Human Respiratory System

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human respiratory system

human respiratory system, the system in humans that
takes up oxygen and expels carbon dioxide.
The design of the respiratory system

The human gas-exchanging organ, the lung, is located in
the thorax, where its delicate tissues are protected by the
bony and muscular thoracic cage. The lung provides the
tissues of the human body with a continuous flow of
human lungs oxygen and clears the blood of the gaseous waste
The lungs serve as the gas- product, carbon dioxide. Atmospheric air is pumped in
exchanging organ for the process of and out regularly through a system of pipes, called
respiration.
conducting airways, which join the gas-exchange region
with the outside of the body. The airways can be divided
into upper and lower airway systems. The transition
between the two systems is located where the pathways
of the respiratory and digestive systems cross, just at the
top of the larynx.
The upper airway system comprises the nose and the

paranasal cavities (or sinuses), the pharynx (or throat),
human nasal cavity and partly also the oral cavity, since it may be used for
Sagittal view of the human nasal breathing. The lower airway system consists of the
cavity.
larynx, the trachea, the stem bronchi, and all the airways
ramifying intensively within the lungs, such as the intrapulmonary bronchi, the bronchioles,
and the alveolar ducts. For respiration, the collaboration of other organ systems is clearly
essential. The diaphragm, as the main respiratory muscle, and the intercostal muscles of the
chest wall play an essential role by generating, under the control of the central nervous system,
the pumping action on the lung. The muscles expand and contract the internal space of the
thorax, the bony framework of which is formed by the ribs and the thoracic vertebrae. The
contribution of the lung and chest wall (ribs and muscles) to respiration is described below in
The mechanics of breathing. The blood, as a carrier for the gases, and the circulatory system
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(i.e., the heart and the blood vessels) are mandatory elements of a working respiratory system
(see blood; cardiovascular system).
Morphology of the upper airways

The nose
The nose is the external protuberance of an internal space, the nasal cavity. It is subdivided
into a left and right canal by a thin medial cartilaginous and bony wall, the nasal septum. Each
canal opens to the face by a nostril and into the pharynx by the choana. The floor of the nasal
cavity is formed by the palate, which also forms the roof of the oral cavity. The complex shape
of the nasal cavity is due to projections of bony ridges, the superior, middle, and inferior
turbinate bones (or conchae), from the lateral wall. The passageways thus formed below each
ridge are called the superior, middle, and inferior nasal meatuses.
On each side, the intranasal space communicates with a series of neighbouring air-filled
cavities within the skull (the paranasal sinuses) and also, via the nasolacrimal duct, with the
lacrimal apparatus in the corner of the eye. The duct drains the lacrimal fluid into the nasal
cavity. This fact explains why nasal respiration can be rapidly impaired or even impeded
during weeping: the lacrimal fluid is not only overflowing into tears, it is also flooding the
nasal cavity.
The paranasal sinuses are sets of paired single or multiple cavities of variable size. Most of
their development takes place after birth, and they reach their final size toward age 20. The
sinuses are located in four different skull bones—the maxilla, the frontal, the ethmoid, and the
sphenoid bones. Correspondingly, they are called the maxillary sinus, which is the largest
cavity; the frontal sinus; the ethmoid sinuses; and the sphenoid sinus, which is located in the
upper posterior wall of the nasal cavity. The sinuses have two principal functions: because they
are filled with air, they help keep the weight of the skull within reasonable limits, and they
serve as resonance chambers for the human voice.
The nasal cavity with its adjacent spaces is lined by a respiratory mucosa. Typically, the
mucosa of the nose contains mucus-secreting glands and venous plexuses; its top cell layer, the
epithelium, consists principally of two cell types, ciliated and secreting cells. This structural
design reflects the particular ancillary functions of the nose and of the upper airways in
general with respect to respiration. They clean, moisten, and warm the inspired air, preparing it
for intimate contact with the delicate tissues of the gas-exchange area. During expiration
through the nose, the air is dried and cooled, a process that saves water and energy.
Two regions of the nasal cavity have a different lining. The vestibule, at the entrance of the
nose, is lined by skin that bears short thick hairs called vibrissae. In the roof of the nose, the
olfactory bulb with its sensory epithelium checks the quality of the inspired air. About two
dozen olfactory nerves convey the sensation of smell from the olfactory cells through the bony
roof of the nasal cavity to the central nervous system.
The pharynx
For the anatomical description, the pharynx can be
divided into three floors. The upper floor, the
nasopharynx, is primarily a passageway for air and
secretions from the nose to the oral pharynx. It is also
connected to the tympanic cavity of the middle ear
through the auditory tubes that open on both lateral
human pharynx
walls. The act of swallowing opens briefly the normally
Sagittal section of the pharynx.
collapsed auditory tubes and allows the middle ears to be
aerated and pressure differences to be equalized. In the
posterior wall of the nasopharynx is located a lymphatic organ, the pharyngeal tonsil. When it
is enlarged (as in tonsil hypertrophy or adenoid vegetation), it may interfere with nasal
respiration and alter the resonance pattern of the voice.
The middle floor of the pharynx connects anteriorly to the mouth and is therefore called the
oral pharynx or oropharynx. It is delimited from the nasopharynx by the soft palate, which
roofs the posterior part of the oral cavity.
The lower floor of the pharynx is called the hypopharynx. Its anterior wall is formed by the
posterior part of the tongue. Lying directly above the larynx, it represents the site where the
pathways of air and food cross each other: Air from the nasal cavity flows into the larynx, and
food from the oral cavity is routed to the esophagus directly behind the larynx. The epiglottis,
a cartilaginous, leaf-shaped flap, functions as a lid to the larynx and, during the act of
swallowing, controls the traffic of air and food.
Morphology of the lower airways

The larynx
The larynx is an organ of complex structure that serves a dual function: as an air canal to the
lungs and a controller of its access, and as the organ of phonation. Sound is produced by
forcing air through a sagittal slit formed by the vocal cords, the glottis. This causes not only
the vocal cords but also the column of air above them to vibrate. As evidenced by trained
singers, this function can be closely controlled and finely tuned. Control is achieved by a
number of muscles innervated by the laryngeal nerves. For the precise function of the
muscular apparatus, the muscles must be anchored to a stabilizing framework. The laryngeal
skeleton consists of almost a dozen pieces of cartilage, most of them very small,
interconnected by ligaments and membranes. The largest cartilage of the larynx, the thyroid
cartilage, is made of two plates fused anteriorly in the midline. At the upper end of the fusion
line is an incision, the thyroid notch; below it is a forward projection, the laryngeal
prominence. Both of these structures are easily felt through the skin. The angle between the
two cartilage plates is sharper and the prominence more marked in men than in women, which
has given this structure the common name of Adam’s apple.
Behind the shieldlike thyroid cartilage, the vocal cords

