Alveolar-capillary membrane

What it normally does

• Air and blood are separated by roughly 0.3 micrometres at the thin part of the barrier: a flattened lining cell (type I pneumocyte), fused basement membranes, and the capillary lining (endothelium). Gas crosses by diffusion alone — the flow rises with surface area and with the pressure difference across the barrier, and falls as the barrier gets thicker (Fick's law).

  Anything that thickens that gap — scar tissue or fluid — slows oxygen transfer first.

• That membrane is spread over roughly 70 square metres across a few hundred million alveoli. A red cell spends around 0.75 seconds in a pulmonary capillary at rest but is fully loaded with oxygen in about 0.25 seconds — a threefold time reserve.

  Early membrane disease is often silent at rest and declares itself on exertion, when transit time shortens; and losing surface area shows up as a low transfer factor (DLCO) even before the resting gas is abnormal.

• Carbon dioxide crosses about twenty times more readily than oxygen because it is far more soluble in tissue.

  A damaged membrane gives a low oxygen with a normal or low carbon dioxide (type 1 respiratory failure), not CO2 retention.

• The airspace is actively kept dry. Pulmonary capillary hydrostatic pressure is low, about 8-10 mmHg, against a plasma oncotic pressure near 25 mmHg; tight junctions seal the epithelium; the alveolar epithelial cells take sodium up through apical channels and pump it out basolaterally with the sodium-potassium ATPase, so water follows out of the airspace; anything that still leaks drains through the interstitium into lymphatics.

  Raise the pressure or break the seal and fluid fills the interstitium and then the alveolus — pulmonary oedema and ARDS.

What goes wrong

• Cardiogenic pulmonary oedema← from “The airspace is actively kept dry. Pulmonary c…”

  The left ventricle fails, or the mitral valve leaks, so pressure backs up through the left atrium into the pulmonary veins and capillaries. Hydrostatic pressure climbs and filtration outruns the lymphatics. Fluid fills the interstitium first — stiff lungs, breathless lying flat — then breaks through the epithelial seal into the alveoli, where it both adds diffusion distance and dilutes surfactant so alveoli collapse.

  Fluid in the interstitium gives orthopnoea and Kerley B lines; the same pressure one step further, into the alveolus, gives crackles, pink frothy sputum and hypoxaemia.

  You would find: Fine crackles at both bases, orthopnoea, waking breathless at night (paroxysmal nocturnal dyspnoea), raised JVP, third heart sound. Chest x-ray: upper lobe blood diversion, Kerley B lines, bat-wing shadowing, small effusions. BNP raised. Blood gas usually shows a low PaO2 with a low PaCO2 from tachypnoea; a normal or rising PaCO2 in a distressed patient is a late and worrying sign.

• Acute respiratory distress syndrome (ARDS)← from “The airspace is actively kept dry. Pulmonary c…”

  Sepsis, aspiration, pancreatitis, major trauma or severe pneumonia sets off neutrophil-driven injury to the endothelium and the type I cells at once. The barrier stops being selective, so protein-rich fluid floods the airspaces at a normal capillary hydrostatic pressure. Type II cells are damaged too, surfactant fails, alveoli collapse, and blood flowing past unventilated units returns to the left heart unoxygenated (shunt) — which is why turning the oxygen up barely helps.

  Cardiogenic oedema is a pressure problem with an intact membrane (transudate); ARDS is a permeability problem with a wrecked membrane (exudate). Hypoxaemia that stays refractory despite high FiO2, with imaging out of proportion to any cardiac cause, points to ARDS — but do not use a normal heart size alone to exclude a cardiac contribution, or a failing heart to exclude ARDS.

  You would find: Berlin definition: onset within a week of a known insult; bilateral opacities on chest imaging not fully explained by effusions, collapse or nodules; respiratory failure not fully explained by cardiac failure or fluid overload; and PaO2/FiO2 at or below 300 mmHg on PEEP or CPAP of at least 5 cmH2O. Note the wording — the older requirement for a low wedge pressure was dropped, so ARDS and cardiac failure can coexist and echocardiography is used to judge how much of the picture is hydrostatic, especially when no ARDS risk factor is obvious. A 2023 global definition extends the same idea to patients on high-flow nasal oxygen and allows SpO2/FiO2 in place of a blood gas.

• Pulmonary fibrosis (idiopathic pulmonary fibrosis)← from “Air and blood are separated by roughly 0.3 mic…”

  Repeated injury to the alveolar epithelium in a susceptible lung — typically an older man, often an ex-smoker — provokes fibroblasts to lay collagen down in the interstitium instead of healing cleanly. The 0.3 micrometre gap thickens several-fold and the lung stiffens. Most of the resting hypoxaemia actually comes from ventilation-perfusion mismatch in the distorted lung rather than from the thickened barrier alone; the barrier matters most on exertion, when the red cell's transit time shortens and oxygen runs out of time to cross. That is why resting saturation can be normal while walking desaturates the patient.

  A falling DLCO is usually the first measurable abnormality, and desaturation on walking with a near-normal resting saturation is the first thing you can pick up at the bedside. Walk the patient; do not trust the sitting-still oximeter.

  You would find: Dry cough and breathlessness creeping over months. Fine end-inspiratory crackles at the bases like Velcro pulling apart, which do not clear with coughing, and finger clubbing. Spirometry is restrictive — FVC down, FEV1/FVC normal or high — with DLCO down out of proportion. HRCT shows subpleural basal honeycombing and traction bronchiectasis.

• Emphysema← from “That membrane is spread over roughly 70 square…”

  Cigarette smoke, or inherited alpha-1 antitrypsin deficiency, tips the protease-antiprotease balance and elastase digests alveolar walls. Whole membrane units vanish, taking their capillaries with them, so the surface area term in Fick's law collapses. The airways also lose the elastic tethers that hold them open, so they collapse on expiration and airflow obstruction is added to lost gas exchange.

  Fibrosis thickens the membrane; emphysema deletes it. Both drop the DLCO — spirometry tells you which.

  You would find: Long smoking history, hyperinflated quiet chest, breathless on minimal effort. Spirometry obstructive on post-bronchodilator testing (FEV1/FVC below 0.7) and not fully reversible, with a low DLCO — a reduced DLCO is the main functional feature separating emphysema from asthma, where it is typically normal or high. In Australia, COPD hospitalisation rates for Aboriginal and Torres Strait Islander people run at around three times those of other Australians, so the threshold for doing spirometry should be low.

What we give, and how it works

Open a drug to see what it binds, what that does to the cell, and what you then see in the patient.