Bronchioles
A sub-millimetre airway with smooth muscle but no cartilage — the lung's adjustable valve, where a small squeeze makes a very large obstruction.
What it normally does
Airways below about 1 mm across have no cartilage rings and no submucosal glands. They are held open by the elastic recoil of the alveolar walls attached to their outside (radial traction, or tethering), which both pulls the airway open and supplies the driving pressure for expiratory flow.
Explains why these airways narrow and close on breathing out once alveolar walls are destroyed — the expiratory flow limitation and air trapping of emphysema.
A circumferential (helical) layer of smooth muscle wraps each bronchiole, and for laminar flow resistance varies inversely with the fourth power of the radius (Poiseuille) — halve the radius and resistance rises sixteen-fold. Counter-intuitively, because the small airways branch into an enormous total cross-sectional area, together they normally account for only a small share of total airway resistance.
Explains why a modest degree of muscle spasm across many small airways produces marked obstruction and wheeze, and why relaxing that muscle relieves an attack within minutes — but also why early small-airway disease is a 'silent zone' that FEV1 detects late.
The bronchiolar wall is thin, with no cartilage and no submucosal glands. Its resident secretory cell is the club cell; goblet cells are sparse here in health and increase with smoking and asthma. Resident mast cells sit in the wall, and eosinophils are recruited into it in type 2 inflammation — all pressed against a lumen roughly 1 mm or less across.
Explains why a fraction of a millimetre of wall oedema or a plug of secretions can occlude a small airway completely — mucus plugging in fatal asthma, and infant bronchiolitis.
The vagus nerve drives contraction through M3 muscarinic receptors, and this cholinergic tone is the main neural input to the muscle. Human airway smooth muscle has little or no functional sympathetic innervation (sympathetic fibres supply airway vessels and glands instead); the relaxing beta-2 receptors on the muscle are extrajunctional, reached by circulating adrenaline or by drug delivered to them. The neural bronchodilator pathway that does exist is non-adrenergic non-cholinergic (VIP and nitric oxide, carried in vagal fibres).
Explains why there is no sympathetic nerve to stimulate for bronchodilatation — a beta-2 agonist has to be delivered to the receptor itself, which in practice is usually by inhalation — and why blocking muscarinic receptors removes resting constrictor tone and widens the airway.
What goes wrong
- Asthma (variable airflow obstruction)← from “A circumferential (helical) layer of smooth mu…”
An allergen, virus or cold air triggers mast cells and type 2 inflammation. The smooth muscle contracts and remains hyperresponsive, the wall swells and mucus is produced. The radius falls, and by the fourth-power relationship resistance climbs steeply — worst on expiration, when the airway is already narrowing. Because the muscle can relax and the inflammation can be treated, the obstruction is variable and largely reversible.
About 1 in 9 Australians (roughly 11%) have asthma. Age-standardised prevalence in Aboriginal and Torres Strait Islander people is around 1.6 times higher, and hospitalisation and death rates are around twice as high or more. Variability over time — on symptoms, peak flow or spirometry — is the hallmark; do not treat bronchodilator reversibility as an absolute asthma-versus-COPD test, since some people with COPD show a significant response and some people with asthma show none on the day you test them.
You would find: Episodic expiratory wheeze, chest tightness and cough, worse at night and in the early morning, worse with exercise and cold air. Spirometry shows obstruction — an FEV1/FVC ratio below the lower limit of normal (the fixed 0.7 cut-off belongs to COPD; in children the ratio is normally above about 0.9) — with a bronchodilator response of at least a 12% and 200 mL rise in FEV1 after salbutamol (Australian Asthma Handbook; the 2022 ERS/ATS interpretive standard instead uses a rise of more than 10% of the predicted value). Crucially, spirometry is often completely normal between episodes, so normal spirometry does not exclude asthma.
- Acute severe asthma← from “A circumferential (helical) layer of smooth mu…”
Sustained muscle spasm plus wall oedema and thick mucus plugs. Air is drawn in past the narrowing but cannot be pushed out in the time available, so the lungs inflate and stay inflated (dynamic hyperinflation), the diaphragm flattens and shortens, and the work of breathing rises until the patient tires.
Silent chest, drowsiness or a normal-to-rising PaCO2 in an asthma attack signals imminent respiratory arrest — call for help. Australian management is oxygen titrated to a target saturation (the Australian Asthma Handbook target is 93–95% in adults and adolescents, and 94–98% in children) rather than routine high-flow, repeated inhaled salbutamol, added ipratropium in severe attacks, and a systemic corticosteroid given early rather than as a last step; intravenous magnesium sulfate is considered in severe or life-threatening attacks not responding. Doses sit in the current Australian Asthma Handbook, not here.
You would find: Cannot finish a sentence, sitting forward, using accessory neck muscles. A quiet chest is the danger sign — no air moving means no wheeze. Early the PaCO2 is low from hyperventilation; a normal or rising PaCO2 means the patient is tiring.