span the laryngeal lumen. They correspond to elastic
ligaments attached anteriorly in the angle of the thyroid
shield and posteriorly to a pair of small pyramidal pieces
of cartilage, the arytenoid cartilages. The vocal ligaments
are part of a tube, resembling an organ pipe, made of
elastic tissue. Just above the vocal cords, the epiglottis is
also attached to the back of the thyroid plate by its stalk.
voice-producing apparatus
The cricoid, another large cartilaginous piece of the
The parts of human anatomy that
laryngeal skeleton, has a signet-ring shape. The broad
produce vocal sound.
plate of the ring lies in the posterior wall of the larynx
and the narrow arch in the anterior wall. The cricoid is located below the thyroid cartilage, to
which it is joined in an articulation reinforced by ligaments. The transverse axis of the joint
allows a hingelike rotation between the two cartilages. This movement tilts the cricoid plate
with respect to the shield of the thyroid cartilage and hence alters the distance between them.
Because the arytenoid cartilages rest upright on the cricoid plate, they follow its tilting
movement. This mechanism plays an important role in altering length and tension of the vocal
cords. The arytenoid cartilages articulate with the cricoid plate and hence are able to rotate and
slide to close and open the glottis.
Viewed frontally, the lumen of the laryngeal tube has an hourglass shape, with its narrowest
width at the glottis. Just above the vocal cords there is an additional pair of mucosal folds
called the false vocal cords or the vestibular folds. Like the true vocal cords, they are also
formed by the free end of a fibroelastic membrane. Between the vestibular folds and the vocal
cords, the laryngeal space enlarges and forms lateral pockets extending upward. This space is
called the ventricle of the larynx. Because the gap between the vestibular folds is always larger
than the gap between the vocal cords, the latter can easily be seen from above with the
laryngoscope, an instrument designed for visual inspection of the interior of the larynx.
The muscular apparatus of the larynx comprises two functionally distinct groups. The intrinsic
muscles act directly or indirectly on the shape, length, and tension of the vocal cords. The
extrinsic muscles act on the larynx as a whole, moving it upward (e.g., during high-pitched
phonation or swallowing) or downward. The intrinsic muscles attach to the skeletal
components of the larynx itself; the extrinsic muscles join the laryngeal skeleton cranially to
the hyoid bone or to the pharynx and caudally to the sternum (breastbone).
The trachea and the stem bronchi

Below the larynx lies the trachea, a tube about 10 to 12 cm (3.9 to 4.7 inches) long and 2 cm
(0.8 inch) wide. Its wall is stiffened by 16 to 20 characteristic horseshoe-shaped, incomplete
cartilage rings that open toward the back and are embedded in a dense connective tissue. The
dorsal wall contains a strong layer of transverse smooth muscle fibres that spans the gap of the
cartilage. The interior of the trachea is lined by the typical respiratory epithelium. The mucosal
layer contains mucous glands.
At its lower end, the trachea divides in an inverted Y into the two stem (or main) bronchi, one
each for the left and right lung. The right main bronchus has a larger diameter, is oriented more
vertically, and is shorter than the left main bronchus. The practical consequence of this
arrangement is that foreign bodies passing beyond the larynx will usually slip into the right
lung. The structure of the stem bronchi closely matches that of the trachea.
Structural design of the airway tree
The hierarchy of the dividing airways, and partly also of

the blood vessels penetrating the lung, largely determines
the internal lung structure. Functionally the
intrapulmonary airway system can be subdivided into
three zones, a proximal, purely conducting zone, a
trachea, bronchi, and bronchioles peripheral, purely gas-exchanging zone, and a
of the human airway tree
transitional zone in between, where both functions grade
An X-ray of the human lungs showing
into one another. From a morphological point of view,
the branching of the airway tree.
however, it makes sense to distinguish the relatively
thick-walled, purely air-conducting tubes from those branches of the airway tree structurally
designed to permit gas exchange.
The structural design of the airway tree is functionally important because the branching pattern
plays a role in determining air flow and particle deposition. In modeling the human airway
tree, it is generally agreed that the airways branch according to the rules of irregular
dichotomy. Regular dichotomy means that each branch of a treelike structure gives rise to two
daughter branches of identical dimensions. In irregular dichotomy, however, the daughter
branches may differ greatly in length and diameter. The models calculate the average path
from the trachea to the lung periphery as consisting of about 24–25 generations of branches.
Individual paths, however, may range from 11 to 30 generations. The transition between the
conductive and the respiratory portions of an airway lies on average at the end of the 16th
generation, if the trachea is counted as generation 0. The conducting airways comprise the
trachea, the two stem bronchi, the bronchi, and the bronchioles. Their function is to further
warm, moisten, and clean the inspired air and distribute it to the gas-exchanging zone of the
lung. They are lined by the typical respiratory epithelium with ciliated cells and numerous
interspersed mucus-secreting goblet cells. Ciliated cells are present far down in the airway
tree, their height decreasing with the narrowing of the tubes, as does the frequency of goblet
cells. In bronchioles the goblet cells are completely replaced by another type of secretory cells
named Clara cells. The epithelium is covered by a layer of low-viscosity fluid, within which
the cilia exert a synchronized, rhythmic beat directed outward. In larger airways, this fluid
layer is topped by a blanket of mucus of high viscosity. The mucus layer is dragged along by
the ciliary action and carries the intercepted particles toward the pharynx, where they are
swallowed. This design can be compared to a conveyor belt for particles, and indeed the
mechanism is referred to as the mucociliary escalator.
Whereas cartilage rings or plates provide support for the walls of the trachea and bronchi, the
walls of the bronchioles, devoid of cartilage, gain their stability from their structural
integration into the gas-exchanging tissues. The last purely conductive airway generations in
the lung are the terminal bronchioles. Distally, the airway structure is greatly altered by the
appearance of cuplike outpouchings from the walls. These form minute air chambers and
represent the first gas-exchanging alveoli on the airway path. In the alveoli, the respiratory
epithelium gives way to a very flat lining layer that permits the formation of a thin air–blood
barrier. After several generations (Z) of such respiratory bronchioles, the alveoli are so densely
packed along the airway that an airway wall proper is missing; the airway consists of alveolar
ducts. The final generations of the airway tree end blindly in the alveolar sacs.
The lungs
Gross anatomy
The lung is parted into two slightly unequal portions, a left lung and a right lung, which
occupy most of the intrathoracic space. The space between them is filled by the mediastinum,
which corresponds to a connective tissue space containing the heart, major blood vessels, the
trachea with the stem bronchi, the esophagus, and the thymus gland. The right lung represents
56 percent of the total lung volume and is composed of three lobes, a superior, middle, and
inferior lobe, separated from each other by a deep horizontal and an oblique fissure. The left
lung, smaller in volume because of the asymmetrical position of the heart, has only two lobes
separated by an oblique fissure. In the thorax, the two lungs rest with their bases on the
diaphragm, while their apexes extend above the first rib. Medially, they are connected with the
mediastinum at the hilum, a circumscribed area where airways, blood and lymphatic vessels,
and nerves enter or leave the lungs. The inside of the thoracic cavities and the lung surface are
covered with serous membranes, respectively the parietal pleura and the visceral pleura, which
are in direct continuity at the hilum. Depending on the subjacent structures, the parietal pleura
can be subdivided into three portions: the mediastinal, costal, and diaphragmatic pleurae. The
lung surfaces facing these pleural areas are named accordingly, since the shape of the lungs is
determined by the shape of the pleural cavities. Because of the presence of pleural recesses,
which form a kind of reserve space, the pleural cavity is larger than the lung volume.
During inspiration, the recesses are partly opened by the expanding lung, thus allowing the
lung to increase in volume. Although the hilum is the only place where the lungs are secured to
surrounding structures, the lungs are maintained in close apposition to the thoracic wall by a
negative pressure between visceral and parietal pleurae. A thin film of extracellular fluid
between the pleurae enables the lungs to move smoothly along the walls of the cavity during
breathing. If the serous membranes become inflamed (pleurisy), respiratory movements can be
painful. If air enters a pleural cavity (pneumothorax), the lung immediately collapses owing to
its inherent elastic properties, and breathing is abolished on this side.
Pulmonary segments
The lung lobes are subdivided into smaller units, the pulmonary segments. There are 10
segments in the right lung and, depending on the classification, eight to 10 segments in the left
lung. Unlike the lobes, the pulmonary segments are not delimited from each other by fissures
but by thin membranes of connective tissue containing veins and lymphatics; the arterial
supply follows the segmental bronchi. These anatomical features are important because
pathological processes may be limited to discrete units, and the surgeon can remove single
diseased segments instead of whole lobes.
The intrapulmonary conducting airways: bronchi and bronchioles

