2: Embryology, anatomy, and physiology of the lung

Embryology, anatomy, and physiology of the lung


atrial septal defect
carbonic anhydrase
carbon dioxide
chronic obstructive pulmonary disease
cerebrospinal fluid
functional residual capacity
hydrogen ion
carbonic acid
bicarbonate ion
mucociliary escalator
non‐noradrenergic, non‐cholinergic
nitric oxide
primary ciliary dyskinesia
partial pressure of carbon dioxide
partial pressure of oxygen
respiratory quotient
sulphur dioxide
ventricular septal defect


The respiratory system’s main role is to provide oxygen (O2) that is required for glycolysis, and the removal of the waste product of respiration, carbon dioxide (CO2). This involves two separate processes: (1) mechanical ventilation whereby air is moved into and out of the lungs, and (2) gas exchange across the alveolar‐capillary membrane.

The respiratory system also has an important role in acid‐base balance, the defence against airborne pathogens, and in phonation, which is essential for audible speech. The conversion of angiotensin 1 to angiotensin 11 occurs in the lungs as does the deactivation of bradykinin, serotonin, and various drugs, including propranolol.

The lungs act as a reservoir of 500 ml blood and therefore participate in heat exchange. The lungs filter and lyse microemboli from the veins, preventing them from reaching the systemic circulation.

Development of the respiratory system

The lungs are not required for respiration in utero, but start working as soon as the baby is born and is independent from its mother. The development of the lungs starts in week three of the embryonic period (3–16 weeks), continues through the foetal period (16–38 weeks), beyond birth, and into childhood. During intrauterine life, the lungs are an important source of amniotic fluid, producing around 15 ml kg−1 of body weight, which flows out via the trachea or is swallowed.

Development of the lungs

During the embryonic period, the structures of the respiratory system are formed: the trachea, bronchial tree, blood vessels, nerves, lymphatics, and the structures of the thoracic cage (Figure 2.1). In the latter part of the second trimester and during the third trimester, there is functional development, with lung maturation and the production of surfactant. Five phases of structural lung development are recognised. In the embryonic phase (3–16 weeks), at approximately 28 days after conception, lung development begins with the formation of the sulcus laryngotrachealis in the lower part of the pharynx. At 30 days, a bud, called the true lung primordium, forms from the lower part of the foregut, but remains in communication with it. The oesophagotracheal ridges then fuse to form the oesophagotracheal septum, which divides the oesophagus from the trachea. Failure of the formation of this septum occurs in 1 : 3000 births and results in the formation of a trachea‐oesophageal fistula.

Diagram of stages of lung development from embryonic period (3–8 weeks) to pseudo-glandular period (5–16 weeks), to canalicular period (16–26 weeks), to saccular period (26–40 weeks), to alveolar period (to childhood).

Figure 2.1 Stages of lung development.

The diaphragm develops in the third week after fertilisation, with transverse and longitudinal folding. The septum transversum is the primitive central tendon and forms in the cervical region and migrates downwards, therefore the innervation is from the phrenic nerve that originates from the cervical spinal cord.

Failure of one of the pleuroperitoneal membranes to close results in a congenital diaphragmatic hernia which occurs in 1 : 2000 births. It occurs more commonly on the left side and results in the intestinal contents moving up into the left hemithorax, compromising lung development resulting in lung hypoplasia. Surgical repair carries a high mortality.

Normal lung development depends on the interaction between the epithelium and the mesenchymal tissue which lies beneath it. During the pseudoglandular period of the embryonic phase (5–16 weeks), there is an asymmetrical subdivision of the lung primordium into the two buds which will form the main bronchi. The smaller left main bronchus is directed more acutely away from the trachea while the larger right main bronchus leads more directly from the trachea. The two main bronchi subdivide unequally, giving rise to three lobes on the right and two lobes on the left.

Progressive branching during the embryonic phase results in the formation of the first 16 generations of the conducting airways, composed of the trachea, bronchi, bronchioles, and terminal bronchioles. Differentiation of the epithelium derived from the endoderm, with formation of cilia in the proximal airways, occurs at 13 weeks and is controlled by the mesenchyme beneath it. This ciliated epithelium lines the entire conducting airway system and is important in host defence. In primary ciliary dyskinesia (PCD), the ciliary structure is abnormal, and the consequences are significant, as discussed in Chapter 12. The innervation of the lungs is derived from the ectoderm while the vascular structures, smooth muscle, cartilage, and connective tissue are derived from the mesoderm.

During the canalicular period (16–26 weeks), there is further branching of the bronchial tree, with the terminal bronchioles dividing into the respiratory bronchioles (generations 20–22), which further subdivide into the alveolar ducts (generations 20–22) and finally the alveolar sacs (generation 23). Generations 17–23 are called the respiratory zones and will be responsible for gas exchange. Once the alveolar sacs have been formed, further growth occurs by elongation and widening of the airways.

Type 1 pneumocytes, the main cells of the alveolus, are formed with very thin membranes. There is vascularization, with establishment of the capillary network very close to the type 1 pneumocytes in preparation for the gas exchange. Type 2 pneumocytes, which contain lamellar (or inclusion) bodies, also develop and will eventually synthesise and store surfactant.