- COPD and emphysema (small airway obstruction)← from “Airways below about 1 mm across have no cartil…”
Cigarette smoke drives protease-rich inflammation. Two things happen together: alveolar walls are destroyed, so the bronchiole loses both the elastic guy-ropes that hold it open and the recoil pressure that drives expiratory flow; and the small airway wall itself is inflamed, thickened, fibrosed and partly plugged with mucus, with many small airways obliterated altogether. When pleural pressure rises during expiration the poorly supported airway is compressed shut and air is trapped behind it.
The obstruction is structural and only partly reversible: it lies both outside the airway (lost tethering and recoil) and within a remodelled small-airway wall. Bronchodilators relieve the residual smooth muscle tone, but no drug rebuilds destroyed alveolar walls. Smoking cessation is the most effective intervention for slowing the accelerated decline in FEV1; pulmonary rehabilitation, vaccination and — in chronic hypoxaemia — long-term oxygen therapy also change outcomes. COPD prevalence in Aboriginal and Torres Strait Islander adults aged 45 and over is roughly 2.5 times higher, with substantially higher hospitalisation and death rates.
You would find: Long smoking history, slowly progressive breathlessness, prolonged expiration, pursed-lip breathing (self-generated back-pressure that splints the airway open), barrel chest. Post-bronchodilator FEV1/FVC below 0.7 that does not normalise — the ratio must be measured after a bronchodilator to make the diagnosis.
- Bronchiolitis (RSV in infants)← from “The bronchiolar wall is thin, with no cartilag…”
RSV infects the bronchiolar epithelium and sheds it. Debris, oedema and mucus fill a lumen that is well under a millimetre across in an infant, so a fraction of a millimetre of swelling closes it. The plugging is patchy — some segments trap air behind a ball-valve, others collapse — which is why the chest sounds and appears uneven.
The commonest reason for hospital admission in Australian infants; rates in remote Aboriginal and Torres Strait Islander communities are among the highest reported anywhere, with later chronic suppurative lung disease and bronchiectasis. Management is supportive: oxygen for persistent desaturation (the Australasian PREDICT guideline uses a saturation persistently below about 90%, and some services use 92%) and feeding or fluid support. Salbutamol, adrenaline, corticosteroids, antibiotics and chest physiotherapy are all specifically not recommended for routine use — the blockage is luminal debris, not smooth muscle.
You would find: Infant under 12 months, a few days of coryza then wheeze with widespread fine crackles, tachypnoea, chest wall recession, nasal flaring, and poor feeding. Winter peak. It is a clinical diagnosis — routine chest X-ray and viral testing do not change management.
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
- Beta-2 adrenoceptor on airway smooth muscle (a Gs-coupled receptor).
- Which does
- Gs activates adenylyl cyclase, cAMP rises, and protein kinase A reduces myosin light chain kinase activity and lowers intracellular calcium. The muscle relaxes.
- So you see
- The airway widens within minutes. Wheeze and breathlessness settle and peak flow and FEV1 rise — this is the bronchodilator response you measure on spirometry.
- And the same mechanism causes
- The same beta-2 receptor sits on skeletal muscle, so as the dose rises a fine tremor of the hands appears — bigger dose, bigger tremor. Beta-2 receptors on vascular smooth muscle cause peripheral vasodilatation and a reflex tachycardia, and cardiac beta-2 receptors add to it. Derive these; do not memorise a generic list.
- Handling
- Inhaling puts the drug on the receptor with only a small systemic dose. A spacer sharply reduces oropharyngeal deposition and improves lung delivery, and in mild-to-moderate acute asthma a pressurised metered-dose inhaler with a spacer performs at least as well as a nebuliser. Beta-2 stimulation of Na/K-ATPase drives potassium into cells, and beta-2-driven glycogenolysis and lipolysis generate lactate — so repeated large doses can produce hypokalaemia and a type B lactic acidosis, the latter causing tachypnoea that can be mistaken for worsening asthma. This is why potassium and lactate are watched in a severe attack.
Catches people out: It only relaxes muscle; it treats none of the underlying inflammation. Reliever overuse is a risk marker: dispensing of three or more canisters a year is associated with a higher risk of severe exacerbations, and twelve or more a year with a higher risk of asthma death. High reliever use is a prompt to review and step up preventer therapy, not to reassure.
- Binds
- The cytoplasmic glucocorticoid receptor in epithelial and inflammatory cells of the airway wall.
- Which does
- The drug-receptor complex translocates to the nucleus, recruits histone deacetylase 2 to switch off NF-kB-driven cytokine genes (transrepression) and induces anti-inflammatory genes (transactivation). Eosinophil numbers fall, mast cell mediators fall, and beta-2 receptor expression is restored.
- So you see
- Over days to weeks the wall is less swollen and less hyperresponsive. Fewer night symptoms, fewer flares, fewer hospital visits.
