwise occur every time the alveolus shrinks during exhalation.
Surfactant Composition
Pulmonary surfactant is approximately 90% lipid and 10% protein by mass. The dominant lipid is dipalmitoylphosphatidylcholine (DPPC, ~50% of total lipid) — its palmitic acid side chains pack tightly at the air-liquid interface to reduce surface tension. Other phospholipids (phosphatidylglycerol, phosphatidylethanolamine) and cholesterol modulate fluidity and spreading. Four surfactant proteins (SP-A, SP-B, SP-C, SP-D) have distinct functions: SP-B and SP-C are hydrophobic proteins critical for surfactant spreading and stability; SP-A and SP-D are collectins with immune-regulatory roles, opsonising pathogens and regulating surfactant recycling.
Surfactant Metabolism
Type II pneumocytes synthesise surfactant components in the endoplasmic reticulum, package them into lamellar bodies (membrane-bound organelles), and secrete them by exocytosis. Surface tension in the alveolus varies dynamically with alveolar radius — surfactant concentrates at the interface and lowers surface tension most effectively when the alveolus is small (end-expiration), counteracting the law of Laplace which would otherwise cause small alveoli to deflate into larger ones. Spent surfactant is recycled by type II pneumocytes (approximately 90%) or cleared by alveolar macrophages.
Neonatal RDS and Surfactant Therapy
Surfactant production begins at approximately 24–28 weeks of gestation, with functional maturity at ~34–35 weeks. Premature birth before adequate surfactant production causes Respiratory Distress Syndrome of the Newborn (RDS) — formerly called hyaline membrane disease — with progressive alveolar collapse, severe hypoxaemia, and diffuse atelectasis visible on chest X-ray ("ground glass" appearance). Treatment with exogenous surfactant instilled through an endotracheal tube, combined with CPAP or mechanical ventilation, has dramatically reduced RDS mortality. Prenatal corticosteroids (betamethasone/dexamethasone) accelerate fetal lung maturation including surfactant production when preterm delivery is anticipated.
Neural and Chemical Control of Breathing — Brainstem Centres and Chemoreceptors
Breathing is unusual among vital functions in being simultaneously under involuntary (automatic) control — maintaining rhythmic ventilation during sleep and anaesthesia — and voluntary control — enabling speech, breath-holding, Valsalva manoeuvre, and conscious hyperventilation. Both types of control converge on the final common pathway: motor neurones innervating the diaphragm (phrenic nerve, C3–C5) and intercostal muscles (thoracic motor neurones). Understanding respiratory control is essential for interpreting arterial blood gas results, managing ventilated patients, and understanding the physiology of sleep apnoea, breath-holding, and altitude acclimatisation.
Pre-Bötzinger Complex — the Respiratory Rhythm Generator
Located in the ventral respiratory group of the medulla oblongata, the pre-Bötzinger complex is the primary generator of the rhythmic respiratory pattern. It contains pacemaker neurons that spontaneously depolarise and fire in bursts, driving inspiratory motor output. Lesion or pharmacological blockade of the pre-Bötzinger complex abolishes rhythmic breathing, establishing it as the essential rhythm generator. Its intrinsic frequency is modulated by the pontine respiratory group and by chemical inputs from chemoreceptors. The mechanism of rhythm generation involves recurrent excitation within the complex and reciprocal inhibition between inspiratory and expiratory neurone populations — the central pattern generator of breathing.
Central Chemoreceptors — CO₂ Sensing in the Medulla
Central chemoreceptors located on the ventral surface of the medulla oblongata respond to changes in the pH of cerebrospinal fluid (CSF) caused by CO₂ diffusing across the blood-brain barrier. CO₂ is highly lipid-soluble and crosses freely; once in the CSF, it is hydrated to carbonic acid (catalysed by carbonic anhydrase), lowering CSF pH. Falling pH (acidosis) stimulates central chemoreceptors, increasing ventilation to blow off CO₂ and restore pH. Rising pH (alkalosis) reduces their activity, decreasing ventilation. Central chemoreceptors are responsible for approximately 70–80% of the ventilatory response to CO₂ and are the dominant drivers of minute-to-minute ventilation regulation. Importantly, the blood-brain barrier is relatively impermeable to H⁺ and HCO₃⁻, meaning central chemoreceptors respond to CO₂ more than to blood pH changes — the distinction matters in metabolic acid-base disturbances.
