Alveoli
The roughly 300 million air sacs where oxygen and carbon dioxide cross between air and blood — held open by a soap-like film the alveolus manufactures for itself.
What it normally does
Type I cells are flat and enormous: they cover about 95% of the alveolar surface and thin the barrier between air and capillary blood to well under a micrometre, over a total area of around 70 m² (type I pneumocytes).
anything that thickens that barrier or fills the sac with fluid drops oxygen transfer long before it touches carbon dioxide, because CO₂ is roughly twenty times more soluble in water and so crosses a wet, thickened barrier far more easily.
Type II cells are cuboidal, sit in the corners, and make surfactant — a detergent-like film of phospholipid (mainly dipalmitoylphosphatidylcholine) plus surfactant proteins, secreted onto the thin layer of water lining the sac. SP-B and SP-C are the small hydrophobic proteins that do the mechanical work of spreading the film; SP-A and SP-D are larger and act mainly in alveolar innate immunity (type II pneumocytes).
the water lining the alveolus is stopped from pulling the walls together. Surfactant does not abolish surface tension, it lowers it dramatically — so when it is absent, inactivated or simply not yet made, alveolar stability is what fails first.
The pressure trying to collapse a fluid-lined sphere is 2T/r — twice the surface tension divided by the radius — so the smallest alveoli have the strongest collapsing pull. Surfactant molecules crowd closer together as an alveolus shrinks, so they drop the tension most exactly where the pull is worst (Laplace's law).
small alveoli stay open instead of emptying into big ones, the lung stays easy to inflate (compliant), and the work of breathing stays low. Mechanical tethering between neighbouring alveoli helps too, but surfactant is what makes the tension itself radius-dependent.
Type II cells are also the repair cell of the alveolus — they divide and turn into type I cells after injury. They begin making surfactant around 24 weeks of gestation and only reach mature output around 34 to 36 weeks, and cortisol accelerates that timetable.
a baby born early has a lung that is structurally close to finished but chemically unfinished, and an adult who loses type II cells to injury loses both the surfactant and the means of healing.
What goes wrong
- Neonatal respiratory distress syndrome← from “Type II cells are also the repair cell of the …”
A baby born before type II cells have ramped up production has too little surfactant. Surface tension goes unopposed, so at the end of every breath out the alveoli shut. Each next breath has to re-inflate collapsed lung from scratch, which takes enormous pressure, and the alveoli that stay shut are still perfused — blood passes through the lung without meeting air (shunt), so oxygen falls and giving more oxygen only partly fixes it.
Not enough surfactant → tension unopposed → end-expiratory collapse → stiff lungs and shunt. Preterm, grunting, ground-glass CXR.
You would find: A preterm baby, tachypnoeic within minutes to hours of birth, with grunting, nasal flaring and intercostal recession. Chest x-ray shows a uniform ground-glass lung with air bronchograms and small volumes. Around 8-9% of Australian births are preterm, and the figure among babies of Aboriginal and Torres Strait Islander mothers is roughly 14% — well above the national rate, so this burden falls unevenly.
After abdominal or thoracic surgery several things push the same way. Anaesthesia and lying flat drop functional residual capacity, so the dependent basal lung is compressed by the abdominal contents and the weight of the lung above it; splinting against pain removes the periodic deep breaths that both re-expand lung and stretch type II cells into releasing stored surfactant; high inspired oxygen and retained secretions let the remaining gas be absorbed. Alveoli at the smallest radius carry the greatest collapsing pressure by Laplace, so they are the ones that shut. Those segments keep their blood supply, so the result is shunt.
Lost FRC and no deep breaths → small alveoli lose to Laplace → basal collapse with volume loss and shunt. The fix is re-expansion (deep breathing, mobilising, CPAP), not antibiotics.
You would find: Day one to two after surgery: low oxygen saturation, reduced breath sounds and dullness at the lung bases, and a basal band of opacity on chest x-ray with signs of lost volume — a raised hemidiaphragm and crowded ribs. Mediastinal or tracheal shift towards the opacity is a feature of large lobar or whole-lung collapse rather than the usual basal postoperative kind. Unlike consolidation, volume is lost, not added.