In the intrapulmonary bronchi, the cartilage rings of the stem bronchi are replaced by irregular
cartilage plates; furthermore, a layer of smooth muscle is added between the mucosa and the
fibrocartilaginous tunic. The bronchi are ensheathed by a layer of loose connective tissue that
is continuous with the other connective tissue elements of the lung and hence is part of the
fibrous skeleton spanning the lung from the hilum to the pleural sac. This outer fibrous layer
contains, besides lymphatics and nerves, small bronchial vessels to supply the bronchial wall
with blood from the systemic circulation. Bronchioles are small conducting airways ranging in
diameter from three to less than one millimetre. The walls of the bronchioles lack cartilage and
seromucous glands. Their lumen is lined by a simple cuboidal epithelium with ciliated cells
and Clara cells, which produce a chemically ill-defined secretion. The bronchiolar wall also
contains a well-developed layer of smooth muscle cells, capable of narrowing the airway.
Abnormal spasms of this musculature cause the clinical symptoms of bronchial asthma.
The gas-exchange region

The gas-exchange region comprises three compartments: air, blood, and tissue. Whereas air
and blood are continuously replenished, the function of the tissue compartment is twofold: it
provides the stable supporting framework for the air and blood compartments, and it allows
them to come into close contact with each other (thereby facilitating gas exchange) while
keeping them strictly confined. The respiratory gases diffuse from air to blood, and vice versa,
through the 140 square metres of internal surface area of the tissue compartment. The gas-
exchange tissue proper is called the pulmonary parenchyma, while the supplying structures,
conductive airways, lymphatics, and non-capillary blood vessels belong to the non-
parenchyma.
The gas-exchange region begins with the alveoli of the first generation of respiratory
bronchioles. Distally, the frequency of alveolar outpocketings increases rapidly, until after two
to four generations of respiratory bronchioles, the whole wall is formed by alveoli. The
airways are then called alveolar ducts and, in the last generation, alveolar sacs. On average, an
adult human lung has about 480 million alveoli. They are polyhedral structures, with a
diameter of about 250 to 300 μm (1 μm = 0.000039 inch), and open on one side, where they
connect to the airway. The alveolar wall, called the interalveolar septum, is common to two
adjacent alveoli. It contains a dense network of capillaries, the smallest of the blood vessels,
and a skeleton of connective tissue fibres. The fibre system is interwoven with the capillaries
and particularly reinforced at the alveolar entrance rings. The capillaries are lined by flat
endothelial cells with thin cytoplasmic extensions. The interalveolar septum is covered on both
sides by the alveolar epithelial cells. A thin, squamous cell type, the type I pneumocyte, covers
between 92 and 95 percent of the gas-exchange surface; a second, more cuboidal cell type, the
type II pneumocyte, covers the remaining surface. The type I cells form, together with the
endothelial cells, the thin air–blood barrier for gas exchange; the type II cells are secretory
cells. Type II pneumocytes produce a surface-tension-reducing material, the pulmonary
surfactant, which spreads on the alveolar surface and prevents the tiny alveolar spaces from
collapsing. Before it is released into the airspaces, pulmonary surfactant is stored in the type II
cells in the form of lamellar bodies. These granules are the conspicuous ultrastructural features
of this cell type. On top of the epithelium, alveolar macrophages creep around within the
surfactant fluid. They are large cells, and their cell bodies abound in granules of various
content, partly foreign material that may have reached the alveoli, or cell debris originating
from cell damage or normal cell death. Ultimately, the alveolar macrophages are derived from
the bone marrow, and their task is to keep the air–blood barrier clean and unobstructed. The
tissue space between the endothelium of the capillaries and the epithelial lining is occupied by
the interstitium. It contains connective tissue and interstitial fluid. The connective tissue
comprises a system of fibres, amorphous ground substance, and cells (mainly fibroblasts),
which seem to be endowed with contractile properties. The fibroblasts are thought to control
capillary blood flow or, alternatively, to prevent the accumulation of extracellular fluid in the
interalveolar septa. If for some reason the delicate fluid balance of the pulmonary tissues is
impaired, an excess of fluid accumulates in the lung tissue and within the airspaces. This
pathological condition is called pulmonary edema. As a consequence, the respiratory gases
must diffuse across longer distances, and proper functioning of the lung is severely
jeopardized.
Blood vessels, lymphatic vessels, and nerves