Peripheral Chemoreceptors — O₂, CO₂, and pH Sensing at the Carotid Bodies
Peripheral chemoreceptors are located in the carotid bodies (at the bifurcation of the common carotid arteries — the clinically dominant site) and aortic bodies (near the aortic arch). They respond to arterial PaO₂ (primarily), PaCO₂, and pH, transmitting signals via the glossopharyngeal nerve (IX, from carotid bodies) and vagus nerve (X, from aortic bodies) to the respiratory centres. The hypoxic ventilatory response is mediated primarily by carotid bodies — type I (glomus) cells depolarise when PaO₂ falls below approximately 60–70 mmHg (corresponding to SaO₂ ~90%) and release neurotransmitters (dopamine, ATP, substance P) that activate afferent nerve endings. This threshold explains why significant hypoxaemia must develop before peripheral chemoreceptors provide a major ventilatory stimulus — and why mild hypoxaemia is not effectively sensed at the carotid bodies. Chronic hypoxaemia (as in COPD with persistent PaO₂ <60 mmHg) may eventually blunt the hypoxic ventilatory response through adaptation.
Pulmonary Stretch Receptors — the Hering-Breuer Reflex
Slowly adapting stretch receptors (SARs) in the airway smooth muscle walls respond to lung inflation, sending impulses via the vagus nerve to the respiratory centres to terminate inspiration — the Hering-Breuer inflation reflex. This reflex prevents over-inflation and sets an upper limit to tidal volume. In humans it is relatively weak during quiet breathing but becomes important at larger tidal volumes. Rapidly adapting receptors (RARs) respond to rapid changes in lung volume and to irritant stimuli (smoke, dust, chemicals), triggering cough and augmented breaths. J-receptors (juxta-capillary receptors, C-fibres) in the alveolar walls near capillaries respond to pulmonary congestion, oedema, and chemical irritants, generating the sensation of dyspnoea and causing rapid shallow breathing — the pattern typical of pulmonary oedema and interstitial lung disease.
Voluntary Control and Higher Centre Inputs
The cortex can override automatic respiratory control for speech, singing, breath-holding, Valsalva manoeuvre, and voluntary hyperventilation. Cortical influence on breathing explains the breathing changes associated with emotional states (anxiety causing hyperventilation; depression causing hypoventilation) and the Cheyne-Stokes breathing pattern seen in heart failure and neurological disease (oscillating hyperpnoea and apnoea caused by circulatory delay in delivering chemoreceptor signals to the brainstem). The hypothalamus and limbic system influence breathing through pain and emotion. The exercise hyperpnoea response — the rapid increase in ventilation matching increased CO₂ production during exercise — involves neural feedforward mechanisms from motor cortex and proprioceptors acting before metabolic changes accumulate, explaining why ventilation increases almost instantaneously at exercise onset before PaCO₂ changes.
Pulmonary Circulation — a Low-Pressure, High-Flow System
The pulmonary circulation receives the entire cardiac output — approximately 5 L/min at rest, increasing to 20–25 L/min during maximal exercise — at pressures far lower than the systemic circulation. Normal pulmonary artery systolic pressure is approximately 25 mmHg (compared to 120 mmHg systemic); mean pulmonary artery pressure (mPAP) is approximately 14–20 mmHg; and pulmonary capillary wedge pressure (PCWP) approximates left atrial pressure at 8–12 mmHg. The low-pressure system is essential: high pulmonary capillary pressures would overwhelm the Starling forces governing capillary fluid balance, causing pulmonary oedema. Pulmonary hypertension (mPAP >20 mmHg at rest) from any cause — left heart disease, lung disease, thromboembolic disease, or idiopathic arteriopathy — progressively overloads the right ventricle, ultimately causing right heart failure (cor pulmonale).
