Unit 14 — Respiratory System · Question Bank

The trachea is the wide central conducting tube that runs from the cricoid cartilage of the larynx to the carina, where it splits into the right and left main bronchi. Its job is to deliver warm, humid, particle-free air to the lungs and to do so reliably during the swings of intrathoracic pressure that accompany every breath and every cough. The wall has been engineered for two competing demands — it must stay permanently open against negative intrathoracic pressure, yet it sits behind the oesophagus and must allow a swallowed bolus to bulge into it without obstruction. The four-layered design — mucosa, submucosa, cartilage-muscle layer and adventitia — resolves both demands at once.

Mucosa — respiratory epithelium and lamina propria

The luminal surface is lined by the classical respiratory epithelium: a pseudostratified ciliated columnar epithelium with interspersed goblet cells. All cells touch the basement membrane but only the tall columnar cells reach the surface, giving the misleading appearance of stratification at low power. The columnar cells carry roughly three hundred motile cilia each (9+2 axoneme, dynein-powered), and the goblet cells are flask-shaped with their cytoplasm filled apically by membrane-bound mucinogen granules. Together they generate and propel the two-phase mucus blanket that defines the mucociliary escalator. The basement membrane beneath this epithelium is notably thick — one of the histological hallmarks of the trachea — and is itself thrown into a thin layer of lamina propria rich in elastic fibres and free lymphocytes, providing recoil and local immune surveillance.

Submucosa — seromucous glands

Just deep to the lamina propria lies a loose submucosa packed with tracheal seromucous glands. Their serous acini secrete the watery sol-phase periciliary fluid in which the ciliary shafts beat, while their mucous acini reinforce the gel phase. These glands are abundant in the trachea, diminish in the bronchi, and disappear entirely at the bronchiole — a transition that is itself examinable. Small ducts pierce the epithelium to deliver the secretions onto the airway surface. Chronic irritation (cigarette smoke) hypertrophies these glands and shifts the secretory balance toward mucus — the morphological basis of chronic bronchitis, where the Reid index (gland-thickness / total-wall-thickness) rises above 0.4.

Cartilage and trachealis muscle — the structural compromise

The signature feature of the trachea is a vertical stack of about 16 to 20 C-shaped hyaline cartilage rings embedded in the wall. They sit anteriorly and laterally, hold the lumen open against the negative pressures of inspiration and the violent pressure swings of cough, and are stiff enough that the trachea is the only large airway you can feel through the skin. The open posterior face of each “C”, which faces the oesophagus, is bridged by a strap of smooth muscle called the trachealis running between the two free ends of the cartilage. This compromise allows a swallowed bolus to bulge briefly into the trachea without being blocked by rigid cartilage, and lets the trachealis contract during cough to narrow the lumen and accelerate expiratory airflow.

Adventitia — binding to surroundings

The outermost layer is a thin adventitia of dense irregular connective tissue that anchors the trachea to the oesophagus posteriorly and to the surrounding mediastinal connective tissue, carrying the trachea’s blood supply and autonomic innervation along with it.

Clinical link

A child who inhales a peanut typically lodges it not in the trachea itself but at the carina or right main bronchus, because the trachea’s cartilage rings keep its lumen wide and open. Tracheomalacia — congenital weakness or absence of the rings — produces a floppy trachea that collapses on expiration, with characteristic inspiratory stridor in infancy. And cigarette smoke flips the entire system at once: it paralyses cilia, hypertrophies the submucosal glands, drives squamous metaplasia of the respiratory epithelium and sets the histological stage for chronic bronchitis and ultimately squamous-cell carcinoma at the carina.

As air descends through the conducting tree, the tube progressively simplifies its wall. Five wall ingredients change in lock-step — epithelium, goblet cells, submucosal glands, cartilage and smooth muscle — and one new cell type (the club cell) appears. The most important examinable transition is the bronchus-to-bronchiole boundary, which is defined histologically by the simultaneous loss of cartilage and glands. Understanding these gradients is what lets you identify any cross-section on a slide and what underpins the pathophysiology of asthma, chronic bronchitis and small-airway disease.

Epithelium

The large bronchi continue the trachea’s pseudostratified ciliated columnar epithelium with goblet cells — this is canonical respiratory epithelium. As the tube narrows, the cells get shorter and the false stratification disappears: in small bronchi it becomes simple columnar ciliated, in larger bronchioles simple columnar to cuboidal ciliated, and in the terminal bronchiole it is simple cuboidal with only the occasional cilium. Goblet cells progressively decrease in number and disappear at the bronchiole level, replaced by the appearance of the club (Clara) cell — a non-ciliated, dome-shaped secretory cuboidal cell with apical granules. The basement membrane and lamina propria also thin out as you descend.

