Gas exchange

The human gas exchange system: airways, lungs and the capillary network

Gas exchange is the uptake of oxygen from the environment into the blood and the excretion of carbon dioxide from the blood to the environment. In a mammal the exchange surface is inside the body, so the air has to be carried to it down a system of branching tubes. The whole system exists to put a large, thin, moist surface within a micrometre of a dense network of capillaries, so that oxygen and carbon dioxide can diffuse between air and blood quickly enough to supply every respiring cell.

Air enters through the nose or mouth and passes down the trachea, a wide tube held open by a series of C-shaped rings of cartilage. The rings are incomplete at the back, next to the oesophagus, which allows a swallowed bolus of food to bulge into the trachea without crushing it. The trachea divides into two bronchi, one entering each lung, and each bronchus branches repeatedly into narrower bronchioles. Left and right are not identical: the right lung has three lobes and the left has two, because the heart takes up space on the left side of the thorax.

The smallest bronchioles, the terminal bronchioles, open into clusters of alveoli. Each pair of lungs contains roughly 300 million alveoli, and each alveolus is wrapped in a network of pulmonary capillaries so dense that almost every part of the alveolar surface is in contact with blood. The pulmonary artery brings deoxygenated blood from the right ventricle to the lungs and the pulmonary vein carries oxygenated blood back to the left atrium. The alveoli contain no muscle and cannot pump: every gas that crosses them crosses by diffusion.

Two cell types line the alveolus. Type I pneumocytes are flattened (squamous) cells that form the wall and carry out gas exchange; they cover most of the surface but have very few organelles. Type II pneumocytes are smaller, more rounded cells that secrete surfactant, a mixture of lipids and proteins that lowers the surface tension of the fluid lining the alveolus. Without surfactant the moist alveolar walls would stick together and the alveoli would collapse as the lungs empty, and inflating the lungs would take much more effort. In a premature baby the type II pneumocytes are not yet mature, so little surfactant is produced and the alveoli tend to collapse; this is respiratory distress syndrome, treated with artificial surfactant and ventilatory support.

• Right lung: three lobes. Left lung: two lobes, because the heart occupies part of that side.
• Trachea -> bronchi -> bronchioles -> alveoli: each division makes the tubes narrower and the total cross-sectional area larger, so air slows down as it approaches the exchange surface.
• Diffusion path from air to blood: alveolar air -> fluid lining the alveolus -> squamous epithelial cell -> fused basement membrane -> capillary endothelial cell -> plasma -> red blood cell.
• Roughly 300 million alveoli per pair of lungs, most of the surface formed by type I pneumocytes, with type II pneumocytes secreting surfactant.

The distribution of tissues: what is where, and what it does

Cartilage is found only in the trachea and the bronchi. In the trachea it forms a series of C-shaped rings of hyaline cartilage; in the bronchi the rings are replaced by irregular plates, which become smaller and more widely spaced as the bronchi branch. Cartilage is firm but flexible: its matrix contains collagen fibres and large amounts of glycosaminoglycan, and the chondrocytes lie in small spaces called lacunae. Its job is mechanical support. When you breathe in, the pressure of the air inside the trachea falls below atmospheric pressure and the tube would collapse without it; the C-shape matters because a complete ring would press on the oesophagus behind the trachea every time food was swallowed.

Ciliated epithelium lines the trachea, the bronchi and the larger bronchioles. It is a columnar epithelium: the cells are taller than they are wide and each carries many cilia on its free surface. Goblet cells are single mucus-secreting cells scattered among the ciliated cells, and mucous glands lie deeper, in the submucosa, with ducts that open onto the epithelial surface. Mucus therefore reaches the surface both from within the epithelium and from below it. As the airways get smaller the epithelium becomes thinner, the goblet cells become fewer and the mucous glands disappear.

Smooth muscle lies inside the cartilage in the trachea and forms the main tissue of the wall of every bronchiole. Because it is involuntary muscle, its contraction changes the diameter of the airway without any conscious control: contracting narrows the airway and reduces airflow, relaxing widens it. Elastic fibres run through the walls of the airways and are especially abundant in the alveolar walls and in the pleural membranes. They stretch as the lungs inflate and recoil when the muscles of inspiration relax, and that recoil produces most of the air movement in quiet expiration.