Right Ventricular Adaptation
The right ventricle generates the force to push blood through the low-resistance pulmonary bed. Its thin, crescentic wall is optimised for volume pumping at low pressure. Acute pressure overload (massive pulmonary embolism) causes right ventricular failure more rapidly than chronic pressure loading (pulmonary hypertension), which allows gradual right ventricular hypertrophy.
Pulmonary Oedema Formation
When PCWP rises above approximately 18–20 mmHg (typically from left ventricular failure or mitral stenosis), fluid is forced out of pulmonary capillaries into the interstitium and then alveoli. Interstitial oedema thickens the blood-air barrier; alveolar flooding prevents gas exchange. Clinically: orthopnoea, paroxysmal nocturnal dyspnoea, crackles at lung bases, pulmonary venous distension on chest X-ray.
Pulmonary Embolism
Thrombus from deep veins (usually legs or pelvis) embolises to the pulmonary vasculature, causing acute dead space, hypoxaemia (V/Q mismatch), right ventricular pressure overload, and reduced left ventricular preload. Massive PE can cause circulatory collapse. D-dimer and CTPA are diagnostic tools; anticoagulation and sometimes thrombolysis are treatment.
Non-Respiratory Functions of the Lungs
The lungs perform several important functions beyond gas exchange that are underappreciated but clinically significant. Their strategic position in the circulation — receiving the entire cardiac output — makes them ideally situated to act as metabolic and immunological filters for the blood.
Angiotensin Converting Enzyme (ACE)
Pulmonary endothelial cells express ACE on their luminal surface, converting the inactive decapeptide angiotensin I to the active vasoconstrictor octapeptide angiotensin II — a key step in the renin-angiotensin-aldosterone system (RAAS) regulating blood pressure and volume. The lung is the primary site of this conversion due to its large endothelial surface area receiving 100% of cardiac output. ACE inhibitors (captopril, lisinopril) block this pulmonary conversion, reducing angiotensin II and peripheral vascular resistance — their primary mechanism of action in hypertension and heart failure.
Alveolar Macrophages and BALT
The lungs represent the body's largest mucosal surface in contact with the external environment and contain a sophisticated immune apparatus. Alveolar macrophages (derived from monocytes and self-renewing) patrol the alveolar surface phagocytosing inhaled particles and pathogens. Bronchus-associated lymphoid tissue (BALT) — organised lymphoid structures in the airway walls — provides local adaptive immune surveillance. Mast cells, dendritic cells, ILC2s, and innate lymphoid cells form a layered innate immune network. Failure of these defences explains why immunocompromised patients (HIV, transplant, chemotherapy) are susceptible to opportunistic pulmonary infections with organisms rarely pathogenic in healthy individuals.
Pulmonary Vascular Volume
The pulmonary circulation contains approximately 450–600 mL of blood at any time, representing about 9–12% of total blood volume. This serves as a dynamic reservoir: increased venous return (exercise, position change from upright to supine) increases pulmonary blood volume; haemorrhage reduces it. The distensible pulmonary vasculature recruits additional capillaries and distends existing ones during exercise to accommodate increased cardiac output without proportionally increasing pulmonary artery pressure — the recruitment and distension response.
Inactivation of Circulating Agents
The pulmonary endothelium inactivates several vasoactive and hormone substances: bradykinin is almost completely inactivated in a single pulmonary passage; serotonin (5-HT) is taken up and metabolised by pulmonary endothelial cells; prostaglandins E₁, E₂, and F₂α are enzymatically inactivated; adenosine and adenine nucleotides are also substantially metabolised. Conversely, prostaglandin I₂ (prostacyclin) and prostaglandin E₂ are synthesised by pulmonary endothelium and released into the circulation. This metabolic function explains why inhaled drug delivery directly to the lung (and systemic circulation) bypasses hepatic first-pass metabolism — a pharmacokinetic advantage exploited for surfactant therapy, inhaled anaesthetics, and pulmonary vasodilators.
