Airway defence and clearance

What it normally does

• The airway lining is covered by two layers: a thin watery layer the cilia beat in (periciliary liquid), and a sticky mucus blanket floating on top of it. Cilia beat at roughly 10-15 times a second, tips catching the blanket and sweeping it towards the throat — of the order of 1 cm a minute in the trachea, and slower in the smaller airways — where it is swallowed without you noticing (the mucociliary escalator).

  the whole system depends on the watery layer being deep enough for cilia to swing freely. Let it dry out and the mucus sits on the cell surface instead of gliding over it.

• The depth of that watery layer is set by salt movement. A chloride channel on the airway cell surface (CFTR) lets chloride flow out down its electrochemical gradient — it is a gated channel, not a pump — and water follows osmotically. CFTR also acts as a brake on the sodium channel next door (ENaC), which absorbs sodium and pulls water back into the cell.

  if CFTR does not work, chloride stops going out and the sodium brake is released, so the surface is stripped of water and the mucus turns to glue.

• Cough is the reserve system. Irritant receptors in the larynx, carina and large bronchi send signals up the vagus to the medulla. You take a deep breath in, the glottis slams shut, expiratory muscles squeeze against it to build pressure, then the glottis opens and air blasts out fast enough to shear mucus off the wall. It needs three things: the sensation, a glottis that closes, and abdominal and intercostal muscle power.

  knock out any one of the three and secretions stay where they are, which is why the sedated, the post-operative and the neurologically weak drown in their own sputum.

• Clearance keeps the bacterial burden of the lower airways very low. (The old teaching that they are sterile is wrong — sequencing shows a low-biomass resident flora — but the principle holds: inhaled organisms rarely get the chance to multiply.) Particles landing on the conducting airways are trapped, moved up and swallowed within hours; what deposits in the alveoli is beyond the escalator and is cleared far more slowly by macrophages. Antibody in the mucus (secretory IgA) plus resident macrophages mop up what is left.

  when clearance fails, bacteria can colonise persistently. The neutrophils sent to fight them release elastase, which digests the airway wall's own elastin and structural matrix.

What goes wrong

• Cystic fibrosis← from “The depth of that watery layer is set by salt …”

  Both copies of the CFTR gene are faulty (autosomal recessive; F508del is the commonest fault in Australia). Chloride cannot leave the cell and the sodium brake is off, so the watery layer collapses. Cilia are stranded in thick mucus, the escalator stops, and the airway is colonised long-term, often with Staphylococcus aureus and Haemophilus influenzae early and Pseudomonas aeruginosa later. The same channel sits in pancreatic ducts, bile ducts, vas deferens and sweat ducts, so this is a multi-system disease rather than a purely respiratory one — although how much each organ is affected varies with genotype, and a minority remain pancreatic sufficient.

  No CFTR chloride secretion, no airway surface water, no ciliary beat. Salty sweat, fatty stools, Pseudomonas. Sweat chloride 60 mmol/L or more.

  You would find: Picked up on the newborn heel prick screen (raised immunoreactive trypsinogen, then genotyping) in roughly 1 in 2500 to 3500 Australian births; about 1 in 25 people of European ancestry carry a fault. Diagnosis is confirmed by a sweat test — sweat chloride 60 mmol/L or more, because the duct cannot reabsorb the chloride it secreted. Also: fatty foul stools and poor weight gain from pancreatic duct blockage, and infertility in the great majority of men from congenital absence of the vas deferens.

• Bronchiectasis← from “Clearance keeps the bacterial burden of the lo…”

  A vicious cycle. Clearance fails for any reason — a severe childhood pneumonia, cystic fibrosis, primary ciliary dyskinesia, an inhaled foreign body, low immunoglobulin. Bacteria settle persistently, neutrophils pour in, and their elastase (with matrix metalloproteinases) digests the elastin and structural matrix of the airway wall. The airway becomes permanently wide and floppy, so it clears even worse, so more bacteria settle. Established structural damage in adults is not expected to reverse — although in children treated early, CT changes can still improve — so the cycle is what you treat.

  Impaired clearance to infection to neutrophil elastase to wall destruction to worse clearance. Daily purulent sputum, coarse crackles, signet ring on HRCT.

  You would find: Daily production of large volumes of thick, often purulent sputum for years, coarse crackles, and sometimes clubbing. The diagnosis is made on high-resolution CT: the airway is wider than the artery beside it (the signet ring sign) and airways are still visible near the pleura. Australian context: post-infectious bronchiectasis falls very heavily on Aboriginal and Torres Strait Islander children, particularly in remote central and northern Australia, where reported rates are among the highest in the world. It usually starts as a chronic wet cough, so a wet cough of more than four weeks in a child is investigated, not watched.

• Sputum retention from a failed cough← from “Cough is the reserve system. Irritant receptor…”

  Cough needs sensation, glottic closure and expiratory muscle force. Opioids and anaesthesia blunt the central response; a stroke or bulbar weakness stops the glottis closing; an upper abdominal wound, rib fractures or motor neurone disease removes the expiratory squeeze. Mucus that the cilia alone cannot shift stays put, plugs a bronchus, and the lung distal to it collapses and can then become infected.

  Sensation, glottis, muscle power — lose any one and you get plugging, collapse and infection. Post-operative and post-stroke, not exotic.

  You would find: Day two after upper abdominal surgery: fever, low oxygen saturation, reduced breath sounds and dullness at a base, and a patient who winces and stops halfway through a cough. Aspiration pneumonia after a stroke is the same failure, with glottic protection as the broken part.

• Smoke-stunned escalator← from “The airway lining is covered by two layers: a …”

  Cigarette smoke slows and shortens the cilia and drives goblet cell hyperplasia and submucosal gland hypertrophy, so far more mucus is made than the belt can carry. More load on a slower belt means mucus accumulates overnight and has to be coughed out on waking, and inhaled bacteria linger long enough to establish infection.

  More mucus on a slower belt. Chronic bronchitis is a symptom definition — three months a year, two years running. Cessation, not a drug, is what lets the escalator recover.

  You would find: Chronic bronchitis is defined clinically as a productive cough on most days for at least three months a year in two consecutive years — typically worst on waking — with repeated chest infections in a smoker. Ciliary function and the cough tend to improve over months after quitting.

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.