The squamous epithelium of the alveoli is the exchange surface itself. Each cell is flattened and its cytoplasm is spread out very thinly, so the distance between the alveolar air and the blood is reduced to a minimum; the cells look like paving stones with a bulge in each one where the nucleus lies. The capillaries around the alveolus are built the same way, from a single flattened layer of endothelial cells. Alveolar epithelium and capillary endothelium are pressed together, so the whole air-blood barrier is only two thin cells deep. There is deliberately no cartilage and no smooth muscle in it, because either would add thickness and slow diffusion down.

Keeping the airway healthy: cilia, mucus and mucous glands

Goblet cells are single secretory cells shaped like a wine glass and packed with vesicles containing mucin. When the vesicles are released, the mucin absorbs water and swells to form mucus, a sticky, viscous fluid. Mucous glands in the submucosa do the same job on a larger scale: they are clusters of secretory cells whose duct opens through the epithelium. Between them, goblet cells and mucous glands cover the epithelium of the trachea, bronchi and larger bronchioles with a continuous film of mucus only a few micrometres thick.

Mucus traps whatever is breathed in: dust, pollen grains, fungal spores, bacteria and viruses. The ciliated epithelial cells carry many cilia on their free surface, each cilium containing microtubules in the 9 + 2 arrangement and beating by the sliding of adjacent microtubules, powered by ATP. The cilia do not beat at random; the wave passes along the epithelium so that the mucus is swept steadily upwards towards the pharynx. This one-way flow is the mucus escalator. The mucus is then swallowed, and the microorganisms in it are destroyed by the hydrochloric acid of the stomach.

The defence stops where the cilia stop. There are no cilia and no mucus in the alveoli, so a particle that reaches them cannot be carried back up the airway. Alveolar macrophages deal with what arrives: these are phagocytic cells that migrate over the alveolar surface, engulfing particles, bacteria and used surfactant. There are therefore two lines of defence, mucus and cilia catching most particles in the larger airways while macrophages mop up whatever gets past them. Keeping particles out of the alveoli matters because the alveolar wall is extremely thin and easily damaged by inflammation, and any inflammation that thickens it slows diffusion.

Smoking breaks the first line of defence. Tar in cigarette smoke paralyses the cilia and, over months and years, destroys the ciliated cells, while the irritants in the smoke make the epithelium produce more mucus. Mucus that cannot be moved accumulates, and the smoker develops the persistent cough that is the body's attempt to clear it. Stagnant mucus is an ideal medium for bacteria, which is why smokers suffer more chest infections. The damage is partly reversible: when a smoker stops, the ciliated epithelium can regenerate and the cough often settles. The same defence can be overwhelmed in other ways. Poultry-house workers breathe air containing a high concentration of ammonia from the litter, which damages the ciliated epithelium, and in cystic fibrosis the mucus is abnormally thick and sticky because the CFTR chloride channel is faulty, so even healthy cilia cannot move it and chronic infection with bacteria such as Pseudomonas aeruginosa follows.

• Goblet cell: a single mucus-secreting cell sitting in the epithelium.
• Mucous gland: a cluster of mucus-secreting cells in the submucosa, with a duct opening onto the epithelial surface.
• Ciliated epithelial cell: a columnar cell carrying many cilia that beat in a coordinated wave.
• Alveolar macrophage: a phagocytic cell on the alveolar surface that engulfs particles, bacteria and used surfactant.
• Smoking: tar paralyses and destroys the cilia and increases mucus production, so mucus collects and chest infections become more likely.
• Cystic fibrosis: the mucus itself is too thick for the cilia to move, so the escalator fails even though the cilia are intact.

Recognising the tissue: slides, photomicrographs and plan diagrams

In a transverse section of the trachea the most obvious feature is the ring of hyaline cartilage, a broad, pale-staining band whose matrix looks smooth and glassy, with chondrocytes sitting in small oval lacunae often in groups of two or four. Inside the cartilage, towards the lumen, lies the smooth muscle, and lining the lumen is the epithelium. That epithelium is pseudostratified ciliated columnar: the nuclei lie at different heights, which makes it look like several layers when in fact every cell rests on the basement membrane. Goblet cells appear as pale, rounded cells among the ciliated cells, and the ducts of mucous glands can be seen crossing the epithelium on their way to the surface.