Phonation and Speech Support
The respiratory system provides the sustained, controlled airflow required for speech. Subglottic air pressure drives vocal cord vibration; the frequency and quality of the resulting sound are shaped by the supraglottic resonating chambers (pharynx, oral cavity, nasal cavity, sinuses) and articulated by the tongue, lips, and soft palate. Respiratory support for speech requires coordinated control of inspiratory and expiratory muscle activity to maintain the subglottic pressure level needed for phonation — disrupted in neurological conditions affecting respiratory control (Parkinson's disease, ALS) and in lung diseases with severely limited expiratory flow (severe COPD).
Evaporative Water and Heat Loss
Approximately 400–500 mL of water evaporates from the respiratory mucosa daily under temperate conditions, contributing to total insensible water loss of approximately 800–1,000 mL/day. This evaporation also removes heat, contributing to thermoregulation — particularly relevant during exercise-induced hyperthermia when increased ventilation markedly enhances evaporative heat loss. In cold environments, the heat exchanger efficiency of nasal turbinates prevents excessive airway heat loss; bypassing the nose (mouth breathing during heavy exercise) increases respiratory heat loss and may cool airways below the threshold for exercise-induced bronchoconstriction in susceptible individuals.
Respiratory Diseases — Pathophysiology, Patterns, and Clinical Correlations
Respiratory disease is among the leading causes of morbidity and mortality globally, encompassing conditions ranging from common acute infections to chronic debilitating illnesses to rapidly fatal emergencies. Understanding the underlying pathophysiology — how each disease disrupts the normal anatomy and physiology described above — is essential for medical, nursing, and allied health students and the foundation for rational clinical management.
Asthma — Reversible Airway Obstruction and Hyperresponsiveness
Asthma is defined by chronic airway inflammation causing episodes of reversible airflow obstruction and airway hyperresponsiveness to stimuli that would not affect normal airways. The underlying inflammation is predominantly type 2 (T-helper 2 lymphocyte-driven), involving mast cells, eosinophils, and IgE-mediated responses to allergens in atopic patients. Pathological features include: eosinophilic airway inflammation, goblet cell hyperplasia and mucus plugging, airway smooth muscle hypertrophy and hypercontractility, subepithelial fibrosis ("remodelling"), and shed epithelium. Physiologically: airflow obstruction reduces FEV₁ and FEV₁/FVC; V/Q mismatch causes hypoxaemia; hyperventilation may cause hypocapnia (respiratory alkalosis). A rising PaCO₂ during an acute asthma attack is an ominous sign — indicating respiratory muscle fatigue and impending respiratory failure. For students working through respiratory physiology assignments, our anatomy and physiology assignment help covers the full pathophysiological framework for asthma and obstructive lung disease.
COPD — Irreversible Airflow Limitation from Emphysema and Chronic Bronchitis
COPD encompasses two pathological processes: emphysema — destruction of alveolar walls with permanent enlargement of air spaces distal to terminal bronchioles, reducing gas-exchange surface area and elastic recoil; and chronic bronchitis — chronic productive cough on most days for at least 3 months in 2 consecutive years due to mucus hypersecretion and airway inflammation. Cigarette smoking causes both through oxidant-driven neutrophilic and macrophage inflammation leading to protease (elastase, MMP) release and net destruction of lung parenchyma. Air trapping — from reduced elastic recoil and dynamic bronchiolar collapse during exhalation — leads to hyperinflation, flattened diaphragm, barrel chest, and paradoxical difficulty with the work of breathing. Spirometry shows irreversible obstruction (FEV₁/FVC <0.70 post-bronchodilator); DLCO is severely reduced in emphysema-dominant disease. Long-term oxygen therapy (LTOT) for 15+ hours/day improves survival when PaO₂ is persistently <55 mmHg (or <60 mmHg with polycythaemia or cor pulmonale).