- Acute respiratory distress syndrome← from “Type I cells are flat and enormous: they cover…”
A systemic insult — sepsis, aspiration, pancreatitis, major trauma — inflames the alveolar-capillary barrier. It becomes leaky, and protein-rich fluid floods the sac. Type I cells die, which both thickens the barrier and strips away the surface for gas exchange, and the plasma protein in the fluid chemically inactivates whatever surfactant is there. So you get flooding and collapse at once: heavy, stiff lungs and hypoxaemia that does not correct with oxygen.
Leaky barrier → protein-rich flooding + surfactant inactivation + type I cell death → shunt refractory to oxygen. Bilateral infiltrates, not cardiac.
You would find: Within a week of a known insult or of new or worsening respiratory symptoms: bilateral opacities on imaging not fully explained by effusion, collapse or nodules; hypoxaemia with a PaO₂/FiO₂ ratio at or below 300 mmHg (about 40 kPa) measured on at least 5 cmH₂O of PEEP or CPAP; and respiratory failure not fully explained by cardiac failure or fluid overload. The clinical hallmark is the amount of oxygen it takes to achieve very little.
- Alveolar flooding in cardiogenic pulmonary oedema← from “Type I cells are flat and enormous: they cover…”
A failing left ventricle raises pressure back through the left atrium into the pulmonary capillaries. Once the hydrostatic pressure exceeds what the lymphatics can drain, water is squeezed across an intact barrier into the interstitium and then into the alveolus. The barrier is not damaged here — it is simply being outpushed — and the water sitting on the type I cells is now the diffusion distance oxygen must cross.
Raised capillary hydrostatic pressure across an intact barrier → transudate into the alveolus → widened diffusion distance. Treat the pressure, not the lung.
You would find: Acute breathlessness worse lying flat, fine inspiratory crackles at both bases, and a chest x-ray with upper-lobe vessel prominence, Kerley B lines and perihilar shadowing. The patient is usually sitting bolt upright.
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.
- Binds
- The glucocorticoid receptor inside fetal type II pneumocytes
- Which does
- The steroid crosses the cell membrane, binds its receptor, and the complex moves into the nucleus and switches on transcription of surfactant proteins B and C and the enzymes that build phosphatidylcholine. It accelerates the cell's maturation timetable, with a measurable effect on surfactant within about a day.
- So you see
- A baby delivered roughly a day to a week after the course has measurably more surfactant, less respiratory distress, less need for ventilation, and lower mortality, necrotising enterocolitis and intraventricular haemorrhage.
- And the same mechanism causes
- The same glucocorticoid signalling acts on every tissue it reaches. In the mother it drives gluconeogenesis and insulin resistance, so blood glucose rises — a real problem in diabetes in pregnancy, where glucose is monitored more closely after a course. In the fetus, glucocorticoids also restrain growth, which is why repeated courses reduce birth weight and head circumference rather than being harmlessly repeatable.
- Handling
- Betamethasone and dexamethasone are chosen because they cross the placenta largely intact; prednisolone and cortisol are inactivated by placental 11β-hydroxysteroid dehydrogenase type 2 and would not reach the fetus in useful amounts. Betamethasone is the agent most used in Australian obstetric practice.
Catches people out: It needs time, because the effect depends on new protein being transcribed and made — the largest benefit is seen in babies delivered more than 24 hours after the course starts. An incomplete course still confers some benefit, which is why imminent delivery is not by itself taken as making the first dose pointless.
- Binds
- No receptor. This is a physical replacement: animal-derived phospholipid carrying surfactant proteins B and C, which insert into the water surface. The immune proteins SP-A and SP-D of native surfactant are not present in these preparations.
- Which does
- The molecules push between the water molecules at the surface and break up their hydrogen bonding, so the surface pulls inwards far less — and because they pack tighter as the alveolus shrinks, they lower tension most in the alveoli closest to collapsing.
- So you see
- Collapsed alveoli recruit and stay open at end-expiration. Compliance improves within minutes, and the oxygen and ventilator pressures needed fall visibly at the bedside.