At the end of the embryonic period (16 weeks), the pulmonary vessels have developed. The pulmonary circulatory system is smaller than the systemic circulatory system and is formed out of the sixth pharyngeal arch artery and a vessel plexus which originates from the aortic sac. The true sixth aortic arch is only then formed after vessels from the dorsal arch grow into this plexus and there is a connection between the truncus pulmonalis and the dorsal aorta.

During the terminal sac period of foetal development (26–38 weeks), there is further differentiation of the type 1 and type 2 pneumocytes, with progressive thinning of the alveolar walls which will facilitate gas exchange.

At full gestation, there are approximately 20 × 106 alveoli, often called ‘primitive saccules’, which mature during the neonatal period and connect to other alveoli through the pores of Kuhn. The pulmonary arterial network gradually develops a muscle layer during childhood and the capillary network extends and becomes entwined between two alveoli. The lungs continue to develop after birth until the age of 8, with the formation of a total of 300 × 106 mature alveoli.

As the alveoli in the foetus contain fluid and not air, the oxygen tension is low, resulting in pulmonary vasoconstriction and diversion of blood across the ductus arteriosus into the systemic circulation. After the first breath is taken, oxygen enters the alveoli, resulting in an increase in oxygen tension and increased blood flow to the alveoli. Nitric oxide (NO), a potent vasodilator, is secreted by the respiratory epithelium which results in significant vasodilation of the pulmonary blood vessels.

Surfactant is composed of a hydrophilic macromolecular complex of phosphatidylcholine (lecithin), phosphatidylglycerol and hydrophobic surface proteins B and C which project into the alveolar gas and float on the surface of the lining fluid. Surfactant decreases surface tension within the alveoli, preventing the collapse of the alveoli during exhalation. In the absence of surfactant, the alveolus would be unstable and would collapse at the end of each breath. During the latter part of gestation, surfactant production and secretion gradually increase. At 36 weeks of gestation there is sufficient surfactant so that spontaneous breathing can occur and the foetus is viable.

Prematurity carries a high mortality and a significant risk of neonatal respiratory distress syndrome. Corticotrophin stimulates the synthesis of the fibroblast pneumocyte factor from the foetal lung fibroblasts which stimulates surfactant production in type 2 cells. Corticosteroids given antenatally to premature babies will promote lung maturity. Exogenous surfactant can also improve the survival of the premature baby.

Amniotic fluid, originating in the foetal lungs and kidneys, is required for normal lung development. During foetal breathing movements, when the upper airways’ resistance is decreased, diaphragmatic movements help maintain lung liquid volume. Oligohydramnios, called Potter’s syndrome, occurs when there is a decreased volume of amniotic fluid, resulting in lung hypoplasia and renal agenesis. Other causes of lung hypoplasia include congenital diaphragmatic hernia, musculoskeletal abnormalities of the thorax which restrict the full expansion of the thoracic cage, and space‐occupying lesions of the thorax.

The respiratory tract

The upper respiratory tract comprises of the nose, the paranasal sinuses, the epiglottis, pharynx, and larynx (Figure 2.2). The larynx is important in speech. During swallowing, the epiglottis closes the larynx which leads to the trachea, preventing food from entering the respiratory tract. Failure of this process will lead to aspiration of food contents into the lungs.

Diagram of the upper respiratory tract with parts labeled sinus, nasal cavity, nostril, external nose, tongue, larynx, oesophagus, epiglottis, glottis, pharynx, and opening of the eustachian tube.

Figure 2.2 The upper respiratory tract.

The lower respiratory tract begins at the trachea, which corresponds to the lower edge of the cricoid cartilage, at the level of the sixth cervical vertebra. The lower respiratory tract is enclosed within the thoracic cavity which is composed of the sternum anteriorly, the vertebral column posteriorly, the mediastinum, the diaphragm, which divides the thorax from the abdomen, and the ribs with their intercostal spaces (Figure 2.3, Figure 2.4). The bony sternum is divided into the manubrium, the body, and the xiphisternum, which is cartilaginous until late adulthood. The manubrium is joined to the cartilages of the first and second ribs at the level of T3 and T4, and to the body by the manubriosternal joint which lies at T4 and is called the angle of Louis or the sternal angle. This is an important landmark in surface anatomy. The body of the sternum joins the second to seventh ribs at the level of T5–T8.

Surface anatomy of the thorax for male (left) and female (right) with parts labeled jugular notch, clavicle, anterior axillary fold, manubrium, costal margin, rib, etc. Costal arch is indicated on the right anatomy.

Figure 2.3 Surface anatomy of the thorax.

Diagram of the lower respiratory tract with parts labeled larynx, trachea, right main bronchus, left main bronchus, diaphragm, and rib.

Figure 2.4 The lower respiratory tract.

The vertebrosternal, or true ribs, are the first to seventh ribs, and are connected to the sternum by their costal cartilages. Inflammation of the costochondral junction (costochondritis) results in ‘pleuritic’ chest pain which is worse on breathing, movement, and palpation. The eighth, ninth, and tenth ribs are called the vertebrochondral, or false ribs, and are joined to the cartilages of the ribs above. The eleventh and twelfth ribs are called floating or vertebral ribs.

Each rib is composed of a head and a shaft. The head is attached to the body and transverse process of the adjacent vertebra, the intervertebral disc, and the vertebra above (Figure 2.5). The shaft curves forward to join the sternum. The joints between the ribs and vertebra act like a hinge, causing the ribs to move during inspiration.

