Lung Alveolus
The alveolus is the terminal respiratory unit — a thin-walled, air-filled polyhedral sac (~0.2 mm diameter) lined by type I (AT1) and type II (AT2) pneumocytes, studded with alveolar macrophages, and surrounded by a dense network of pulmonary capillaries. Gas exchange follows Fick's law across the alveolar-capillary barrier (total thickness 0.2–0.7 µm). AT2 cells secrete pulmonary surfactant — a phospholipid-protein film dominated by DPPC — that reduces alveolar surface tension from ~70 mN/m (air-water interface) to below 5 mN/m, counteracting the LaPlace pressure that would collapse small alveoli. AT2 cells also serve as the alveolar progenitor, replenishing AT1 cells after injury. Alveolar macrophages provide first-line innate immune defence via pattern recognition (TLR4/CD14), and SP-A and SP-D act as soluble collectins that opsonise pathogens. Dysfunction of the alveolar unit underlies ARDS, pulmonary fibrosis, infant RDS, and severe pneumonia.
Overview
The alveolus is the terminal gas-exchange unit of the mammalian lung — a polyhedral air sac (mean diameter ~200 µm) at the end of alveolar ducts (generations 20–22 by Weibel's model) and alveolar sacs (generation 23). Each lung contains approximately 300–500 million alveoli providing a collective gas-exchange surface area of roughly 70 m² — roughly the floor area of a studio apartment — folded into an organ that weighs only ~350 g per side.
The alveolar wall (septum) consists of the capillary endothelium, fused basement membranes, and the overlying pneumocyte layer, with a total thickness averaging 0.2–0.7 µm on the thin (gas-exchange) side. This extraordinarily slim barrier enables the rapid diffusion equilibration of O₂ and CO₂ that sustains aerobic life.
Alveolar Cell Types
Type I Pneumocytes (AT1)
Flat, squamous epithelial cells covering approximately 95% of the alveolar surface area despite constituting only ~40% of alveolar cells by number. Individual cells are extremely thin — cytoplasmic thickness 0.1–0.5 µm over the gas-exchange zones — and spread over areas up to 5,000 µm². Joined by tight junctions (ZO-1, claudin-3/18) that prevent alveolar flooding. AT1 cells lack proliferative capacity; after injury they must be replenished by AT2-to-AT1 transdifferentiation.
Type II Pneumocytes (AT2)
Cuboidal cells covering only ~5% of alveolar surface area but accounting for ~60% of alveolar epithelial cells by number; preferentially located at alveolar corners. Contain distinctive lamellar bodies — the intracellular storage organelle for surfactant — which exocytose their contents to form the surface-active film. AT2 cells are the alveolar stem cell: they self-renew and transdifferentiate into AT1 cells during normal epithelial turnover and after acute lung injury, driven by Wnt/β-catenin and EGF receptor signalling.
Alveolar Macrophages (AMs)
Tissue-resident macrophages that patrol the alveolar airspace. Derived from fetal liver monocytes and maintained locally by self-renewal, supplemented by blood-borne monocytes under inflammatory conditions. Primary functions: phagocytosis of inhaled particles and microorganisms; TLR4/CD14 sensing of lipopolysaccharide (LPS) from gram-negative bacteria; secretion of TNF-α, IL-1β, IL-6, and IL-12 upon activation; removal of apoptotic cells (efferocytosis) to maintain alveolar homeostasis. AMs simultaneously suppress excessive inflammation via IL-10 and TGF-β to prevent immunopathology.
Club Cells (Clara Cells) at the Junction
Non-ciliated secretory cells concentrated at the bronchiolar-alveolar junction (terminal and respiratory bronchioles). Secrete Club Cell Secretory Protein (CC16/CC10/uteroglobin), a potent anti-inflammatory protein that suppresses phospholipase A2. Also express CYP450 enzymes (CYP1B1, CYP2B6) for detoxification of inhaled hydrophobic compounds. Serve as progenitors for the bronchiolar epithelium. Their CYP450 activity makes them preferential targets of inhaled toxicants such as naphthalene.
Pulmonary Surfactant — Composition and Biophysics
Pulmonary surfactant is an organised mixture of phospholipids and proteins secreted by AT2 cells, stored in lamellar bodies, and deployed at the air-liquid interface lining each alveolus. Its defining function is to reduce surface tension, opposing the LaPlace pressure that would otherwise collapse small alveoli during exhalation.