- And the same mechanism causes
- Because it is instilled as a liquid bolus it transiently obstructs the airway: desaturation and bradycardia during administration are expected, not a complication. Afterwards compliance improves abruptly, so ventilator settings chosen for a stiff lung will now over-inflate a soft one — hypocapnia and barotrauma follow unless the settings come down promptly. (Surfactant lowers the overall rate of air leak; the risk here is failing to wean, not the drug itself.) The same jump in compliance and pulmonary blood flow can unmask a patent ductus arteriosus and precipitate pulmonary haemorrhage.
Catches people out: It has not been shown to help in adult ARDS. There the leak is ongoing, so plasma protein inactivates the surfactant about as fast as it is given, and trials have found no mortality benefit. No drug currently fixes the ARDS alveolus itself — the mainstay is a ventilator strategy that keeps alveoli open without over-stretching them (low tidal volume, adequate PEEP, proning when severe), plus treating the cause.
- Binds
- No receptor — it acts as a substrate, steepening the alveolar-to-capillary diffusion gradient.
- Which does
- A higher alveolar partial pressure of oxygen means a steeper gradient into the capillary, so blood leaving a well-ventilated alveolus leaves essentially fully saturated.
- So you see
- Oxygen saturation rises — but only for blood that passes an alveolus containing gas. Blood shunted past a collapsed or flooded alveolus never meets it, which is why pure shunt corrects poorly with oxygen and needs pressure (CPAP or PEEP) to reopen the sac.
- And the same mechanism causes
- Nitrogen is barely absorbed from the alveolus, so it acts as a splint holding the sac open. High inspired oxygen washes that nitrogen out, and the remaining oxygen is taken up by blood faster than it is replaced — so a poorly ventilated alveolus absorbs itself shut. Giving high-flow oxygen for atelectasis can therefore deepen it (absorption atelectasis). In preterm babies excess arterial oxygen disturbs retinal vessel growth — first shutting immature vessels down, then driving disordered neovascularisation — and contributes to retinopathy of prematurity, which is why neonatal saturation targets are deliberately set lower than adult ones.
Catches people out: Oxygen treats a number, not a cause. Reaching for more oxygen when the problem is collapsed lung delays the thing that actually works: re-expansion.
- Binds
- The sodium-potassium-two-chloride cotransporter (NKCC2) on the luminal membrane of the thick ascending limb of the loop of Henle
- Which does
- Blocking the transporter stops salt reabsorption there and dissipates the medullary concentration gradient, so water cannot be reclaimed further down the nephron and leaves in the urine with the salt.
- So you see
- Circulating volume falls, so left atrial and pulmonary capillary hydrostatic pressure fall, and fluid stops being pushed into the alveolus and starts draining back. Breathlessness eases and the crackles clear.
- And the same mechanism causes
- Salt that is not reabsorbed in the loop is delivered to the collecting duct, where the extra sodium load and the secondary aldosterone rise from volume loss drive potassium and hydrogen ion secretion — hence hypokalaemia and metabolic alkalosis, and low potassium is arrhythmogenic in exactly the failing heart being treated. Blocking NKCC2 also abolishes the lumen-positive potential that normally drives paracellular magnesium and calcium reabsorption, so both are wasted too. The same volume loss drops blood pressure and renal perfusion if pushed too far. The closely related NKCC1 in the stria vascularis of the inner ear explains ototoxicity with high or rapidly infused doses.
- Handling
- It has to be secreted into the tubule by proximal organic anion transporters to reach its target from the luminal side, so in poor kidney function, or when other organic anions compete, less drug arrives at the transporter and the response is blunted.
Catches people out: It works when the flooding is a pressure problem. In ARDS the barrier is leaky, so a diuretic cannot fix the leak — though once the patient is out of shock, a conservative fluid strategy does improve oxygenation and shorten time on the ventilator. The physiology of the two floods is different even though the chest x-rays look similar.
Grunting in a preterm baby is the whole page in one sign. The baby is breathing out against a partly closed glottis to hold pressure in the lung — generating their own PEEP — because the surfactant that should stop the alveoli collapsing is not there yet. It is Laplace's law failing, audibly. That is also why CPAP works: it does from outside what the grunt is trying to do from inside, and what surfactant would do chemically.
Now test whether it stuck
Reading this through is not the same as being able to reconstruct it. Every question in the bank is free, with a full debrief on each option.