Diagram of a rib with parts labeled costal groove where the intercostals vein, artery and nerve run; articular facet articulates with the vertebra above; tubercle articulates with equivalent vertebra; etc.

Figure 2.5 Structure of the rib.

The rib cage protects the heart, lungs, and great vessels from damage. Trauma to the chest wall can result in fracture of the shaft of the ribs at the angle of the rib. Multiple rib fractures can result in a ‘flail’ segment which can cause significant difficulty with inspiration. The clavicles protect the first and second ribs which are less likely to fracture than the other ribs.

One in 200 people have a cervical rib which is attached to the transverse process of C7. A cervical rib can press on the brachial plexus and cause neurological symptoms, including paraesthesia of the arms and hands. Pressure on the subclavian artery can cause vascular symptoms.

The intercostal spaces between the ribs contain external and internal intercostal muscles (Figure 2.6). The fibres of the external intercostal muscles pass downwards and forwards between the ribs, while the fibres of the internal intercostal muscles pass downwards and backwards. There is also an incomplete innermost intercostal layer. The intercostal muscles are innervated by the intercostal nerves, which are the anterior primary rami of thoracic nerves. The intercostal veins, arteries and nerves lie in grooves on the under‐surface of the corresponding ribs, with the vein above, the artery in the middle and the nerve below. It is important, therefore, to avoid the underside of the rib when carrying out pleural procedures, but to insert the needle or drain just above the rib into the pleural space.

Diagram of the ribs and intercostal space with parts labeled intercostal nerve, intercostal artery, intercostal vein, external intercostal muscle, internal intercostal muscle, rib, etc.

Figure 2.6 The ribs and intercostal space.

The diaphragm, which means ‘partition’ in Greek, has a central tendon which is attached to the pericardium, and thick skeletal muscle on either side, which separates the thoracic and abdominal cavities. It is the most important muscle of inspiration. Several key structures traverse the diaphragm between the abdomen and thorax. The sternal part of the diaphragm consists of two strips of muscle that arises from the posterior surface of the xiphisternum. The costal part comprises of six muscular strips that originate from the seventh–twelfth ribs and their costal cartilages. The vertebral part of the diaphragm originates from the crura and the arcuate ligaments on both sides. The muscular right crus arises from the bodies and intervertebral discs of the three lumbar vertebrae, and the left crus arises from the bodies and intervertebral discs of the upper two lumbar vertebrae. The medial and lateral arcuate ligaments are thickenings of the fascia overlying the psoas major and the quadratus lumborum respectively.

The inferior vena cava and right phrenic nerve pass through the diaphragm at T8, the oesophagus, branches of the left gastric artery, the gastric vein, and both vagi pass through at T10, and the aorta, thoracic duct, and zygos vein pass behind the diaphragm between the left and right crus at T12 (Figure 2.7). The sympathetic trunk passes through the diaphragm under the medial lumbocostal arch, and branches of the internal thoracic artery and lymphatics pass through the foramina of Morgagni.

Diagram of the diaphragm and the structures that traverse it, with parts labeled xiphisternum, costal part of diaphragm, inferior vena cava, vagi, left phrenic nerve, right crus, oesophagus, aorta, etc.

Figure 2.7 Diaphragm and the structures that traverse it.

The phrenic nerves (C3, C4, and C5) supply motor and sensory innervation to the diaphragm. Pain from irritation of the diaphragm is referred to the corresponding dermatome for C4 at the shoulder. Irritation to the phrenic nerve can cause intractable hiccoughs. The lower intercostal (T5–T11) and subcostal (T12) nerves supply sensory fibres to the peripheral diaphragm. Damage to the phrenic nerve, for example, by a tumour, will result in a unilateral diaphragmatic palsy, as discussed in Chapter 9.

The blood supply to the diaphragm is from the pericardiophrenic, musculophrenic, lower internal intercostal and inferior phrenic arteries. The superior and inferior phrenic veins drain blood from the diaphragm into the brachiocephalic vein, the azygos vein, the inferior vena cava, and the left suprarenal vein.

Muscles of respiration and mechanical ventilation

The inspiratory muscles are the diaphragm, and the intercostal and the scalene muscles. When they contract to expand the thoracic cavity, there is a decrease in intrapleural and alveolar pressure which creates a pressure gradient between the alveoli and the mouth, resulting in air entering the lungs. Elastic recoil of the lungs and the chest wall results in expiration, which is a passive process, not requiring any muscular activity. Forced expiration, for example, coughing, will require contraction of the abdominal muscles which push the diaphragm upwards.

Inspiration is an active process. The domed diaphragm is the main muscle of inspiration and is positioned high in the thorax at the end of expiration. During quiet breathing, the diaphragm contracts and moves down by 1.5 cm, pushing the abdominal contents down. This increases the intra‐abdominal pressure and pushes the abdominal wall and the lower ribs outwards and downwards. During deep breathing, the diaphragm contracts harder and can move by as much as 6–7 cm.

During quiet breathing, the first rib remains almost motionless and the intercostal muscles elevate and evert the other ribs. The intercostal muscles support the intercostal spaces preventing them from being sucked in during inspiration. The scalene muscles, which insert into the first two ribs, are also active in normal inspiration. Movement of the upper ribs upwards pushes the sternum forward (the pump action), increasing the anterior–posterior diameter of the chest, and as the sloping lower ribs rise, they move out (the bucket handle action), and the transverse diameter of the chest wall increases. At the beginning of inspiration, the inspiratory muscles contract to overcome the impedance offered by the lungs and chest wall. The volume of the thoracic cavity can increase from 1.5 l up to 8 l with deep inspiration.