With respect to blood circulation, the lung is a complex organ. It has two distinct though not
completely separate vascular systems: a low-pressure pulmonary system and a high-pressure
bronchial system. The pulmonary (or lesser) circulation is responsible for supplying oxygen to
the tissues of the body. Blood, low in oxygen content but laden with carbon dioxide, is carried
from the right heart through the pulmonary arteries to the lungs. On each side, the pulmonary
artery enters the lung in the company of the stem bronchus and then divides rapidly, following
relatively closely the course of the dividing airway tree. After numerous divisions, small
arteries accompany the alveolar ducts and split up into the alveolar capillary networks.
Because intravascular pressure determines the arterial wall structure, the pulmonary arteries,
which have on average a pressure five times lower than systemic arteries, are much flimsier
than systemic arteries of corresponding size. The oxygenated blood from the capillaries is
collected by venules and drained into small veins. These do not accompany the airways and
arteries but run separately in narrow strips of connective tissue delimiting small lobules. The
interlobular veins then converge on the intersegmental septa. Finally, near the hilum the veins
merge into large venous vessels that follow the course of the bronchi. Generally, four
pulmonary veins drain blood from the lung and deliver it to the left atrium of the heart.
The bronchial circulation has a nutritional function for the walls of the larger airways and
pulmonary vessels. The bronchial arteries originate from the aorta or from an intercostal artery.
They are small vessels and generally do not reach as far into the periphery as the conducting
airways. With a few exceptions, they end several generations short of the terminal bronchioles.
They split up into capillaries surrounding the walls of bronchi and vessels and also supply
adjacent airspaces. Most of their blood is naturally collected by pulmonary veins. Small
bronchial veins exist, however; they originate from the peribronchial venous plexuses and
drain the blood through the hilum into the azygos and hemiazygos veins of the posterior
thoracic wall.
The lymph is drained from the lung through two distinct but interconnected sets of lymphatic
vessels. The superficial, subpleural lymphatic network collects the lymph from the peripheral
mantle of lung tissue and drains it partly along the veins toward the hilum. The deep lymphatic
system originates around the conductive airways and arteries and converges into vessels that
mostly follow the bronchi and arterial vessels into the mediastinum.
Within the lung and the mediastinum, lymph nodes exert their filtering action on the lymph
before it is returned into the blood through the major lymphatic vessels, called
bronchomediastinal trunks. Lymph drainage paths from the lung are complex. The precise
knowledge of their course is clinically relevant, because malignant tumours of the lung spread
via the lymphatics.
The pleurae, the airways, and the vessels are innervated by afferent and efferent fibres of the
autonomic nervous system. Parasympathetic nerve fibres from the vagus nerve (10th cranial
nerve) and sympathetic branches of the sympathetic nerve trunk meet around the stem bronchi
to form the pulmonary autonomic nerve plexus, which penetrates into the lung along the
bronchial and vascular walls. The sympathetic fibres mediate a vasoconstrictive action in the
pulmonary vascular bed and a secretomotor activity in the bronchial glands. The
parasympathetic fibres stimulate bronchial constriction. Afferent fibres to the vagus nerve
transmit information from stretch receptors, and those to the sympathetic centres carry sensory
information (e.g., pain) from the bronchial mucosa.
Lung development
After early embryogenesis, during which the lung primordium is laid down, the developing
human lung undergoes four consecutive stages of development, ending after birth. The names
of the stages describe the actual morphology of the prospective airways. The pseudoglandular
stage exists from five to 17 weeks; the canalicular stage, from 16 to 26 weeks; the saccular
stage, from 24 to 38 weeks; and finally the alveolar stage, from 36 weeks of fetal age to about
11/2 to two years after birth.
The lung appears around the 26th day of intrauterine life as a ventral bud of the prospective
esophagus. The bud separates distally from the gut, divides, and starts to grow into the
surrounding mesenchyme. The epithelial components of the lung are thus derived from the gut
(i.e., they are of endodermal origin), and the surrounding tissues and the blood vessels are
derivatives of the mesoderm.
Following rapid successive dichotomous divisions, the lung begins to look like a gland, giving
the first stage of development (pseudoglandular) its name. At the same time the vascular
connections also develop and form a capillary plexus around the lung tubules. Toward week
17, all the conducting airways of the lung are preformed, and it is assumed that, at the
outermost periphery, the tips of the tubules represent the first structures of the prospective gas-
exchange region.
During the canalicular stage, the future lung periphery develops further. The prospective
airspaces enlarge at the expense of the intervening mesenchyme, and their cuboidal epithelium
differentiates into type I and type II epithelial cells or pneumocytes. Toward the end of this
stage, areas with a thin prospective air–blood barrier have developed, and surfactant
production has started. These structural and functional developments give a prematurely born
fetus a small chance to survive at this stage.
During the saccular stage, further generations of airways are formed. The tremendous
expansion of the prospective respiratory airspaces causes the formation of saccules and a
marked decrease in the interstitial tissue mass. The lung looks more and more “aerated,”
although it is filled with fluid originating from the lungs and from the amniotic fluid
surrounding the fetus. Some weeks before birth, alveolar formation begins by a septation
process that subdivides the saccules into alveoli. At this stage of lung development, the infant
is born.
At birth the intrapulmonary fluid is rapidly evacuated and the lung fills with air with the first
breaths. Simultaneously, the pulmonary circulation, which before was practically bypassed and
very little perfused, opens up to accept the full cardiac output.
The newborn lung is far from being a miniaturized version of the adult lung. It has only about
20 million to 50 million alveoli, just a small percentage of the full adult complement.
Therefore, alveolar formation is completed in the early postnatal period. Although it was
previously thought that alveolar formation could continue to age eight and beyond, it is now
accepted that the bulk of alveolar formation is concluded much earlier, probably before age
two. Even with complete alveolar formation, the lung is not yet mature. The newly formed
interalveolar septa still contain a double capillary network instead of the single one of the adult
lungs. This means that the pulmonary capillary bed must be completely reorganized during
and after alveolar formation; it has to mature. Only after full microvascular maturation, which
is terminated sometime between ages two and five, is the lung development completed, and
the lung can enter a phase of normal growth.
Peter H. Burri
Control of breathing
Breathing is an automatic and rhythmic act produced by networks of neurons in the hindbrain
(the pons and medulla). The neural networks direct muscles that form the walls of the thorax
and abdomen and produce pressure gradients that move air into and out of the lungs. The
respiratory rhythm and the length of each phase of respiration are set by reciprocal stimulatory
and inhibitory interconnection of these brain-stem neurons.
An important characteristic of the human respiratory system is its ability to adjust breathing
patterns to changes in both the internal milieu and the external environment. Ventilation
increases and decreases in proportion to swings in carbon dioxide production and oxygen
consumption caused by changes in metabolic rate. The respiratory system is also able to
compensate for disturbances that affect the mechanics of breathing, such as the airway
narrowing that occurs in an asthmatic attack. Breathing also undergoes appropriate
adjustments when the mechanical advantage of the respiratory muscles is altered by postural
changes or by movement.
This flexibility in breathing patterns in large part arises from sensors distributed throughout
the body that send signals to the respiratory neuronal networks in the brain. Chemoreceptors
detect changes in blood oxygen levels and change the acidity of the blood and brain.
Mechanoreceptors monitor the expansion of the lung, the size of the airway, the force of
respiratory muscle contraction, and the extent of muscle shortening.
Although the diaphragm is the major muscle of breathing, its respiratory action is assisted and
augmented by a complex assembly of other muscle groups. Intercostal muscles inserting on
the ribs, the abdominal muscles, and muscles such as the scalene and sternocleidomastoid that
attach both to the ribs and to the cervical spine at the base of the skull also play an important
role in the exchange of air between the atmosphere and the lungs. In addition, laryngeal
muscles and muscles in the oral and nasal pharynx adjust the resistance of movement of gases
through the upper airways during both inspiration and expiration. Although the use of these
different muscle groups adds considerably to the flexibility of the breathing act, they also
complicate the regulation of breathing. These same muscles are used to perform a number of
other functions, such as speaking, chewing and swallowing, and maintaining posture. Perhaps
because the “respiratory” muscles are employed in performing nonrespiratory functions,
breathing can be influenced by higher brain centres and even controlled voluntarily to a
substantial degree. An outstanding example of voluntary control is the ability to suspend
breathing by holding one’s breath. Input into the respiratory control system from higher brain
centres may help optimize breathing so that not only are metabolic demands satisfied by
breathing but ventilation also is accomplished with minimal use of energy.
Central organization of respiratory neurons

The respiratory rhythm is generated within the pons and medulla oblongata. Three main
aggregations of neurons are involved: a group consisting mainly of inspiratory neurons in the
dorsomedial medulla, a group made up of inspiratory and expiratory neurons in the
ventrolateral medulla, and a group in the rostral pons consisting mostly of neurons that
discharge in both inspiration and expiration. It is thought that the respiratory cycle of
inspiration and expiration is generated by synaptic interactions within these groups of neurons.
The inspiratory and expiratory medullary neurons are connected to projections from higher
brain centres and from chemoreceptors and mechanoreceptors; in turn they drive cranial motor
neurons, which govern the activity of muscles in the upper airways and the activity of spinal
motor neurons, which supply the diaphragm and other thoracic and abdominal muscles. The
inspiratory and expiratory medullary neurons also receive input from nerve cells responsible
for cardiovascular and temperature regulation, allowing the activity of these physiological
systems to be coordinated with respiration.
Neurally, inspiration is characterized by an augmenting discharge of medullary neurons that