Surfactant composition (by mass of dry weight) is approximately:
| Component | Proportion | Function |
|---|---|---|
| DPPC (dipalmitoylphosphatidylcholine) | ~50% | Principal surface-tension-reducing lipid; saturated acyl chains pack densely at low lung volumes, achieving surface tensions <5 mN/m at end-expiration |
| Unsaturated phosphatidylcholines (POPC etc.) | ~25% | Maintain fluidity and film spreading at higher lung volumes; prevent crystallisation |
| Phosphatidylglycerol (PG) | ~10% | Anionic lipid; interacts with SP-B/C; immunomodulatory (TLR4 antagonist) |
| Other lipids (cholesterol, PI, PE) | ~10% | Structural and regulatory roles |
| SP-A (surfactant protein A) | ~5% protein | Hydrophilic collectin; opsonises bacteria, fungi, viruses via lectin domain; activates alveolar macrophages; regulates surfactant pool size |
| SP-B | <1% protein | Small, amphipathic; critical for lamellar body formation and tubular myelin assembly; essential for life — SP-B null is lethal at birth |
| SP-C | <1% protein | Extremely hydrophobic transmembrane protein; inserts into lipid monolayer, stabilises film during compression; mutations → familial interstitial pneumonia |
| SP-D (surfactant protein D) | <1% protein | Hydrophilic collectin; binds carbohydrate patterns on pathogens; anti-inflammatory; regulates AM activation; SP-D knock-out mice develop emphysema-like pathology |
Surfactant reduces alveolar surface tension from ~70 mN/m (pure air-water interface) to <5 mN/m at end-expiration. This 14-fold reduction in T lowers the LaPlace pressure proportionally, allowing normal alveoli to remain open at physiological transpulmonary pressures of 5–10 cmH₂O. Surfactant also exhibits surface-tension–area hysteresis: tension rises during inspiration as the film is diluted and falls during expiration as lipids re-pack — a key stabilising feature that couples alveolar stability to the breathing cycle.
Gas Exchange — Fick's Law and Diffusing Capacity
Gas exchange across the alveolar-capillary membrane follows Fick's law of diffusion. The rate of transfer is proportional to the diffusion coefficient of the gas and the driving partial pressure gradient, and inversely proportional to membrane thickness:
O₂ diffusion: Alveolar PO₂ ~100 mmHg vs. mixed venous PO₂ ~40 mmHg → net diffusion into capillary blood. Capillary transit time at rest ~0.75 s; O₂ equilibrates in ~0.25 s, leaving a threefold diffusion reserve. Equilibration is diffusion-limited only in extreme exertion or when the barrier is thickened (interstitial lung disease) or surface area is lost (emphysema).
CO₂ transfer: Mixed venous PCO₂ ~46 mmHg vs. alveolar PCO₂ ~40 mmHg. Despite the smaller gradient (6 vs. 60 mmHg for O₂), CO₂ equilibrates rapidly due to its ~20-fold greater solubility. The Haldane effect amplifies CO₂ unloading: O₂ binding to haemoglobin in the alveolus reduces Hb's affinity for CO₂ (decreasing carbamino-CO₂) and raises the pKa of carbonic acid, shifting the bicarbonate equilibrium toward CO₂ release — augmenting CO₂ excretion by approximately 60% beyond simple dissolved-gas diffusion.
The diffusing capacity of the lung for CO (DLCO) is the clinically measured integrative index of the gas-exchange surface area and membrane properties:
Alveolar-Capillary Barrier Architecture
The blood-gas barrier through which O₂ and CO₂ diffuse consists of three layers, each contributed by distinct cell types, but functionally fused to minimise thickness:
| Layer | Cell / Structure | Thickness | Key Features |
|---|---|---|---|
| Alveolar epithelium | AT1 pneumocyte cytoplasm | 0.1–0.3 µm | Squamous; ZO-1/claudin tight junctions prevent alveolar flooding; aquaporin-5 (AQP5) water channel |
| Fused basement membranes | Epithelial + endothelial BM fused on thin side | 0.05–0.1 µm | Collagen IV, laminin, perlecan; separated (with interstitial space) on thick side to allow fluid drainage |
| Capillary endothelium | Pulmonary capillary endothelial cell | 0.1–0.3 µm | Fenestrated or non-fenestrated; continuous tight junctions; ACE on surface converts AngI → AngII |
Total barrier thickness on the thin (gas-exchange) side: 0.2–0.7 µm — thinner than the wavelength of visible light. The thick side (0.5–2 µm) contains the interstitial space, fibroblasts, and pericytes, allowing fluid and macromolecule movement via lymphatics. Pathological thickening of this barrier — as in pulmonary fibrosis (collagen deposition) or pulmonary oedema (fluid accumulation) — impairs O₂ transfer preferentially, because CO₂'s greater diffusivity compensates for increased distance.