Diaphragmatic paralysis results in paradoxical movement: as the intercostal muscles contract and the ribs move, the diaphragm is sucked into the chest due to a fall in intrathoracic pressure. In a high cervical cord transection, all the respiratory muscles are paralysed, but when the damage is below the phrenic nerve roots, breathing continues via the diaphragm alone. In infants, the movement of the horizontal ribs cannot increase the volume of the chest, and breathing is reliant on diaphragmatic contraction alone; this is called abdominal breathing. As the infant grows, the ribs become more oblique and contribute to thoracic inspiration.

When the rate of ventilation or the resistance to breathing increases, the scalene muscles, sternocleidomastoids, and serratus anterior, which are called the accessory inspiratory muscles, are recruited to help inspiration. Splinting of the arms, for example, by grasping the edge of the table, will result in contraction of the pectoralis major muscle which will expand the chest further. When ventilation exceeds 40 l min−1, there is activation of the expiratory muscles, especially the abdominal muscles, the rectus abdominis, the external and internal oblique, which speed up recoil of the diaphragm by raising intra‐abdominal pressure.

At functional residual capacity (FRC), the respiratory muscles are relaxed, and the outward recoil of the chest wall exactly balances the inward recoil of the lungs which creates a negative pressure in the space between them (Figure 2.8).

Illustrations of elastic recoil and functional residual capacity, with arrows indicating outward recoil of chest wall, inward recoil of alveoli, and etc. during inspiration (left) and end of expiration (right).

Figure 2.8 Relationship between elastic recoil and functional residual capacity.

In lung fibrosis, the lungs are stiff (decreased lung compliance) and have increased elastic recoil, so the FRC is smaller. In emphysema, the FRC increases due to loss of alveolar tissue, loss of elastic recoil, increase in lung compliance, and air trapping. This leads to the development of a barrel chest. Mouth breathing, as adopted by patients with chronic obstructive pulmonary disease (COPD), decreases the FRC, enabling these patients to inspire.

Dynamic and static lung volumes and their measurements are discussed in detail in Chapter 4. The normal breath is called the tidal volume and is about 500 ml at rest, which is 10% of the vital capacity. At a normal respiratory rate of 15 breaths min−1, the minute ventilation, which is the volume of air entering the lungs each minute is 7500 ml min−1 (500 × 15). Alveolar ventilation is the actual volume taking part in gas exchange every minute. As the dead space is 150 ml, alveolar ventilation is 5250 ml min−1 (7500‐2250 ml/min).

The main resistance to airflow occurs in the upper respiratory tract, especially the nose, pharynx, and the large airways. The intrapleural pressure can be indirectly assessed from oesophageal pressure using a small pressure transducer. During inspiration, the chest wall expands and the intrapleural pressure falls. This increases the pressure gradient between the intrapleural space and the alveoli, stretching the lungs. The alveoli expand, and alveolar pressure falls, creating a pressure gradient between the mouth and the alveoli, causing air to flow into the lungs. During expiration, both intrapleural pressure and alveolar pressure rise. In quiet breathing, the intrapleural pressure remains negative for the whole respiratory cycle, whereas alveolar pressure is negative during inspiration and positive during expiration. Alveolar pressure is always higher than intrapleural pressure because of the recoil of the lungs. It is zero at the end of both inspiration and expiration, and airflow ceases momentarily. When ventilation is increased, the changes in intrapleural pressure and alveolar pressure are greater, and in expiration intrapleural pressure may rise above atmospheric pressure. In forced expiration, such as coughing or sneezing, intrapleural pressure may rise to +8 kPa or more.

Structure of the lungs

The right lung has three lobes and the left lung has two lobes (Figure 2.9). The heart lies close to the left lung which has a cardiac notch. The conducting airways comprise of the trachea which bifurcates at the carina (T4/T5) into the two main bronchi which divide into smaller bronchi, eventually leading to the terminal bronchioles. The bifurcation of the trachea corresponds on the surface anatomy (see Figure 2.3) to the sternal angle or angle of Louis.

Diagram of the lungs with parts labeled right upper lobe, horizontal fissure, right middle lobe, oblique fissure, right lower lobe, left upper lobe, oblique fissure, and left lower lobe.

Figure 2.9 Lobes and fissures of the lungs.

The trachea is a semi‐rigid structure which leads from the oropharynx into the thoracic cavity. The trachea and main bronchi have U‐shaped cartilage linked posteriorly by smooth muscle. The anterior and lateral walls of the trachea are supported by rings of cartilage, but the posterior wall does not have any cartilage and is therefore collapsible. Diseases of the cartilage, such as tracheobronchomalacia, can affect the entire tracheobronchial tree.

The right main bronchus is wider, shorter, and more vertical than the left main bronchus, so inhaled material is more likely to enter the right main bronchus. The left main bronchus is longer and leaves the carina at a more abrupt angle. The right lung is divided by the horizontal and oblique fissures into the upper, middle, and lower lobes. The left lung is divided into the upper and lower lobes by the oblique fissure. The vessels, nerves, and lymphatics enter the lungs on their medial surfaces at the hilum. Each lobe is divided into several wedge‐shaped bronchopulmonary segments with their apices at the hilum and bases at the lung surface. Each bronchopulmonary segment has a bronchus, artery, and vein (Figure 2.10).