terminates abruptly. After a gap of a few milliseconds, inspiratory activity is restarted, but at a
much lower level, and gradually declines until the onset of expiratory neuron activity. Then the
cycle begins again. The full development of this pattern depends on the interaction of several
types of respiratory neurons: inspiratory, early inspiratory, off-switch, post-inspiratory, and
expiratory.
Early inspiratory neurons trigger the augmenting discharge of inspiratory neurons. This
increase in activity, which produces lung expansion, is caused by self-excitation of the
inspiratory neurons and perhaps by the activity of an as yet undiscovered upstream pattern
generator. Off-switch neurons in the medulla terminate inspiration, but pontine neurons and
input from stretch receptors in the lung help control the length of inspiration. When the vagus
nerves are sectioned or pontine centres are destroyed, breathing is characterized by prolonged
inspiratory activity that may last for several minutes. This type of breathing, which
occasionally occurs in persons with diseases of the brain stem, is called apneustic breathing.
Post-inspiratory neurons are responsible for the declining discharge of the inspiratory muscles
that occurs at the beginning of expiration. Mechanically, this discharge aids in slowing
expiratory flow rates and probably assists the efficiency of gas exchange. It is thought by some
that these post-inspiratory neurons have inhibitory effects on both inspiratory and expiratory
neurons and therefore play a significant role in determining the length of the respiratory cycle
and the different phases of respiration.
As the activity of the post-inspiratory neurons subsides, expiratory neurons discharge and
inspiratory neurons are strongly inhibited. There may be no peripheral manifestation of
expiratory neuron discharge except for the absence of inspiratory muscle activity, although in
upright humans the lower expiratory intercostal muscles and the abdominal muscles may be
active even during quiet breathing. Moreover, as the demand to breathe increases (for example,
with exercise), more expiratory intercostal and abdominal muscles contract. As expiration
proceeds, the inhibition of the inspiratory muscles gradually diminishes and inspiratory
neurons resume their activity.
Chemoreceptors
One way in which breathing is controlled is through feedback by chemoreceptors. There are
two kinds of respiratory chemoreceptors: arterial chemoreceptors, which monitor and respond
to changes in the partial pressure of oxygen and carbon dioxide in the arterial blood, and
central chemoreceptors in the brain, which respond to changes in the partial pressure of carbon
dioxide in their immediate environment. Ventilation levels behave as if they were regulated to
maintain a constant level of carbon dioxide partial pressure and to ensure adequate oxygen
levels in the arterial blood. Increased activity of chemoreceptors caused by hypoxia or an
increase in the partial pressure of carbon dioxide augments both the rate and depth of
breathing, which restores partial pressures of oxygen and carbon dioxide to their usual levels.
On the other hand, too much ventilation depresses the partial pressure of carbon dioxide,
which leads to a reduction in chemoreceptor activity and a diminution of ventilation. During
sleep and anesthesia, lowering carbon dioxide levels three to four millimetres of mercury
below values occurring during wakefulness can cause a total cessation of breathing (apnea).
Peripheral chemoreceptors
Hypoxia, or the reduction of oxygen supply to tissues to below physiological levels (produced,
for example, by a trip to high altitudes), stimulates the carotid and aortic bodies, the principal
arterial chemoreceptors. The two carotid bodies are small organs located in the neck at the
bifurcation of each of the two common carotid arteries into the internal and external carotid
arteries. This organ is extraordinarily well perfused and responds to changes in the partial
pressure of oxygen in the arterial blood flowing through it rather than to the oxygen content of
that blood (the amount of oxygen chemically combined with hemoglobin). The sensory nerve
from the carotid body increases its firing rate hyperbolically as the partial pressure of oxygen
falls. In addition to responding to hypoxia, the carotid body increases its activity linearly as the
partial pressure of carbon dioxide in arterial blood is raised. This arterial blood parameter rises
and falls as air enters and leaves the lungs, and the carotid body senses these fluctuations,
responding more to rapid than to slow changes in the partial pressure of carbon dioxide. Larger
oscillations in the partial pressure of carbon dioxide occur with breathing as metabolic rate is
increased. The amplitude of these fluctuations, as reflected in the size of carotid body signals,
may be used by the brain to detect changes in the metabolic rate and to produce appropriate
adjustment in ventilation.
The carotid body communicates with medullary respiratory neurons through sensory fibres
that travel with the carotid sinus nerve, a branch of the glossopharyngeal nerve.
Microscopically, the carotid body consists of two different types of cells. The type I cells are
arranged in groups and are surrounded by type II cells. The type II cells are generally not
thought to have a direct role in chemoreception. Fine sensory nerve fibres are found in
juxtaposition to type I cells, which, unlike type II cells, contain electron-dense vesicles.
Acetylcholine, catecholamines, and neuropeptides such as enkephalins, vasoactive intestinal
polypeptide, and substance P, are located within the vesicles. It is thought that hypoxia and
hypercapnia (excessive carbon dioxide in the blood) cause the release of one or more of these
neuroactive substances from the type I cells, which then act on the sensory nerve. It is possible
to interfere independently with the responses of the carotid body to carbon dioxide and
oxygen, which suggests that the same mechanisms are not used to sense or transmit changes in
oxygen or carbon dioxide. The aortic bodies located near the arch of the aorta also respond to
acute changes in the partial pressure of oxygen, but less well than the carotid body responds to
changes in the partial pressure of carbon dioxide. The aortic bodies are responsible for many
of the cardiovascular effects of hypoxia.
Central chemoreceptors
Carbon dioxide is one of the most powerful stimulants of breathing. As the partial pressure of
carbon dioxide in arterial blood rises, ventilation increases nearly linearly. Ventilation
normally increases by two to four litres per minute with each one millimetre of mercury
increase in the partial pressure of carbon dioxide. Carbon dioxide increases the acidity of the
fluid surrounding the cells but also easily passes into cells and thus can make the interior of
cells more acid. It is not clear whether the receptors respond to the intracellular or extracellular
effects of carbon dioxide or acidity.
Even if both the carotid and aortic bodies are removed, inhaling gases that contain carbon
dioxide stimulates breathing. This observation shows that there must be additional receptors
that respond to changes in the partial pressure of carbon dioxide. Current thinking places these
receptors near the undersurface (ventral part) of the medulla. However, microscopic
examination has not conclusively identified specific chemoreceptor cells in this region. The
same areas of the ventral medulla also contain vasomotor neurons that are concerned with the
regulation of blood pressure. Some investigators suspect that respiratory responses produced at
the ventral medullary surface are direct and are caused by interference with excitatory and
inhibitory inputs to respiration from these vasomotor neurons. They further suspect that
respiratory chemoreceptors that respond to carbon dioxide are more diffusely distributed in the
brain.
Muscle and lung receptors