Cartilage

The continuous C-shaped hyaline rings of the trachea have already broken into irregular plates of hyaline cartilage in the bronchi, scattered around the entire circumference rather than confined anteriorly. These plates shrink and become more sparse with each branching, and when the airway falls below approximately 1 mm in diameter, cartilage disappears completely. The disappearance of cartilage is the formal histological definition of crossing from bronchus into bronchiole. With cartilage gone, the bronchiole has lost the structural prop that holds its lumen open in inspiration; from this point downward, patency depends on the radial tug of the surrounding lung parenchyma (the elastic fibres of the alveolar septa) — which is why emphysema, by destroying that parenchyma, lets small airways collapse on expiration.

Submucosal glands

Bronchial submucosa still contains seromucous glands, although in declining numbers compared to the trachea, contributing both serous sol-phase fluid and additional mucus to the airway lining. At the bronchiolar transition these glands vanish together with cartilage — bronchioles have no submucosal glands at all. Mucus production in the bronchiole is therefore minimal in health, and the club cell’s lipoprotein secretion plus the sol-phase fluid migrating down from above are what keeps the lumen lubricated.

Smooth muscle and club cells

In the bronchi a continuous helical layer of smooth muscle appears between the epithelium and the cartilage plates. In the bronchioles, because the wall is so much thinner overall, this smooth-muscle layer is now relatively prominent compared to wall thickness — this is the layer that contracts in asthma to produce bronchospasm. The replacement of goblet cells by club (Clara) cells is the other defining bronchiolar change: club cells secrete a surfactant-like lipoprotein and CC16, detoxify inhaled xenobiotics through cytochrome P450, and act as the local progenitor cell after airway injury. By the terminal bronchiole, simple cuboidal epithelium dominated by club cells, encased in a relatively thick smooth-muscle wrap, with no cartilage and no glands, gives you the unmistakable identification.

Clinical link

Every distal pulmonary disease can be mapped onto these gradients. Asthma is a disease of the smooth-muscle layer that is most prominent in bronchioles. Chronic bronchitis is a disease of the submucosal glands and goblet cells of bronchi (hence its name and the Reid-index criterion). Bronchiolitis in infants is inflammation of a tube that has no cartilage to keep it open and so collapses easily. And centrilobular emphysema from smoking destroys the alveolar septa that radially tether the bronchiole, letting it close on expiration even when its own wall is intact.

The alveolus is the terminal functional unit of the lung — a polyhedral air pocket roughly 200 µm across whose entire wall is the gas-exchange surface. There are about 300 million alveoli in the adult lung, giving a total exchange area of around 75 m², and the architecture of the alveolar wall — thin type I cells, fused basement membranes, a dense capillary mesh and a surfactant film — exists to make that vast surface thin enough for oxygen and CO₂ to diffuse across in milliseconds. The diffusion membrane itself is called the blood-air barrier, and it is the structure whose definition every TMU paper has asked for.

The alveolar wall — type I and type II pneumocytes

The wall is built from two epithelial cell types in a strikingly lopsided division of labour. Type I pneumocytes are extreme simple squamous cells, with cytoplasm reduced to a few hundred nanometres around a flattened nucleus. Only about 40% of the cells in the wall are type I, yet they cover roughly 95% of the surface area. Their thinness is the point: type I cells form the air-facing leaf of the blood-air barrier and let gases diffuse across in milliseconds. They are post-mitotic and cannot replace themselves. Type II pneumocytes are the opposite cell: cuboidal, occupying the corners between adjacent type I sheets, and stuffed with characteristic whorled lamellar bodies that store surfactant — a mixture dominated by dipalmitoylphosphatidylcholine (DPPC) plus surfactant proteins SP-A through SP-D. Type II cells exocytose lamellar bodies onto the alveolar surface, where the lipid unfolds into a thin film that lowers surface tension. They are also the alveolar stem cell: after a type I cell dies, a neighbouring type II divides and one daughter flattens out into a new type I.