Illustration of bronchopulmonary segments, including left lower lobe, right lower lobe, lingula, left upper lobe, right middle lobe, and right upper lobe. Trachea and subdivisions of each segment are indicated.

Figure 2.10 Bronchopulmonary segments.

Each lung is lined by visceral pleura which is continuous with the parietal pleura, lining the chest wall, diaphragm, pericardium, and mediastinum. In health, the space between the parietal and visceral layer is very small with a few millilitres of pleural fluid. The right and left pleural cavities are separate and each extends as the costodiaphragmatic recess below the lungs. The parietal pleura is segmentally innervated by intercostal nerves and by the phrenic nerve (C3, C4, and C5), so pain from pleural inflammation is often referred to the chest wall or shoulder tip. The visceral pleura lacks sensory innervation.

The main bronchi divide into the three main lobar bronchi on the right (upper, middle, and lower) and into two lobar bronchi on the left (upper and lower). These lobar bronchi divide further into segmental bronchi (generations 3 and 4) which continue to divide further into 22 generations, each successive generation approximately doubling in number. Generations 5–11 are small bronchi, the smallest measuring 1 mm in diameter. The lobar, segmental, and small bronchi are supported by irregular plates of cartilage, with bronchial smooth muscle forming overlapping helical bands. The muscle coat becomes more complex distally as the cartilaginous plate becomes more fragmentary and contributes 20% to the thickness of the walls in the distal airways.

The conducting airways from the trachea to the respiratory bronchioles are lined with ciliated columnar epithelial cells which become flatter through successive generations. The cilia beat synchronously, with a whip‐like action, and waves of contraction pass in an organised fashion from cell to cell so that material trapped in the sticky mucus layer above the cilia is moved upwards and swallowed. The mucociliary escalator (MCE) is an important part of the lungs’ defences. The larger bronchi have acinar mucus‐secreting glands in the submucosa. These and goblet cells secrete mucus and become hypertrophied in chronic bronchitis. The function of the conducting airways is the filtration and humidification of air. Beyond this, there is a gradual transition from conduction to gas exchange.

Bronchioles, which start at generation 12, have no cartilage in their walls and are embedded in lung tissue and kept open by the tethering force of elastic recoil. Terminal bronchioles (generation 16) lead to respiratory bronchioles (generations 17–19), which represent the transition zone between the conducting airways and the gas‐exchange part, containing ciliated and non‐ciliated cells, and a well‐marked muscle layer in their walls. The respiratory bronchioles lead to alveolar ducts and finally to the alveolar sacs (generation 23) which are entirely composed of blind‐ending alveoli. The elastic tissue in the parenchyma enables the lungs to stretch when inflated and recoil during expiration.

An adult male has approximately 300 million alveoli. These are irregular polyhedrons measuring 0.1–0.2 mm in diameter. The number of alveoli depends on the height of the individual, and the size of the alveolus depends on the volume of air in the lungs. The acinus is the unit of respiratory function distal to the terminal bronchioles, comprising of the respiratory bronchioles, the alveolar ducts, and the alveoli. Many acinar together form a pulmonary lobule, which is separated by septae. The connections between these units lead to structural interdependence, which prevents the collapse of an individual unit, which is kept open by the expansion of the surrounding acinar.

Alveoli are lined by a thin layer of unciliated, squamous epithelial cells, of which there are two types. Type 1 pneumocytes have flattened processes that extend to cover most of the internal surfaces of the alveoli and do not contain any organelles. Type 1 pneumocytes rest on the basement membrane and interface closely with the capillary membrane, forming the alveolar‐capillary unit where gas exchange occurs (Figure 2.11). This membrane is less than 0.4 μm, facilitating the easy movement of gases from the alveoli to the capillaries. The interstitial space contains pulmonary capillaries, elastin, and collagen fibres. This interface is affected in pulmonary fibrosis and pulmonary oedema.

Diagram of alveolar‐capillary unit with lines indicating capillary, capillary endothelium, basement membrane, type I pneumocyte, alveolus, red blood corpuscle, and type II pneumocyte.

Figure 2.11 Alveolar‐capillary unit.

Type 2 pneumocytes are less numerous, make up only a small proportion of the alveolar surface area, and are found at the junction between alveoli. They are round, have large nuclei, microvilli, and lamellar (inclusion) bodies which store and secrete surfactant, which reduces surface tension in the alveolar fluid as discussed later. Surfactant also plays a part in lung immunity.

Club cells (bronchiolar exocrine cells) are non‐ciliated cells found in the epithelium of the bronchioles close to their junction with alveoli. They have microvilli and contain a lot of smooth endoplasmic reticulum which contains Cytochrome‐P450. They secrete glycosaminoglycans, which are similar in composition to surfactants, into the alveolar space, which prevents alveolar collapse. They also secrete tryptase and uteroglobin. They may act as stem cells, multiplying and differentiating into ciliated epithelial cells. The club cells are the origin of bronchioalveolar carcinoma of the lungs (see Chapter 9).

The conducting airways, with a volume of 150 ml, form the anatomical dead space as they do not participate in gas exchange. The role of the conducting airways is to humidify, warm, and filter the air. Any alveoli that do not participate in gas exchange contribute to the dead space.