Receptors in the respiratory muscles and in the lung can also affect breathing patterns. These
receptors are particularly important when lung function is impaired, since they can help
maintain tidal volume and ventilation at normal levels.
Changes in the length of a muscle affect the force it can produce when stimulated. Generally
there is a length at which the force generated is maximal. Receptors, called spindles, in the
respiratory muscles measure muscle length and increase motor discharge to the diaphragm and
intercostal muscles when increased stiffness of the lung or resistance to the movement of air
caused by disease impedes muscle shortening. Tendon organs, another receptor in muscles,
monitor changes in the force produced by muscle contraction. Too much force stimulates
tendon organs and causes decreasing motor discharge to the respiratory muscles and may
prevent the muscles from damaging themselves.
Inflation of the lungs in animals stops breathing by a reflex described by German physiologist
Ewald Hering and Austrian physiologist Josef Breuer. The Hering-Breuer reflex is initiated by
lung expansion, which excites stretch receptors in the airways. Stimulation of these receptors,
which send signals to the medulla by the vagus nerve, shortens inspiratory times as tidal
volume (the volume of air inspired) increases, accelerating the frequency of breathing. When
lung inflation is prevented, the reflex allows inspiratory time to be lengthened, helping to
preserve tidal volume.
There are also receptors in the airways and in the alveoli that are excited by rapid lung
inflations and by chemicals such as histamine, bradykinin, and prostaglandins. The most
important function of these receptors, however, may be to defend the lung against noxious
material in the atmosphere. When stimulated, these receptors constrict the airways and cause
rapid shallow breathing, which inhibits the penetration of injurious agents into the bronchial
tree. These receptors are supplied, like the stretch receptors, by the vagus nerve. Some of these
receptors (called irritant receptors) are innervated by myelinated nerve fibres, others (the J
receptors) by unmyelinated fibres. Stimulation of irritant receptors also causes coughing.
Variations in breathing
Exercise
One of the remarkable features of the respiratory control system is that ventilation increases
sufficiently to keep the partial pressure of carbon dioxide in arterial blood nearly unchanged
despite the large increases in metabolic rate that can occur with exercise, thus preserving acid–
base homeostasis. A number of signals arise during exercise that can augment ventilation.
Sources of these signals include mechanoreceptors in the exercising limbs; the arterial
chemoreceptors, which can sense breath-by-breath oscillations in the partial pressure of carbon
dioxide; and thermal receptors, because body temperature rises as metabolism increases. The
brain also seems to anticipate changes in the metabolic rate caused by exercise, because
parallel increases occur in the output from the motor cortex to the exercising limbs and to
respiratory neurons. Changes in the concentration of potassium and lactic acid in the
exercising muscles acting on unmyelinated nerve fibres may be another mechanism for
stimulation of breathing during exercise. It remains unclear, however, how these various
mechanisms are adjusted to maintain acid–base balance.
Sleep
During sleep, body metabolism is reduced, but there is an even greater decline in ventilation so
that the partial pressure of carbon dioxide in arterial blood rises slightly and arterial partial
pressure of oxygen falls. The effects on ventilatory pattern vary with sleep stage. In slow-wave
sleep, breathing is diminished but remains regular, while in rapid eye movement sleep,
breathing can become quite erratic. Ventilatory responses to inhaled carbon dioxide and to
hypoxia are less in all sleep stages than during wakefulness. Sufficiently large decreases in the
partial pressure of oxygen or increases in the partial pressure of carbon dioxide will cause
arousal and terminate sleep.
During sleep, ventilation may swing between periods when the amplitude and frequency of
breathing are high and periods in which there is little attempt to breathe, or even apnea
(cessation of breathing). This rhythmic waxing and waning of breathing, with intermittent
periods of apnea, is called Cheyne-Stokes breathing, after the physicians who first described it.
The mechanism that produces the Cheyne-Stokes ventilation pattern is unclear, but it may
entail unstable feedback regulation of breathing. Similar swings in ventilation sometimes
occur in persons with heart failure or with central nervous system disease.
In addition, ventilation during sleep may intermittently fall to low levels or cease entirely
because of partial or complete blockage of the upper airways. In some individuals, this
intermittent obstruction occurs repeatedly during the night, leading to severe drops in the
levels of blood oxygenation. The condition, called sleep apnea, occurs most commonly in the
elderly, in the newborn, in males, and in the obese. Because arousal is often associated with
the termination of episodes of obstruction, sleep is of poor quality, and complaints of excessive
daytime drowsiness are common. Snoring and disturbed behaviour during sleep may also
occur.
In some persons with sleep apnea, portions of the larynx and pharynx may be narrowed by fat
deposits or by enlarged tonsils and adenoids, which increase the likelihood of obstruction.
Others, however, have normal upper airway anatomy, and obstruction may occur because of
discoordinated activity of upper airway and chest wall muscles. Many of the upper airway
muscles, like the tongue and laryngeal adductors, undergo phasic changes in their electrical
activity synchronous with respiration, and the reduced activity of these muscles during sleep
may lead to upper airway closure.
Neil S. Cherniack
The mechanics of breathing
Air moves in and out of the lungs in response to
differences in pressure. When the air pressure within the
alveolar spaces falls below atmospheric pressure, air
enters the lungs (inspiration), provided the larynx is
open; when the air pressure within the alveoli exceeds
atmospheric pressure, air is blown from the lungs
(expiration). The flow of air is rapid or slow in
diaphragm; breathing proportion to the magnitude of the pressure difference.
The diaphragm contracts and relaxes, Because atmospheric pressure remains relatively
forcing air in and out of the lungs.
constant, flow is determined by how much above or
below atmospheric pressure the pressure within the lungs rises or falls.
Alveolar pressure fluctuations are caused by expansion and contraction of the lungs resulting
from tensing and relaxing of the muscles of the chest and abdomen. Each small increment of
expansion transiently increases the space enclosing lung air. There is, therefore, less air per
unit of volume in the lungs and pressure falls. A difference in air pressure between atmosphere
and lungs is created, and air flows in until equilibrium with atmospheric pressure is restored at
a higher lung volume. When the muscles of inspiration relax, the volume of chest and lungs
decreases, lung air becomes transiently compressed, its pressure rises above atmospheric
pressure, and flow into the atmosphere results until pressure equilibrium is reached at the
original lung volume. This, then, is the sequence of events during each normal respiratory
cycle: lung volume change leading to pressure difference, resulting in flow of air into or out of
the lung and establishment of a new lung volume.
The lung–chest system

The forces that normally cause changes in volume of the chest and lungs stem not only from
muscle contraction but from the elastic properties of both the lung and the chest. A lung is
similar to a balloon in that it resists stretch, tending to collapse almost totally unless held
inflated by a pressure difference between its inside and outside. This tendency of the lung to
collapse or pull away from the chest can be measured by carefully placing a blunt needle
between the outside of the lung and the inside of the chest wall, thereby allowing the lung to
separate from the chest at this particular spot. The pressure measured in the small pleural space
so created is substantially below atmospheric pressure at a time when the pressure within the
lung itself equals atmospheric pressure. This negative (below-atmospheric) pressure is a
measure, therefore, of the force required to keep the lung distended. The force increases
(pleural pressure becomes more negative) as the lung is stretched and its volume increases
during inspiration. The force also increases in proportion to the rapidity with which air is
drawn into the lung and decreases in proportion to the force with which air is expelled from
the lungs. In summary, the pleural pressure reflects primarily two forces: (1) the force required
to keep the lung inflated against its elastic recoil and (2) the force required to cause airflow in
and out of the lung. Because the pleural pressure is below atmospheric pressure, air is sucked
into the chest and the lung collapses (pneumothorax) when the chest wall is perforated, as by a
wound or by a surgical incision.
The force required to maintain inflation of the lung and to cause airflow is provided by the
chest and diaphragm (the muscular partition between chest and abdomen), which are in turn
stretched inward by the pull of the lungs. The lung–chest system thus acts as two opposed
coiled springs, the length of each of which is affected by the other. Were it not for the outward
traction of the chest on the lungs, these would collapse; and were it not for the inward traction
of the lungs on the chest and diaphragm, the chest would expand to a larger size and the
diaphragm would fall from its dome-shaped position within the chest.
The role of muscles

The respiratory muscles displace the equilibrium of elastic forces in the lung and chest in one
direction or the other by adding muscular contraction. During inspiration, muscle contraction
is added to the outward elastic force of the chest to increase the traction on the lung required
for its additional stretch. When these muscles relax, the additional retraction of lung returns
the system to its equilibrium position.
Contraction of the abdominal muscles displaces the equilibrium in the opposite direction by
adding increased abdominal pressure to the retraction of lungs, thereby further raising the
diaphragm and causing forceful expiration. This additional muscular force is removed on
relaxation and the original lung volume is restored. During ordinary breathing, muscular
contraction occurs only on inspiration, expiration being accomplished “passively” by elastic
recoil of the lung.
At total relaxation of the muscles of inspiration and expiration, the lung is distended to a
volume—called the functional residual capacity—of about 40 percent of its maximum volume
at the end of full inspiration. Further reduction of the lung volume results from maximal
contraction of the expiratory muscles of chest and abdomen. The volume in these
circumstances is known as the residual volume; it is about 20 percent of the volume at the end
of full inspiration (known as the total lung capacity). Additional collapse of the lung to its
“minimal air” can be accomplished only by opening the chest wall and creating a
pneumothorax.
The membranes of the surface of the lung (visceral pleura) and on the inside of the chest
(parietal pleura) are normally kept in close proximity (despite the pull of lung and chest in
opposite directions) by surface tension of the thin layer of fluid covering these surfaces. The
strength of this bond can be appreciated by the attempt to pull apart two smooth surfaces, such
as pieces of glass, separated by a film of water.
The respiratory pump and its performance