Alveolar macrophages

Wandering across the alveolar lumen and through the septal connective tissue are alveolar macrophages, traditionally called dust cells. They are mononuclear phagocytes derived from blood monocytes that phagocytose inhaled carbon, silica, bacteria and recycled surfactant. Most then ride the mucociliary escalator out; a few drain through lymphatics. Loaded with carbon they cause black anthracotic stippling on the pleural surface; loaded with haemosiderin in left heart failure they become the golden-brown “heart failure cells” visible in the sputum.

The interalveolar septum

Between two adjacent alveoli lies the interalveolar septum, which is far more than a passive wall — it is the meeting place of the two lung circulations. It carries a dense, continuous capillary network, with the capillary endothelium often pressing its basement membrane directly against the type I cell’s basement membrane to form the fused barrier. It also holds elastic and reticular fibres (the source of lung recoil), free macrophages, and the occasional pore of Kohn — a 5–15 µm hole that permits collateral ventilation between alveoli when a small airway is obstructed.

The blood-air barrier

The diffusion membrane between alveolar air and capillary blood is astonishingly thin, only 0.2–0.5 µm, and is built from three layers. Travelling from air to blood you cross: (1) the surfactant film and the cytoplasm of a type I pneumocyte; (2) the fused basal laminae of the pneumocyte and the endothelium — in most places these two basement membranes are pressed together so tightly that they appear as one electron-dense layer; (3) the cytoplasm of the capillary endothelial cell. The fusion of basement membranes is the geometric trick that minimises diffusion distance, and Fick’s law explains why: oxygen flux is proportional to surface area divided by thickness, so 75 m² over 0.3 µm is what makes effortless breathing possible.

Clinical link

Every alveolar disease can be read off this anatomy. Neonatal RDS happens when premature type II cells have not yet packed enough lamellar bodies, so surfactant is insufficient and alveoli collapse with each breath, throwing protein-rich exudate onto the wall (the eponymous “hyaline membranes”). ARDS in adults causes diffuse alveolar damage with the same hyaline-membrane appearance and a follow-on phase of type II hyperplasia. Emphysema destroys the elastic fibres of the septum so that alveoli enlarge and the barrier surface area collapses. Pulmonary oedema and idiopathic pulmonary fibrosis thicken the barrier and produce hypoxaemia long before CO₂ retention, because oxygen is the more diffusion-limited gas.

The alveolar wall is built from two epithelial cell types that look nothing like each other, occupy the wall in opposite proportions and do entirely different jobs — yet they sit on a shared basement membrane and depend on each other for the alveolus to work. Type I pneumocytes are extreme squamous gas-exchange cells; type II pneumocytes are cuboidal secretory and progenitor cells. Together they reconcile the alveolus’s two non-negotiable requirements: a membrane thin enough to allow oxygen diffusion in milliseconds, and a population of cells able to make surfactant and to regenerate the lining after injury.

Type I pneumocyte

The type I cell is a simple squamous cell whose cytoplasm is reduced to a thin sheet only a few hundred nanometres deep around a flattened nucleus. On electron microscopy you see almost no organelles in the cytoplasm — everything is sacrificed for thinness. Although type I cells make up only about 40% of the alveolar wall cell population, they cover roughly 95% of the alveolar surface area because each cell spreads itself so widely. They form the air-facing leaf of the blood-air barrier, with their basement membrane fused to the capillary endothelial basement membrane in most places. Type I cells are post-mitotic — once injured they cannot divide to replace themselves. They are also joined to neighbouring cells by occluding tight junctions that seal the alveolar lining and prevent fluid from leaking into the airspace.

Type II pneumocyte

The type II cell is the opposite cell in every dimension. It is cuboidal, sits tucked into the corners between adjacent type I sheets, and its cytoplasm is unusually rich in organelles for an epithelial cell. The hallmark organelle is the lamellar body: a membrane-bound storage vesicle filled with concentric whorls of phospholipid (dominated by dipalmitoylphosphatidylcholine, DPPC) plus the surfactant proteins SP-A, SP-B, SP-C and SP-D. Lamellar bodies are exocytosed onto the alveolar surface, where the lipid unfolds into a thin surfactant film that lowers surface tension and equalises pressures across alveoli of different sizes, preventing the Laplace-law collapse of the small ones into the large ones. Type II cells are more numerous than type I cells (about 60% of the wall cell population) but each covers only a tiny patch of the surface — together perhaps 5%. Crucially, type II cells are the alveolar stem cell: after injury they divide, and one daughter flattens and spreads to become a new type I cell while the other remains type II. They are also the cell that takes up extracellular water and pumps it out of the airspace through their apical sodium channels, helping keep the alveolus dry.