Innate Immunity at the Alveolar Surface
The alveolus is continuously exposed to inhaled air carrying microorganisms, particles, and antigens. Several overlapping mechanisms provide rapid innate defence without triggering destructive inflammation:
| Mechanism | Mediator / Receptor | Function |
|---|---|---|
| Collectin opsonisation | SP-A, SP-D (surfactant proteins) | Bind carbohydrate patterns on bacterial, fungal, and viral surfaces via C-type lectin domain; promote phagocytosis by alveolar macrophages; SP-A activates AM phagocytosis via calreticulin/CD91; SP-D neutralises influenza A |
| LPS sensing | TLR4/CD14/MD-2 complex on AMs | Detect gram-negative LPS; activate NF-κB → TNF-α, IL-1β, IL-6, IL-8 (CXCL8) → neutrophil recruitment |
| Neutrophil recruitment | IL-8 (CXCL8), C5a, LTB4 | AM-derived CXCL8 binds CXCR2 on circulating neutrophils → diapedesis through capillary wall → alveolar space; neutrophils deploy MPO, elastase, NETs |
| Mucociliary escalator | Ciliated epithelium + mucus (conducting zone) | Clears particles >5 µm before reaching alveoli; impaired in cystic fibrosis (ΔF508 CFTR → thick mucus) and primary ciliary dyskinesia |
| Antimicrobial peptides | β-defensins, lysozyme, lactoferrin | Secreted by AT2 cells, club cells, macrophages; disrupt microbial membranes; synergise with SP-A/D |
Paradoxically, alveolar macrophages maintain tonic immunosuppression under homeostatic conditions — producing IL-10, TGF-β, and PGE₂ to prevent sterile inflammation from the constant low-level antigenic load of inhaled air. This tolerance is rapidly overridden by strong TLR signals, but its disruption by, e.g., influenza infection leaves the alveolus hyper-responsive to secondary bacterial superinfection (S. aureus, S. pneumoniae).
Pathology
ARDS — Acute Respiratory Distress Syndrome (Diffuse Alveolar Damage)
Berlin Definition (2012): acute onset (<7 days), bilateral radiographic infiltrates not fully explained by heart failure, PaO₂/FiO₂ <300 on PEEP ≥5 cmH₂O. Underlying histology = diffuse alveolar damage (DAD): exudative phase (0–7 days) — capillary endothelial and AT1 injury → protein-rich alveolar exudate → hyaline membrane formation + AT2 hyperplasia; proliferative phase (7–21 days) — AT2 progenitor expansion → attempted re-epithelialisation; fibrotic phase (>21 days, in non-resolving ARDS) — collagen deposition → honeycombing. Triggers: pneumonia (including COVID-19), sepsis, aspiration, trauma, pancreatitis. Mortality 35–45% for severe ARDS (P/F <100). Treatment: lung-protective ventilation (6 mL/kg IBW, plateau P <30 cmH₂O), prone positioning (12+ h/day), conservative fluid strategy; no proven pharmacotherapy.
Idiopathic Pulmonary Fibrosis (IPF) — TGF-β Driven Alveolar Remodelling
Progressive fibrotic replacement of the alveolar architecture — the usual interstitial pneumonia (UIP) pattern on HRCT: basal, subpleural honeycombing, traction bronchiectasis, and heterogeneous fibrosis. Pathogenesis: repetitive microinjury to the alveolar epithelium (AT2 cells) → aberrant wound healing → TGF-β1 hypersecretion → myofibroblast activation → excessive collagen deposition → alveolar obliteration. Key driver: TGF-β1 binds TGF-βRII/ALK5 → SMAD2/3 phosphorylation → pro-fibrotic gene programme (collagen I/III, fibronectin, α-SMA). Anti-fibrotic therapies: nintedanib (tyrosine kinase inhibitor — PDGFR, VEGFR, FGFR — slows FVC decline ~50%) and pirfenidone (TGF-β/TNF-α inhibitor — slows decline ~50%). Median survival without treatment 3–5 years. Only cure: lung transplantation.