The energy expended on breathing is used primarily in stretching the lung–chest system and
thus causing airflow. It normally amounts to 1 percent of the basal energy requirements of the
body but rises substantially during exercise or illness. The respiratory pump is versatile,
capable of increasing its output 25 times, from a normal resting level of about six litres (366
cubic inches) per minute to 150 litres per minute in adults. Pressures within the lungs can be
raised to 130 centimetres of water (about 1.8 pounds per square inch) by the so-called Valsalva
maneuver—i.e., a forceful contraction of the chest and abdominal muscles against a closed
glottis (i.e., with no space between the vocal cords). Airflow velocity, normally reaching 30
litres per minute in quiet breathing, can be raised voluntarily to 400 litres per minute. Cough is
accomplished by suddenly opening the larynx during a brief Valsalva maneuver. The resultant
high-speed jet of air is an effective means of clearing the airways of excessive secretions or
foreign particles. The beating of cilia (hairline projections) from cells lining the airways
normally maintains a steady flow of secretions toward the nose, cough resulting only when
this action cannot keep pace with the rate at which secretions are produced.
An infant takes 33 breaths per minute with a tidal volume (the amount of air breathed in and
out in one cycle) of 15 millilitres, totaling about 0.5 litre—approximately one pint—per
minute as compared to adult values of 14 breaths, 500 millilitres, and seven litres, respectively.
If the force of surface tension is responsible for the adherence of parietal and visceral pleurae,
it is reasonable to question what keeps the lungs’ alveolar walls (also fluid-covered) from
sticking together and thus eliminating alveolar airspaces. In fact, such adherence occasionally
does occur and is one of the complications of premature births. Normal lungs, however,
contain a substance—a phospholipid surfactant—that reduces surface tension and keeps
alveolar walls separated.
Arthur A. Siebens
Gas exchange
Respiratory gases—oxygen and carbon dioxide—move between the air and the blood across
the respiratory exchange surfaces in the lungs. The structure of the human lung provides an
immense internal surface that facilitates gas exchange between the alveoli and the blood in the
pulmonary capillaries. The area of the alveolar surface in the adult human is about 50–100
square metres. Gas exchange across the membranous barrier between the alveoli and
capillaries is enhanced by the thin nature of the membrane, about 0.5 μm, or 1/100 of the
diameter of a human hair.
Respiratory gases move between the environment and the respiring tissues by two principal
mechanisms, convection and diffusion. Convection, or mass flow, is responsible for movement
of air from the environment into the lungs and for movement of blood between the lungs and
the tissues. Respiratory gases also move by diffusion across tissue barriers such as membranes.
Diffusion is the primary mode of transport of gases between air and blood in the lungs and
between blood and respiring tissues in the body. The process of diffusion is driven by the
difference in partial pressures of a gas between two locales. In a mixture of gases, the partial
pressure of each gas is directly proportional to its concentration. The partial pressure of a gas
in fluid is a measure of its tendency to leave the fluid when exposed to a gas or fluid that does
not contain that gas. A gas will diffuse from an area of greater partial pressure to an area of
lower partial pressure regardless of the distribution of the partial pressures of other gases.
There are large changes in the partial pressures of oxygen and carbon dioxide as these gases
move between air and the respiring tissues. The partial pressure of carbon dioxide in this
pathway is lower than the partial pressure of oxygen, due to differing modes of transport in the
blood, but almost equal quantities of the two gases are involved in metabolism and gas
exchange.
Oxygen and carbon dioxide are transported between tissue cells and the lungs by the blood.
The quantity transported is determined both by the rapidity with which the blood circulates
and the concentrations of gases in blood. The rapidity of circulation is determined by the
output of the heart, which in turn is responsive to overall body requirements. Local flows can
be increased selectively, as occurs, for example, in the flow through skeletal muscles during
exercise. The performance of the heart and circulatory regulation are, therefore, important
determinants of gas transport.
Oxygen and carbon dioxide are too poorly soluble in blood to be adequately transported in
solution. Specialized systems for each gas have evolved to increase the quantities of those
gases that can be transported in blood. These systems are present mainly in the red blood cells,
which make up 40 to 50 percent of the blood volume in most mammals. Plasma, the cell-free
liquid portion of blood, plays little role in oxygen exchange but is essential to carbon dioxide
exchange.
Transport of oxygen
Oxygen is poorly soluble in plasma, so that less than 2
percent of oxygen is transported dissolved in plasma.
The vast majority of oxygen is bound to hemoglobin, a
protein contained within red cells. Hemoglobin is
composed of four iron-containing ring structures (hemes)
chemically bonded to a large protein (globin). Each iron
atom can bind and then release an oxygen molecule.
Enough hemoglobin is present in normal human blood to
permit transport of about 0.2 millilitre of oxygen per
hemoglobin
Hemoglobin is a protein made up of millilitre of blood. The quantity of oxygen bound to

four polypeptide chains (α1, α2, β1,
hemoglobin is dependent on the partial pressure of
and β2). Each chain is attached to a
heme group composed of porphyrin
oxygen in the lung to which blood is exposed. The curve
(an organic ringlike compound) representing the content of oxygen in blood at various
attached to an iron atom. These iron-
partial pressures of oxygen, called the oxygen-
porphyrin complexes coordinate
oxygen molecules reversibly, an ability dissociation curve, is a characteristic S-shape because
directly related to the role of
binding of oxygen to one iron atom influences the ability
hemoglobin in oxygen transport in the
blood. of oxygen to bind to other iron sites. In alveoli at sea
level, the partial pressure of oxygen is sufficient to bind
oxygen to essentially all available iron sites on the hemoglobin molecule.
Not all of the oxygen transported in the blood is transferred to the tissue cells. The amount of
oxygen extracted by the cells depends on their rate of energy expenditure. At rest, venous
blood returning to the lungs still contains 70 to 75 percent of the oxygen that was present in
arterial blood; this reserve is available to meet increased oxygen demands. During extreme
exercise the quantity of oxygen remaining in venous blood decreases to 10 to 25 percent. At
the steepest part of the oxygen-dissociation curve (the portion between 10 and 40 millimetres
of mercury partial pressure), a relatively small decline in the partial pressure of oxygen in the
blood is associated with a relatively large release of bound oxygen.
Hemoglobin binds not only to oxygen but to other substances such as hydrogen ions (which
determine the acidity, or pH, of the blood), carbon dioxide, and 2,3-diphosphoglycerate (2,3-
DPG; a salt in red blood cells that plays a role in liberating oxygen from hemoglobin in the
peripheral circulation). These substances do not bind to hemoglobin at the oxygen-binding
sites. However, with the binding of oxygen, changes in the structure of the hemoglobin
molecule occur that affect its ability to bind other gases or substances. Conversely, binding of
these substances to hemoglobin affects the affinity of hemoglobin for oxygen. (Affinity
denotes the tendency of molecules of different species to bind to one another.) Increases in
hydrogen ions, carbon dioxide, or 2,3-DPG decrease the affinity of hemoglobin for oxygen,
and the oxygen-dissociation curve shifts to the right. Because of this decreased affinity, an
increased partial pressure of oxygen is required to bind a given amount of oxygen to
hemoglobin. A rightward shift of the curve is thought to be of benefit in releasing oxygen to
the tissues when needs are great in relation to oxygen delivery, as occurs with anemia or
extreme exercise. Reductions in normal concentrations of hydrogen ions, carbon dioxide, and
2,3-DPG result in an increased affinity of hemoglobin for oxygen, and the curve is shifted to
the left. This displacement increases oxygen binding to hemoglobin at any given partial
pressure of oxygen and is thought to be beneficial if the availability of oxygen is reduced, as
occurs at extreme altitude.
Temperature changes affect the oxygen-dissociation curve similarly. An increase in

temperature shifts the curve to the right (decreased affinity; enhanced release of oxygen); a
decrease in temperature shifts the curve to the left (increased affinity). The range of body
temperature usually encountered in humans is relatively narrow, so that temperature-associated
changes in oxygen affinity have little physiological importance.
Transport of carbon dioxide