Pneumonia — Alveolar Consolidation and Gas Exchange Failure
Pneumonia is infection of the lung parenchyma — alveolar spaces fill with exudate (plasma proteins, red blood cells, leucocytes, bacteria) replacing normal air with fluid, creating radiological consolidation and the clinical signs of bronchial breathing, dullness to percussion, and crackles. Gas exchange is severely impaired in consolidated areas: blood flowing through consolidated alveoli cannot be oxygenated (perfusion without ventilation — intrapulmonary shunt), creating a low V/Q region that causes hypoxaemia resistant to oxygen supplementation (because shunt bypasses the alveolar gas completely). Hypoxic pulmonary vasoconstriction limits but cannot fully compensate for the shunt. The clinical severity of pneumonia-related hypoxaemia correlates with the extent of consolidation visible on imaging. Productive cough is the physiological response — the airway mucosa attempts to clear the infectious exudate using increased mucus secretion and ciliary activity, amplified by the cough reflex.
Pulmonary Fibrosis — Restrictive Physiology from Architectural Destruction
Idiopathic pulmonary fibrosis (IPF) and other fibrotic lung diseases replace normal alveolar architecture with collagenous scar tissue — thickening the alveolar walls, reducing lung compliance, and destroying both gas-exchange surface and the alveolar capillary network. The physiological consequences are restrictive: reduced TLC, FVC, and FRC; preserved or elevated FEV₁/FVC ratio; severely reduced DLCO (thickened blood-air barrier and lost surface area). Hypoxaemia is characteristically worse on exercise than at rest because the reduced diffusing capacity becomes the limiting step when cardiac output increases and pulmonary capillary transit time shortens. Honeycombing (subpleural cysts on HRCT) represents end-stage architectural destruction. Antifibrotic agents (pirfenidone, nintedanib) slow decline in FVC, the primary endpoint in IPF clinical trials. Lung transplantation remains the only treatment that significantly alters the natural history.
ARDS — Catastrophic Diffuse Alveolar Damage
Acute Respiratory Distress Syndrome (ARDS) is a life-threatening inflammatory lung injury characterised by rapid-onset bilateral alveolar oedema, severe hypoxaemia (PaO₂/FiO₂ <300 mmHg), and diffuse radiological infiltrates, not explained by cardiac failure alone (Berlin Definition, 2012). Triggers include sepsis, aspiration, trauma, pancreatitis, and major transfusion. Pathophysiology: alveolar macrophage activation releases cytokines that damage the alveolar-capillary barrier, causing protein-rich oedema to flood alveoli; surfactant inactivation causes diffuse alveolar collapse; inflammatory cell infiltration further damages type I and II pneumocytes. The result is the worst possible combination of restrictive physiology (stiff, oedematous lungs) and refractory hypoxaemia (massive intrapulmonary shunt from flooded alveoli). Lung-protective ventilation (tidal volume 6 mL/kg predicted body weight, limiting plateau pressure ≤30 cmH₂O, PEEP to recruit alveoli) reduces ventilator-induced lung injury and has become the standard of care, reducing ARDS mortality from approximately 60% to 30–40%.
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Oxygen Delivery, Altitude Physiology, and Exercise Responses
The respiratory system does not function in isolation — it must be evaluated in the context of total oxygen delivery to tissues (DO₂), which depends on both pulmonary gas exchange and cardiovascular function. Total oxygen delivery is calculated as: DO₂ = CO × CaO₂ × 10, where CO is cardiac output (L/min) and CaO₂ is arterial oxygen content (mL/dL). Normal resting DO₂ is approximately 1,000 mL O₂/min, of which approximately 250 mL/min is consumed (VO₂). The ratio VO₂/DO₂ — the oxygen extraction ratio — is approximately 0.25 at rest, meaning tissues extract only about 25% of delivered oxygen, providing a large reserve. In shock or severe exercise, extraction rises toward 70–80% as DO₂ falls or VO₂ rises.