Infant Respiratory Distress Syndrome (RDS/IRDS) — Surfactant Deficiency
Affects premature infants, especially <28 weeks' gestation, before AT2 cell maturation and surfactant production reach adequate levels (glucocorticoid-dependent maturation pathway: cortisol → glucocorticoid receptor → SP-A/B/C gene transcription + phospholipid synthesis). Inadequate surfactant → alveolar collapse at end-expiration (atelectasis) + high work of breathing → progressive hypoxic respiratory failure. Treatment: exogenous surfactant replacement (beractant [bovine lipid extract, contains SP-B analogue] or poractant alfa — instilled via endotracheal tube) plus CPAP/positive-pressure ventilation. Antenatal betamethasone (2 doses, 24 h apart, 24–34 weeks) accelerates fetal AT2 maturation and reduces RDS incidence by ~50%.
Pneumonia — Lobar vs. Bronchopneumonia
Lobar pneumonia: Homogeneous consolidation of an entire lobe or segment; classic S. pneumoniae community-acquired pattern; four stages — congestion → red hepatisation (alveoli fill with RBCs + fibrin + neutrophils) → grey hepatisation (RBC lysis, macrophages) → resolution. Bronchopneumonia: Patchy, multifocal, peribronchiolar consolidation; typical of S. aureus, K. pneumoniae, gram-negatives, viral (influenza, COVID-19); affects multiple lobes. Both patterns result in V/Q mismatch (perfused but unconsolidated alveoli do not ventilate → shunt → hypoxaemia). Atypical pneumonia (Mycoplasma, Legionella, Chlamydophila) — interstitial pattern; alveolar septum thickened without frank consolidation.
Pulmonary Oedema — Hydrostatic vs. Increased Permeability
Hydrostatic (cardiogenic) oedema: Left heart failure → elevated pulmonary capillary wedge pressure (>18 mmHg) → fluid filtration exceeds lymphatic drainage → interstitial then alveolar oedema. Bat-wing perihilar distribution on CXR; frothy, protein-poor fluid. Treatment: diuretics (furosemide), preload reduction, treat underlying cardiac cause. Increased-permeability oedema (non-cardiogenic / ARDS): Endothelial and epithelial injury → disruption of tight junctions → protein-rich fluid floods alveoli. Distinguished from cardiogenic by PCWP ≤18 mmHg, high BAL protein:plasma protein ratio (>0.7), bilateral infiltrates. The two forms can co-exist — distinction critical because diuresis is therapeutic in hydrostatic oedema but must be balanced against cardiac output in ARDS.
Cross-Atlas Connections
References
- Weibel ER. On the tricks alveolar epithelial cells play to make a good lung. Am J Respir Crit Care Med. 2015;191(5):504–13. doi:10.1164/rccm.201409-1663OE
- Whitsett JA, Wert SE, Weaver TE. Alveolar surfactant homeostasis and the pathogenesis of pulmonary disease. Annu Rev Med. 2010;61:105–19. doi:10.1146/annurev.med.60.041807.123500
- Matthay MA, Zemans RL, Zimmerman GA, et al. Acute respiratory distress syndrome. Nat Rev Dis Primers. 2019;5(1):18. doi:10.1038/s41572-019-0069-0
- Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. Lancet. 2017;389(10082):1941–52. doi:10.1016/S0140-6736(17)30866-8
- West JB, Luks AM. West's Respiratory Physiology: The Essentials. 10th ed. Wolters Kluwer; 2016. ISBN 978-1-4963-1011-8.
- Seeger W, Günther A, Walmrath HD, et al. Alveolar surfactant and adult respiratory distress syndrome: pathogenetic role and therapeutic prospects. Clin Investig. 1993;71(3):177–90. doi:10.1007/BF00184908
- Whitsett JA, Alenghat T. Respiratory epithelial cells orchestrate pulmonary innate immunity. Nat Immunol. 2015;16(1):27–35. doi:10.1038/ni.3045