- And the same mechanism causes
- Most of a dose taken from a pressurised inhaler without a spacer lands in the mouth and throat. Two separate consequences follow, and they have different mechanisms: local immunosuppression of the oropharyngeal mucosa lets Candida overgrow, giving oral thrush; and steroid deposited on the larynx causes a local myopathy of the vocal cord adductor muscles, giving hoarseness — dysphonia is not a fungal infection and does not respond to antifungals. Both are reduced by using a spacer and by rinsing and spitting after a dose.
- Handling
- Because ICS alone prevents rather than rescues, the Australian Asthma Handbook now prefers a combined inhaled corticosteroid plus formoterol inhaler (for example budesonide-formoterol) as the reliever in adults and adolescents aged 12 and over, either as-needed alone in mild asthma or as maintenance-and-reliever therapy — so every rescue puff also delivers anti-inflammatory. This works because formoterol is a long-acting beta-2 agonist with a rapid onset; an ICS combined with salmeterol or vilanterol is not used as a reliever, as those partners have a slower onset and are not approved for that use. The strategy does not extend to younger children.
Catches people out: Inhaled corticosteroid on its own is not a rescue drug. A patient who takes their steroid-only preventer during an attack and waits for it to work is losing time.
- Binds
- M3 muscarinic receptors on airway smooth muscle. The same receptors on submucosal glands drive mucus secretion, but those glands sit in the larger cartilaginous airways — bronchioles have none — so the anti-secretory effect is an upstream one. Ipratropium is non-selective across M1-M3; tiotropium dissociates from M3 far more slowly than from M2, which gives it both its kinetic selectivity and its once-daily dosing.
- Which does
- Blocks acetylcholine released by the vagus, so Gq/IP3 signalling stops and intracellular calcium falls. Resting cholinergic constrictor tone is removed and the muscle relaxes.
- So you see
- Airways widen more slowly and less dramatically than with salbutamol, but cholinergic tone is the major reversible component of COPD obstruction. LAMAs improve breathlessness and exercise capacity and reduce exacerbations; ipratropium is a short-acting add-on rather than an exacerbation-preventing drug.
- And the same mechanism causes
- Same receptor, different tissue. M3 on salivary glands gives dry mouth. Nebulised mist escaping a loose-fitting mask reaches M3 on the iris sphincter and ciliary muscle, causing mydriasis and blurred vision, and can precipitate acute angle-closure glaucoma in a susceptible eye — hence a mouthpiece or a well-fitting mask. The small absorbed fraction can add a peripheral antimuscarinic effect, so constipation and, in men with prostatic obstruction, urinary retention are recognised though uncommon.
- Handling
- Both are quaternary ammonium compounds, so the swallowed fraction is poorly absorbed from the gut and they cross the blood-brain barrier poorly — unwanted effects stay largely peripheral and mostly local, and central effects such as confusion are not expected. Tiotropium is a maintenance drug with a slow onset and is not used for acute relief.
Catches people out: No drug restores destroyed alveolar walls. Bronchodilators treat symptoms; smoking cessation is the most effective intervention for slowing the accelerated decline in FEV1.
- Binds
- The same glucocorticoid receptor as the inhaled steroid, reached in every tissue via the bloodstream.
- Which does
- Switches off transcription of inflammatory cytokines, reducing mucosal oedema and mucus production, and restores beta-2 receptor expression and responsiveness so salbutamol works better again.
- So you see
- Shortens the attack and prevents relapse — but because the benefit depends on changing gene transcription it takes several hours to appear (commonly quoted as about four to six), which is precisely why it is given at the start of treatment rather than at the end.
- And the same mechanism causes
- The same receptor in liver and muscle drives gluconeogenesis and insulin resistance, so blood glucose climbs during the course — predictable, and sometimes dangerous, in a patient with diabetes. Hydrocortisone additionally has appreciable mineralocorticoid activity, so it promotes sodium and water retention and renal potassium loss, compounding the hypokalaemia already being caused by repeated salbutamol.
- Handling
- A short course in someone not already on long-term steroids can be stopped without tapering, because the hypothalamic-pituitary-adrenal axis has not had time to suppress. Guidelines place it early in the acute attack alongside oxygen and salbutamol; the drug, dose and duration sit in the current Australian Asthma Handbook or COPD-X.
Catches people out: It is not a bronchodilator and it will not correct hypoxia now — oxygen and salbutamol do that. Its benefit is measured in hours, not minutes.
Reversibility is the organising idea. Bronchiolar smooth muscle tone is the part of small-airway obstruction you can undo in minutes — so salbutamol works well in asthma; works only partly in COPD, where the airway has also lost its tethering and recoil and the wall itself is remodelled; and is not recommended in infant bronchiolitis, where the lumen is filled with shed epithelium and mucus and there is nothing for a bronchodilator to relax.
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.