What they share

Both pneumocytes rest on the alveolar basement membrane, and the two are joined to each other and to their own neighbours by tight junctions that seal the alveolar lining. Both are part of the alveolar epithelium and both ultimately derive from the foregut endodermal bud. After diffuse alveolar damage of any cause (ARDS, viral pneumonitis), it is the type II cell that hyperplasias first — you see a wall transiently lined by cuboidal type II cells before they flatten back into type I shape.

Clinical link

The clinical signature of each cell type matches its function. Loss of type I cells (as in diffuse alveolar damage and ARDS) destroys the gas-exchange surface and produces refractory hypoxaemia; healing depends on type II hyperplasia and re-differentiation. Failure of type II cell maturation in the premature neonate means too few lamellar bodies and too little surfactant, so alveoli collapse on every expiration — the histology shows protein-rich exudate plastered against denuded walls (the “hyaline membranes” of neonatal RDS). Type II cells are also the cell of origin of pulmonary adenocarcinoma, the most common lung cancer in non-smokers and women.

Telling a bronchus from a bronchiole from an alveolar duct on a slide is one of the most consistently asked exam tasks in respiratory histology, and the trick is to read three features off each cross-section in turn: cartilage and glands, epithelium type, and the integrity of the wall. As you descend the airway tree, all three change in a strict order, and each named segment occupies a different combination. Get those three features right and you can identify any cut.

Bronchus

A bronchus is still very much a conducting tube. Its wall carries the four classical layers in modified form: a mucosa of pseudostratified ciliated columnar epithelium with goblet cells on a thick basement membrane, a lamina propria that includes a thin band of helical smooth muscle (separating mucosa from submucosa), a submucosa containing seromucous glands, and an outer fibrocartilaginous layer with scattered irregular plates of hyaline cartilage arranged all the way round the circumference (no longer the trachea’s tidy C-shaped rings). The combination of cartilage plates plus glands is the bronchial fingerprint — if you see both, you are in a bronchus. Bronchi range from the main bronchi down to lobar, segmental and small bronchi, with the cartilage plates shrinking at each step.

(Terminal) bronchiole

Below approximately 1 mm in diameter the airway loses its cartilage and its submucosal glands together — that simultaneous disappearance is what makes a bronchus a bronchiole. The wall is now a thin tube of simple columnar to cuboidal ciliated epithelium with the goblet cells replaced by dome-shaped club (Clara) cells, encased in a relatively thick band of smooth muscle — the layer that contracts in asthma to produce bronchospasm. The terminal bronchiole, the last purely conducting segment, is lined by simple cuboidal epithelium dominated by club cells with only the occasional cilium, and its wall is still continuous — no alveoli yet. “No cartilage, no glands, no alveoli on the wall” is the terminal bronchiole’s fingerprint.

Respiratory bronchiole

The respiratory bronchiole is the transition segment and the first part of the respiratory portion. It still has a recognisable bronchiolar wall — simple cuboidal epithelium of club and ciliated cells, smooth muscle around it — but that wall is now interrupted at intervals by alveoli opening directly into the lumen, so gas exchange begins (intermittently) along its length. You identify it on a slide by seeing both an intact bronchiolar wall in part of the cut and obvious alveolar pouches budding off the rest.

Alveolar duct

Further down still, the wall gives up entirely. The alveolar duct is little more than a linear corridor whose own wall has been replaced by the continuous opening of one alveolus after another. What remains of the wall is a thin spiral of simple squamous to cuboidal epithelium with characteristic knobs of smooth muscle at the alveolar openings — these are easy to see on histological slides and are the hallmark of the alveolar duct. Several alveolar ducts terminate in a common chamber, the alveolar sac, into which a cluster of alveoli opens.

Clinical link

Each segment has a signature disease. Disease of the bronchi is dominated by gland and goblet pathology — chronic bronchitis (hypertrophied submucosal glands, raised Reid index) and squamous-cell lung carcinoma (arising from metaplastic bronchial epithelium at the carina). Disease of the bronchiole is dominated by its prominent smooth muscle layer (asthma) and by its loss of cartilage (bronchiolitis in infants, who simply have no cartilage to keep the small airway open when the wall swells). And disease of the alveolar duct and respiratory bronchiole is centrilobular emphysema — the smoker’s lung — where alveolar walls destruct precisely at this proximal acinar level.