Blood supply of the lungs

The lungs and associated structures receive their blood supply from both the systemic and the pulmonary circulations. The pulmonary circulation has a pulmonary vascular resistance of 1/6th of the systemic circulation. The right ventricle, which needs only to generate a mean pulmonary artery pressure of 15–20 mmHg to pump blood through the lungs, is less muscular than the left ventricle.

The main pulmonary trunk arises from the right ventricle and divides into the right and left pulmonary arteries, the landmark for this division being on the left of the sternal angle. These two large pulmonary arteries divide progressively into smaller branches, with the eventual formation of capillaries which run alongside the bronchial tree and carry deoxygenated blood from the entire body to the respiratory bronchioles, alveolar ducts, and ultimately the alveolar sacs. This dense capillary network in the alveolar walls provides an extensive surface area for gas exchange, and is very close to the alveolar surface, so that the distance that O2 needs to diffuse is less than 0.5 μm. The capillary network offers little resistance to blood flow; the capillaries are easily opened as the blood supply increases. The average transit time for a red blood cell to travel through the pulmonary circulation is 0.75 seconds, and during this time it can traverse several alveoli. The oxygenated blood drains into the left atrium through four peripheral pulmonary veins which arise in each lobe of the lung, although the right upper and middle lobe veins unite.

The pulmonary arteries are thinner and are more elastic than the systemic arteries. They transmit deoxygenated blood away from the heart to the lungs at a pressure of 20–30 mmHg. The right pulmonary artery is longer and wider than the left pulmonary artery, passes inferior to the arch of the aorta, and enters the left hilum of the lungs. It is connected to the arch of the aorta by the ligamentum arteriosum which is the fibrous remnant of the ductus arteriosus which closes at birth.

Pulmonary vascular resistance, which determines blood flow, is controlled by neural and non‐neural factors. Efferent fibres from parasympathetic, sympathetic, and non‐adrenergic, non‐cholinergic fibres act on the arterioles. Whereas systemic arterioles dilate in response to hypoxia, resulting in an increase in oxygen delivery, the pulmonary arterioles undergo vasoconstriction in the presence of hypoxia. This diverts blood away from the under‐ventilated areas of the lungs to the well‐ventilated areas. This will occur, for example, when there is consolidation or atelectasis in an area of the lung resulting in reduced ventilation. There is no autoregulation of blood flow in the lungs as occurs in the brain or the kidneys.

Blood flow is greater at the lung base compared to the apex, partly due to gravity. Ventilation is also greater at the base, but the difference in the perfusion gradient is greater than the ventilation gradient, so that in a normal lung the bases are effectively over‐perfused and the apices over‐ventilated.

The bronchial arteries carry less than 1% of the cardiac output, arise from the descending aorta and supply blood to the trachea and the entire conducting system, down to the terminal bronchioles, but do not participate in gas exchange. They also supply the pulmonary vessels, nerves, interstitium, and pleura. After supplying the conducting airways, the deoxygenated blood drains into radicles of the pulmonary vein and then into the left atrium, contributing 2–5% to the right‐to‐left physiological shunt. Chronic pulmonary inflammation, for example, due to recurrent infections as may occur in a patient with bronchiectasis, can result in hypertrophy of the bronchial arteries and can be a cause of major haemoptysis. This can be treated with therapeutic bronchial artery embolisation.

Nervous supply of the lungs

The lungs are innervated by sympathetic and parasympathetic nerves which combine to form a nerve plexus behind the hila. The vagi contain parasympathetic fibres to the heart, motor fibres to the larynx and pharynx, and sensory secretomotor efferent nerves to the bronchial mucosa which are responsible for the cough reflex. The vagi also contain non‐cholinergic fibres. The right recurrent laryngeal nerve arises as the vagus crosses anterior to the subclavian artery, hooks around that vessel and ascends between the trachea and oesophagus. The left recurrent laryngeal nerve arises as the vagus crosses the left side of the arch of the aorta, hooks around the inferior side of the arch to the left of the ligamentum arteriosum, and then ascends on the right side of the arch between the trachea and oesophagus. This nerve is liable to damage from tumours in the left lung which will result in hoarseness (see Chapter 9).

The sympathetic fibres arise from the second–fourth thoracic ganglia of the sympathetic trunk and enter the thorax anterior to the necks of the ribs. The thoracic part of each trunk has a dozen ganglia, the first of which is often found with the inferior cervical ganglion to form the stellate ganglia. Pre‐ganglionic fibres from segments T1–T6 of the sympathetic chain supply the heart, coronary vessels and bronchial tree. The main visceral branches are the three splanchnic nerves. Pain fibres from the lungs and other thoracic structures travel to the spinal cord. The smooth muscle is supplied by a few sympathetic, noradrenergic fibres, which do not significantly affect smooth muscle tone. The smooth muscle contains β‐2 adrenergic receptors which cause relaxation when stimulated by circulating adrenaline.

Lymphatics of the lungs

Lymph drains via superficial and deep lymphatic plexuses. The deep lymphatic plexus originates from between the alveoli and travels alongside the bronchopulmonary bundle to bronchopulmonary nodes at the hilum, then to the tracheobronchial nodes at the bifurcation of the trachea, which drains into the tracheal or paratracheal nodes. The superficial lymphatic plexus is subpleural. The visceral nodes drain the lungs, pleura and mediastinum. Mediastinal nodes in the superior mediastinum receive lymphatics from the thymus, pericardium, and heart. The efferents of the tracheal and mediastinal nodes form a bronchomediastinal trunk on each side of the trachea. Some lymph from the lower lobe drains to the posterior mediastinal nodes which drain directly into the thoracic duct.