A bronchus looks like a smaller trachea, but its cartilage is in irregular plates instead of one C-shaped ring and its smooth muscle is more prominent. A bronchiole is easy to tell apart once you know what to look for: no cartilage at all, a thick band of smooth muscle, an epithelium often folded into the lumen, and ciliated columnar or cuboidal cells. An alveolus is little more than a thin wall. The squamous cells may show flattened nuclei, and the red blood cells in the capillaries around it appear as small biconcave discs. In an electron micrograph of the air-blood barrier you can make out the nucleus of an endothelial cell, the fused basement membrane and the two very thin layers of cytoplasm on either side of it.

The practical skill attached to this topic is making a plan diagram of a transverse section of the wall of the trachea or bronchus. A plan diagram shows the outline of the tissue layers and nothing else. Use a sharp pencil, draw single continuous unbroken lines to mark the boundaries between layers, keep the drawing in proportion and make it fill the space available. Do not shade, do not colour, and do not draw individual cells: staining differences and cell detail do not appear in a plan. Label with straight lines that do not cross each other, do not end in arrowheads and touch the structure they name, write the name of the structure rather than a description of what it does, and give the drawing a title such as 'transverse section of the wall of the trachea'.

Sizes are read from images with magnification = image size / actual size, so actual size = image size / magnification. On a photomicrograph taken at a magnification of x200, a band of cartilage that measures 24 mm across in the image must be 24 / 200 = 0.12 mm in reality, and because 1 mm = 1000 µm that is 120 µm. The same relationship works in reverse: if you know the true thickness of the wall, divide the image measurement by it to find the magnification. Convert both measurements to the same unit before dividing, and if the question asks for a percentage change or a ratio, write the division out so that the examiner can see where each number came from.

Ventilation: changing the volume of the thorax to move air

Ventilation is the movement of air into and out of the lungs. Air moves because of a pressure difference, and the pressure difference is produced by changing the volume of the thorax. During inspiration the diaphragm, a dome-shaped sheet of muscle supplied by the phrenic nerve, contracts and flattens, and the external intercostal muscles contract to raise the ribs and swing them upwards and outwards. The volume of the thorax increases, so the pressure inside it falls below atmospheric pressure, and air flows down the pressure gradient through the airways into the alveoli. Because the airways are wide, only a very small pressure difference is needed to move a large volume of air.

Quiet expiration is largely passive. The muscles of inspiration relax, the ribs fall, the abdominal organs push the diaphragm back up into its dome shape, and the elastic fibres in the lungs and airways recoil. The volume of the thorax falls, the pressure inside rises above atmospheric pressure and air is pushed out. Forced expiration, as in blowing out a candle or coughing, uses the internal intercostal muscles and the muscles of the abdominal wall to squeeze the thorax and push the diaphragm up further and faster.

The lungs follow the movements of the thorax because of the pleural membranes. The visceral pleura is attached to the surface of the lung and the parietal pleura lines the inside of the thorax, and a thin film of pleural fluid between them holds the two together by surface tension. The lung is therefore pulled outwards when the chest wall moves. The pressure in the pleural cavity is slightly below atmospheric pressure, which keeps the lungs partly inflated even at the end of a full expiration. If air gets into the pleural cavity, for example through a stab wound or a fractured rib, that seal is lost and the lung collapses because nothing holds it against the chest wall. This is a pneumothorax, and it is a medical emergency.

A bell-jar lung model demonstrates the principle: a glass jar stands for the thorax, a tube with a Y-piece stands for the trachea and bronchi, two balloons stand for the lungs, and a rubber sheet across the bottom stands for the diaphragm. Pulling the sheet downwards increases the volume inside the jar, the pressure inside falls below atmospheric pressure and the balloons inflate; pushing it up deflates them. The model is useful because it isolates one idea, but it is not the real thing. It has no ribs, no intercostal muscles and no pleural membranes, the balloons have smooth walls instead of millions of alveoli, and it does not show that the airway must stay open for air to move at all. Criticising a model in these terms is exactly what evaluation questions look for.