Altitude Physiology — Acclimatisation to Hypoxia
At altitude, atmospheric pressure falls, reducing PO₂ proportionally (FiO₂ remains 21% but partial pressure falls). At 3,000 m (10,000 ft), PaO₂ falls to approximately 60 mmHg — on the steep portion of the oxygen-haemoglobin dissociation curve — causing significant desaturation. The respiratory response to acute altitude exposure involves: immediate hypoxic ventilatory response (carotid body activation causes hyperventilation, lowering PCO₂ and raising pH — respiratory alkalosis); followed over days by renal excretion of bicarbonate to compensate the alkalosis (metabolic compensation), allowing further hyperventilation; increased erythropoietin (EPO) secretion driving increased red blood cell production (haematological acclimatisation); increased 2,3-DPG shifting the oxygen-haemoglobin curve rightward to enhance O₂ unloading; and improved capillarity in skeletal muscle from angiogenesis. Altitude sickness results from acute hypoxia before acclimatisation — headache, nausea, fatigue — treated by descending and supplemental oxygen. High-altitude cerebral and pulmonary oedema (HACE and HAPE) are life-threatening complications.
Exercise demands explain much of respiratory physiology in clinical context. During maximal exercise, ventilation increases from approximately 6 L/min at rest to 100–200 L/min; O₂ consumption rises from 250 mL/min to 3,500+ mL/min; and cardiac output triples. The remarkable capacity of the respiratory system to maintain adequate gas exchange under these conditions reflects the large functional reserves built into alveolar surface area, diffusing capacity, and ventilatory mechanics. Diseases that compromise these reserves — by reducing alveolar surface area (emphysema), thickening the blood-air barrier (fibrosis), reducing ventilatory capacity (neuromuscular disease), or limiting cardiac output — unmask as exercise limitation and dyspnoea before producing symptoms at rest.
Respiratory Pharmacology — Drugs Acting on the Respiratory System
The respiratory system is a major target for pharmacological intervention, with drugs acting across airway smooth muscle, mucociliary clearance, inflammatory cells, surfactant production, and central respiratory control. Understanding the physiological basis of respiratory drug targets is essential for nursing and prescribing students.
| Drug Class | Mechanism | Target | Clinical Use | Key Examples |
|---|---|---|---|---|
| SABA | β₂ adrenoceptor agonist — bronchodilation via ↑cAMP → smooth muscle relaxation | Airway smooth muscle | Acute asthma, exercise-induced bronchoconstriction; COPD rescue | Salbutamol (albuterol), terbutaline |
| LABA | Long-acting β₂ agonist — sustained bronchodilation ≥12 hours | Airway smooth muscle | Maintenance treatment in asthma (always with ICS), COPD maintenance | Salmeterol, formoterol, indacaterol |
| ICS | Inhaled corticosteroid — suppress airway eosinophilic inflammation via glucocorticoid receptor | Airway epithelium, immune cells | Asthma maintenance (cornerstone); COPD with frequent exacerbations | Beclometasone, budesonide, fluticasone |
| LAMA | Long-acting muscarinic antagonist — blocks M₃ receptors preventing cholinergic bronchoconstriction | Airway smooth muscle M₃ | COPD maintenance bronchodilation; add-on in uncontrolled asthma | Tiotropium, umeclidinium, aclidinium |
| Methylxanthines | PDE inhibitor (↑cAMP) + adenosine receptor antagonist → bronchodilation; central respiratory stimulation | Airway smooth muscle, respiratory centres | COPD (adjunct), neonatal apnoea of prematurity (caffeine, theophylline) | Theophylline, aminophylline, caffeine |
| Exogenous Surfactant | Replaces deficient endogenous surfactant; reduces alveolar surface tension, prevents atelectasis | Alveolar surface | Neonatal RDS; investigated in ARDS (mixed results) | Poractant alfa (Curosurf), beractant (Survanta) |
| Biologics (anti-IL-5, anti-IgE) | Target specific inflammatory mediators or cells in type 2 airway inflammation | Eosinophils, IgE, IL-4Rα | Severe eosinophilic or atopic asthma refractory to high-dose ICS/LABA | Mepolizumab (anti-IL-5), omalizumab (anti-IgE), dupilumab (anti-IL-4Rα) |
Frequently Asked Questions About the Respiratory System
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