The thoracic duct extends from the abdomen to the neck where it drains into the right and left brachiocephalic veins. Lymphatics have valves to prevent backflow. The total flow of lymph from the lungs is 0.5 ml min−1. The lymph nodes may become enlarged in lung malignancies, infections, for example, Mycobacterium tuberculosis infection, and granulomatous conditions, such as sarcoidosis.

Control of breathing

Central control

The control of breathing is complex and conducted through inspiratory and expiratory neurones in the pons and lower medulla. The ventrolateral medulla contains a column of neurones called the ventral respiratory group which extends from the lateral reticular nucleus to the nucleus ambiguous. This is divided into four groups: (1) the caudal group which contains both inspiratory and expiratory neurones; (2) the rostral group which controls the functions of the larynx and pharynx; (3) the pre‐Botzinger complex which contains inspiratory neurones (often called the Central Pattern Generator); and (4) the Botzinger complex which contains expiratory neurones. The respiratory rhythm begins with these associated groups of neurones generating regular bursts of activity lasting a few seconds, which stimulate the diaphragm and external intercostals to initiate inspiration. The antagonistic expiratory neurones then fire for a few seconds to cease inspiration and to initiate expiration. This interaction between inspiratory and expiratory neurones results in spontaneous ventilation or eupnoea.

The medulla also contains the dorsal respiratory group which lies close to the nucleus tractus solitarium and contains inspiratory neurones. These neurones receive input from the higher centres, including the cortex and hypothalamus via cranial nerves IX and X to modulate the response of the ventral respiratory group (Figure 2.12). The respiratory rhythm can be altered in response to smell, temperature, and emotion. The neurones of the dorsal respiratory group also receive feedback from central and peripheral chemoreceptors. Feedback from the stretch receptors in the lungs via the vagi is important in ceasing inspiration as lung volume increases. Voluntary control of breathing is mediated by motor nerves from the cortex contained in the pyramidal tracts which bypass the dorsal respiratory centre and directly stimulate the muscles of respiration.

Flow diagram for control of breathing from cortex to hypothalamus, to pneumotaxic centre in pons, to dorsal and ventral respiratory groups, to spinal cord, to respiratory muscles. Arrow from cortex points to spinal cord.

Figure 2.12 Control of breathing.

Congenital central hypoventilation syndrome, called Ondine’s curse, is a rare cause of fatal apnoea during sleep due to the failure of the autonomic control of respiration. Trauma to the brain can also result in a similar presentation.

Lung receptors and reflexes

There are various receptors throughout the conducting airways and alveoli which respond to irritants, stretch, inflammation, oedema, and position. These receive and send signals through the vagi.

Slow‐adapting stretch receptors are located within the smooth muscle of the bronchial walls and fire with the continuing stimulation caused by distension of the lungs. The efferent nerves from the stretch receptors ascend via the vagi and result in shorter and shallower inspiration, delaying the next cycle of inspiration.

Irritant receptors are found between the epithelial cells in the bronchial smooth muscle throughout the airways and are stimulated by smoke, dust, and noxious gases, such as SO2, O3, and by histamine. These rapid‐adapting receptors receive a parasympathetic bronchoconstrictor nerve supply of myelinated fibres from the vagi, which act via acetylcholine and muscarinic type 3 receptors. Stimulation of the irritant receptors in the smaller airways results in the deep sighs which occur periodically at rest and which prevent the lungs from collapsing. The receptors in the trachea are responsible for the powerful cough reflex, which expels particles and is an important part of the lung’s defence system. Stimulation of these receptors also causes reflex constriction of the larynx and bronchi.

Juxtapulmonary (J) receptors, which are located on the alveolar and bronchial walls close to the capillaries, are stimulated by pulmonary congestion, pulmonary oedema, microemboli, and inflammatory mediators, such as histamine. Their afferents are small unmyelinated C‐fibres or myelinated nerves in the vagi. Activation of the J receptors results in depression of somatic and visceral activity, with apnoea, rapid shallow breathing, a fall in heart rate, a fall in blood pressure, laryngeal constriction, and relaxation of skeletal muscles.

Proprioreceptors are found in the Golgi tendon organs, muscle spindles, and joints of the respiratory muscles, but not the diaphragm, and the afferents lead to the spinal cord via dorsal roots. These proprioreceptors are stimulated by shortening and load in respiratory muscles and are important during exercise.


Chemical control of ventilation is mediated via central chemoreceptors which detect arterial partial pressure of carbon dioxide (PCO2) and pH, and peripheral chemoreceptors which detect PCO2, pH, and partial pressure of oxygen (PO2) and feedback to the neurones in the dorsal respiratory group.

The central chemoreceptors lie near the venterolateral surface of the medulla, near the exit of cranial nerves IX and X. A tight, endothelial layer forms the blood‐brain barrier which separates the cerebrospinal fluid (CSF) from blood and is impermeable to charged molecules such as hydrogen ions (H+) and bicarbonate ions (HCO3), but permeable to CO2, which can easily cross the barrier. The pH of CSF is therefore determined by arterial PCO2 and CSF HCO3, and not affected directly by changes in blood pH. CSF contains little protein, so its buffering capacity is low. Therefore, a small change in the PCO2 will result in a large change in the pH in CSF. The neurones of the central chemoreceptors are therefore very sensitive to CO2, and an increase in PCO2 in the CSF will result in an increase in minute ventilation in a linear fashion. These central chemoreceptors are therefore less sensitive to H+ than they are to CO2. The central chemoreceptors are responsible for about 80% of the response to CO2. The response time is 20 seconds as CO2 needs to diffuse across the blood‐brain barrier. The central chemoreceptors do not respond to a drop in PO2 (hypoxia).