Gas exchange at the alveolus: diffusion down a steep gradient

Gas exchange between the air in the alveoli and the blood in the capillaries takes place by diffusion. Air arriving in the alveoli is rich in oxygen, while the blood arriving in the pulmonary capillaries has just returned from the tissues and is poor in oxygen, so oxygen diffuses from the alveolar air, through the fluid lining, the squamous epithelium, the basement membrane and the capillary endothelium, into the plasma and then into the red blood cells. Carbon dioxide moves the other way, from the blood into the alveolar air, because the blood reaching the lungs has a higher concentration of carbon dioxide than the air in the alveoli.

Four features of the alveolus make this diffusion rapid. It has a large surface area: roughly 300 million alveoli give a total surface area of around 70 m2 in an adult, many times the surface area of the body itself. The diffusion distance is very short: the barrier is one squamous epithelial cell plus one endothelial cell, less than a micrometre thick in total. The surface is moist, so the gases dissolve in the fluid film before they diffuse, which they must do to cross the membrane. And the alveolus has a rich blood supply, so blood is constantly carrying oxygen away and bringing more carbon dioxide. Carbon dioxide also diffuses about twenty times more readily than oxygen through the same tissue, because it is far more soluble in water.

These ideas are collected into one relationship: the rate of diffusion across the alveolar wall is proportional to (surface area x difference in concentration) / thickness of the surface. That single expression answers almost every question on the topic. Doubling the surface area doubles the rate, halving the thickness doubles the rate, and a larger difference in concentration between the air and the blood gives a faster rate. It also separates the lung diseases neatly: pulmonary fibrosis and oedema increase the thickness of the barrier, while emphysema and lung cancer destroy its surface area.

The gradient has to be maintained, because diffusion stops as soon as the concentrations on the two sides become equal. Two processes keep it steep. Ventilation replaces the air in the alveoli with fresh air, so the oxygen concentration in the alveolar air stays higher than in the blood and the carbon dioxide concentration stays lower. Blood flow through the pulmonary capillaries removes the oxygen that has diffused in and brings more blood loaded with carbon dioxide. At rest, blood passes through the pulmonary capillaries in well under a second and the blood leaving the lungs is normally almost fully saturated with oxygen. During hard exercise the blood spends less time in the capillaries, and in disease, when the barrier is thickened or the surface area is reduced, blood can leave the lungs without becoming fully saturated.

Surface area to volume ratio: why there are millions of small alveoli

Surface area to volume ratio is the surface area of an object divided by its volume, given as a ratio such as 6:1 or simply as the number of square units of surface per cubic unit of volume. A cube with sides of 1 cm has a surface area of 6 x 1 x 1 = 6 cm2 and a volume of 1 cm3, so its surface area to volume ratio is 6:1. A cube with sides of 2 cm has a surface area of 6 x 2 x 2 = 24 cm2 and a volume of 8 cm3, so its ratio is 3:1. Doubling the size of the object halved the ratio, because surface area is proportional to the square of the length while volume is proportional to the cube.

This matters because gas exchange depends on the surface across which the gases diffuse, while the demand for oxygen depends on the volume of respiring tissue. A large organism therefore has a problem: its surface area to volume ratio is small, and its outer surface alone could never supply all of its cells by diffusion. A mammal solves it by folding the exchange surface inside the body and by making the exchange units small and numerous. Dividing one large sphere into millions of tiny spheres leaves the volume almost unchanged but multiplies the total surface area enormously, and that is exactly what the alveoli do. Having the surface inside the body also keeps it moist, reduces evaporative water loss and protects it from damage.

Very small animals do not need this. An insect has a tracheal system: air enters through valves called spiracles and travels along a branching network of tracheae and fluid-filled tracheoles that carry it directly to the tissues, so oxygen reaches the cells without ever travelling in blood. That system works only because an insect is small enough for the tubes to reach every cell, and it is one reason insects cannot grow very large. A fish uses the opposite strategy of exposing a very large surface to the medium: four gill arches carrying thousands of fine gill lamellae, with the water flowing over the lamellae in one direction and the blood flowing through them in the other. Because the two flows are countercurrent, blood always meets water that contains more oxygen than itself, so oxygen keeps diffusing in along the whole length of the lamella instead of only at the start of it.

Questions that ask you to compare two exchange surfaces are almost always asking about the same three things: how large the surface is, how thin it is, and how the concentration difference across it is kept large. Answer under those three headings and you cannot go far wrong. If the question supplies measurements, calculate the ratio properly. For a sphere, surface area = 4 x pi x r^2 and volume = (4 / 3) x pi x r^3, so the ratio simplifies to 3 / r, which shows that the ratio falls as the radius grows. Give ratios as numbers with the units cancelled, for example 6:1 rather than 6 cm2:1 cm3.

When gas exchange fails, and how it is measured

Emphysema is a condition in which the walls between adjacent alveoli break down, so that many small alveoli merge into a few large air spaces. The total surface area available for diffusion falls, and the rate at which oxygen can enter the blood falls with it. Emphysema is part of chronic obstructive pulmonary disease (COPD), and its main cause is smoking: cigarette smoke attracts neutrophils to the lungs, the neutrophils release the enzyme elastase, and elastase digests the elastin of the alveolar walls. A small number of people inherit alpha-1-antitrypsin deficiency, in which the normal inhibitor of elastase is missing, so they develop emphysema early even if they have never smoked. Because the elastic fibres are destroyed as well, the lungs lose their recoil, the patient cannot empty them properly, the chest becomes barrel-shaped and expiration has to be driven by the muscles of the abdominal wall.

In asthma the smooth muscle in the walls of the bronchioles contracts, the epithelium becomes inflamed and swollen, and extra mucus is secreted, so airflow is obstructed, especially on expiration. This produces the characteristic wheeze and a fall in the volume of air that can be forced out in one second. The obstruction is caused by muscle contraction and inflammation rather than by destruction of tissue, so it is reversible: the drugs used are bronchodilators such as salbutamol, which relax the smooth muscle, together with corticosteroids that reduce the inflammation. Pulmonary fibrosis is a different problem again. Scar tissue forms in the alveolar walls and thickens the air-blood barrier, so although the surface area is unchanged the diffusion distance is much greater and the rate of diffusion falls. Asbestosis, caused by inhaling asbestos fibres, and silicosis, caused by inhaling fine silica dust in mining and stone-working, are two well-known occupational forms of pulmonary fibrosis.

Lung function is measured with a spirometer, which produces a trace of volume against time from which tidal volume, vital capacity and breathing rate can be read. A forced expiration gives two further values: the forced expiratory volume in one second (FEV1) and the forced vital capacity (FVC), the total volume that can be forced out. Their ratio is the key measurement. In an obstructive disease such as asthma or emphysema the airways are narrowed, so FEV1 falls much more than FVC and the FEV1/FVC ratio is reduced. In a restrictive disease such as fibrosis both values fall, so the ratio stays about the same or even rises. Interpreting traces of this kind is why spirometer data appear so often in practical and data-handling questions.

Other measurements describe the blood rather than the air. A pulse oximeter clipped to a finger estimates the percentage saturation of haemoglobin with oxygen, and blood gas analysis of an arterial sample gives the partial pressures of oxygen and carbon dioxide directly. The same reasoning applies outside hospital. At high altitude the atmospheric pressure is lower, so the partial pressure of oxygen in the air is lower, the difference in concentration across the alveolar wall is smaller and haemoglobin leaves the lungs less saturated. The body responds by increasing ventilation, which is one reason people breathe more deeply when they first arrive in the mountains; full acclimatisation takes days, and going up too quickly causes altitude sickness. The same argument explains why a patient with emphysema becomes breathless sooner in the mountains than at sea level.

• Emphysema: alveoli merge, surface area falls, elastic recoil is lost, expiration becomes an active effort.
• Asthma: smooth muscle contracts, the epithelium becomes inflamed and mucus increases, and the obstruction is reversible.
• Fibrosis (asbestosis, silicosis): scar tissue thickens the air-blood barrier, so the diffusion distance increases while the surface area stays the same.
• FEV1/FVC is reduced in obstructive disease and normal or slightly raised in restrictive disease.
• Pulse oximetry and arterial blood gas analysis measure the gas content of the blood, not the volumes in the lungs.