An increase in alveolar PCO2 above the normal value of 5.3 kPa results in a linear increase in minute ventilation (litres ventilated/minute) by about 15–25 l min−1 for each kPa rise in PCO2. There is considerable variation between individuals. Athletes and patients with chronic respiratory disease often have a reduced response to PCO2. If PCO2 increases above 10 kPa, ventilation decreases due to direct suppression of the central neurones. Metabolic acidosis shifts the CO2‐ventilation response curve to the left whereas a metabolic alkalosis shifts it to the right.

There is little increase in ventilation until the PO2 falls below 8 kPa (60 mmHg). The effect of reducing PO2 is potentiated if the PCO2 rises, so there is a synergistic relationship between the effects of PO2 and PCO2.

The peripheral chemoreceptors lie within the carotid and aortic bodies, both of which receive high blood flow relative to their size and respond within seconds to small changes in PCO2, pH, and PO2 by increasing the rate of firing, which will result in an increase in ventilation, especially if the PO2 drops below 8 kPa. The carotid body is a 2 mg structure located at the bifurcation of the common carotid artery, just above the carotid sinus and contains type 1 glomus cells and type 2 sheath cells. The glomus cells contain dense granules of neurotransmitters and the sheath cells protect and support the glomus cells. The carotid body is innervated by the carotid sinus nerve, which leads to the glossopharyngeal nerve and responds to an increase in PCO2 or H+ and a decrease in PO2 by increasing ventilation. The aortic bodies are distributed around the aortic arch, are innervated by the vagi, and they too respond to a drop in PO2 and an increase in PCO2 and H+.

Adaptation of the chemoreceptors occurs in chronic respiratory disease and in those living at high altitude. When hypercapnia is prolonged, for example, in COPD, CSF pH gradually returns to normal with an adaptive and compensatory increase in HCO3 which is transported across the blood‐brain barrier. The drive to breathe from the central chemoreceptor is consequently reduced, even though the PCO2 is still high. There is also reduced sensitivity to further increases in PCO2, so that a patient’s ventilation is mainly controlled by the level of PO2, which is called the hypoxic drive. If the hypoxic drive is suppressed by giving O2, then this decreases ventilation. Therefore, in these patients, O2 must be given cautiously, starting at a low level of 23–28%, with the lowest amount of inspired oxygen above 21% (room air) that is possible.

At high altitude, ventilation is stimulated by the low atmospheric PO2 which results in hypocapnia and alkalosis and decreased ventilation. Over a few days of acclimatisation, the pH of CSF returns to normal due to HCO3 transport out of the CSF, even though the PCO2 remains low, and consequently ventilation increases again. Over a longer period, blood pH returns to normal due to renal compensation.

Transport of oxygen

Oxygen is not very soluble in plasma and is therefore bound to haemoglobin (HB) to form oxyhaemoglobin and is transported from the lungs to all tissues. The oxygen capacity of haemoglobin is the amount of O2 bound to HB, with each gram of HB combining with approximately 1.34 ml O2. Therefore, in an individual with a normal HB of 150 g l−1, blood will contain 200 ml l−1 O2. Arterial blood has a PO2 of approximately 13 kPa (100 mmHg) and an O2 saturation of 97%. The oxygen dissociation curve flattens at the higher levels of O2 saturation, therefore hyperventilation and hypoventilation will cause little change in the arterial oxygen content. However, if the PO2 drops below 8 kPa (60 mmHg), there will be a significant reduction in O2 saturation and content.

The affinity of haemoglobin (HB) for O2 depends on pH, PCO2 and temperature and is called the Bohr effect (Figure 2.13). An increase in hydrogen ion (H+) (a decrease in pH), an increase in PCO2 and an increase in temperature, as occurs in metabolically active tissue, result in a shift of the oxygen dissociation curve to the right. A rise in the concentration of 2,3‐diphosphoglycerate, caused by glycolysis in red cells, also results in a right shift. This results in the release of oxygen from HB to the tissues which require oxygen. Conversely, in the alveoli, the lower temperature, lower PCO2, and higher pH result in a left shift of the dissociation curve and in an increased affinity of haemoglobin for O2.

Graph of PO2 vs. oxyhaemoglobin displaying 3 ascending curves for normal pH, DPG, and temperature; decrease in pH and temperature and increase in DPG; and increase in pH and decrease in DPG and temperature.

Figure 2.13 Oxygen‐Haemoglobin Dissociation Curve and the Bohr Effect.

Transport of carbon dioxide

Carbon dioxide (CO2) is 20 times more soluble in plasma than O2 and 10% is carried dissolved in plasma. Some 60% of CO2 is transported as bicarbonate ions. The relationship between pH, PCO2 and HCO3 is described by the Henderson‐Hasselbalch equation:


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Jun 4, 2019 | Posted by in RESPIRATORY | Comments Off on 2: Embryology, anatomy, and physiology of the lung
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