Transport of carbon dioxide in the blood is considerably more complex. A small portion of
carbon dioxide, about 5 percent, remains unchanged and is transported dissolved in blood. The
remainder is found in reversible chemical combinations in red blood cells or plasma. Some
carbon dioxide binds to blood proteins, principally hemoglobin, to form a compound known as
carbamate. About 88 percent of carbon dioxide in the blood is in the form of bicarbonate ion.
The distribution of these chemical species between the interior of the red blood cell and the
surrounding plasma varies greatly, with the red blood cells containing considerably less
bicarbonate and more carbamate than the plasma.
Less than 10 percent of the total quantity of carbon dioxide carried in the blood is eliminated
during passage through the lungs. Complete elimination would lead to large changes in acidity
between arterial and venous blood. Furthermore, blood normally remains in the pulmonary
capillaries less than a second, an insufficient time to eliminate all carbon dioxide.
Carbon dioxide enters blood in the tissues because its local partial pressure is greater than its
partial pressure in blood flowing through the tissues. As carbon dioxide enters the blood, it
combines with water to form carbonic acid (H2CO3), a relatively weak acid, which dissociates
into hydrogen ions (H+) and bicarbonate ions (HCO3-). Blood acidity is minimally affected by
the released hydrogen ions because blood proteins, especially hemoglobin, are effective
buffering agents. (A buffer solution resists change in acidity by combining with added
hydrogen ions and, essentially, inactivating them.) The natural conversion of carbon dioxide to
carbonic acid is a relatively slow process; however, carbonic anhydrase, a protein enzyme
present inside the red blood cell, catalyzes this reaction with sufficient rapidity that it is
accomplished in only a fraction of a second. Because the enzyme is present only inside the red
blood cell, bicarbonate accumulates to a much greater extent within the red cell than in the
plasma. The capacity of blood to carry carbon dioxide as bicarbonate is enhanced by an ion
transport system inside the red blood cell membrane that simultaneously moves a bicarbonate
ion out of the cell and into the plasma in exchange for a chloride ion. The simultaneous
exchange of these two ions, known as the chloride shift, permits the plasma to be used as a
storage site for bicarbonate without changing the electrical charge of either the plasma or the
red blood cell. Only 26 percent of the total carbon dioxide content of blood exists as
bicarbonate inside the red blood cell, while 62 percent exists as bicarbonate in plasma;
however, the bulk of bicarbonate ions is first produced inside the cell, then transported to the
plasma. A reverse sequence of reactions occurs when blood reaches the lung, where the partial
pressure of carbon dioxide is lower than in the blood.
Hemoglobin acts in another way to facilitate the transport of carbon dioxide. Amino groups of
the hemoglobin molecule react reversibly with carbon dioxide in solution to yield carbamates.
A few amino sites on hemoglobin are oxylabile, that is, their ability to bind carbon dioxide
depends on the state of oxygenation of the hemoglobin molecule. The change in molecular
configuration of hemoglobin that accompanies the release of oxygen leads to increased
binding of carbon dioxide to oxylabile amino groups. Thus, release of oxygen in body tissues
enhances binding of carbon dioxide as carbamate. Oxygenation of hemoglobin in the lungs has
the reverse effect and leads to carbon dioxide elimination.
Only 5 percent of carbon dioxide in the blood is transported free in physical solution without
chemical change or binding, yet this pool is important, because only free carbon dioxide easily
crosses biologic membranes. Virtually every molecule of carbon dioxide produced by
metabolism must exist in the free form as it enters blood in the tissues and leaves capillaries in
the lung. Between these two events, most carbon dioxide is transported as bicarbonate or
carbamate.
Gas exchange in the lung

The introduction of air into the alveoli allows the removal of carbon dioxide and the addition
of oxygen to venous blood. Because ventilation is a cyclic phenomenon that occurs through a
system of conducting airways, not all inspired air participates in gas exchange. A portion of the
inspired breath remains in the conducting airways and does not reach the alveoli where gas
exchange occurs. This portion is approximately one-third of each breath at rest but decreases
to as little as 10 percent during exercise, due to the increased size of inspired breaths.
In contrast to the cyclic nature of ventilation, blood flow through the lung is continuous, and
almost all blood entering the lungs participates in gas exchange. The efficiency of gas
exchange is critically dependent on the uniform distribution of blood flow and inspired air
throughout the lungs. In health, ventilation and blood flow are extremely well matched in each
exchange unit throughout the lungs. The lower parts of the lung receive slightly more blood
flow than ventilation because gravity has a greater effect on the distribution of blood than on
the distribution of inspired air. Under ideal circumstances, partial pressures of oxygen and
carbon dioxide in alveolar gas and arterial blood are identical. Normally there is a small
difference between oxygen tensions in alveolar gas and arterial blood because of the effect of
gravity on matching and the addition of a small amount of venous drainage to the bloodstream
after it has left the lungs. These events have no measurable effect on carbon dioxide partial
pressures because the difference between arterial and venous blood is so small.
Abnormal gas exchange

Lung disease can lead to severe abnormalities in blood gas composition. Because of the
differences in oxygen and carbon dioxide transport, impaired oxygen exchange is far more
common than impaired carbon dioxide exchange. Mechanisms of abnormal gas exchange are
grouped into four categories—hypoventilation, shunting, ventilation–blood flow imbalance,
and limitations of diffusion.
If the quantity of inspired air entering the lungs is less than is needed to maintain normal
exchange—a condition known as hypoventilation—the alveolar partial pressure of carbon
dioxide rises and the partial pressure of oxygen falls almost reciprocally. Similar changes
occur in arterial blood partial pressures because the composition of alveolar gas determines
gas partial pressures in blood perfusing the lungs. This abnormality leads to parallel changes in
both gas and blood and is the only abnormality in gas exchange that does not cause an increase
in the normally small difference between arterial and alveolar partial pressures of oxygen.
In shunting, venous blood enters the bloodstream without passing through functioning lung
tissue. Shunting of blood may result from abnormal vascular (blood vessel) communications
or from blood flowing through unventilated portions of the lung (e.g., alveoli filled with fluid
or inflammatory material). A reduction in arterial blood oxygenation is seen with shunting, but
the level of carbon dioxide in arterial blood is not elevated even though the shunted blood
contains more carbon dioxide than arterial blood.
The differing effects of shunting on oxygen and carbon dioxide partial pressures are the result
of the different configurations of the blood-dissociation curves of the two gases. As noted
above, the oxygen-dissociation curve is S-shaped and plateaus near the normal alveolar
oxygen partial pressure, but the carbon dioxide-dissociation curve is steeper and does not
plateau as the partial pressure of carbon dioxide increases. When blood perfusing the
collapsed, unventilated area of the lung leaves the lung without exchanging oxygen or carbon
dioxide, the content of carbon dioxide is greater than the normal carbon dioxide content. The
remaining healthy portion of the lung receives both its usual ventilation and the ventilation that
normally would be directed to the abnormal lung. This lowers the partial pressure of carbon
dioxide in the alveoli of the normal area of the lung. As a result, blood leaving the healthy
portion of the lung has a lower carbon dioxide content than normal. The lower carbon dioxide
content in this blood counteracts the addition of blood with a higher carbon dioxide content
from the abnormal area, and the composite arterial blood carbon dioxide content remains
normal. This compensatory mechanism is less efficient than normal carbon dioxide exchange
and requires a modest increase in overall ventilation, which is usually achieved without
difficulty. Because the carbon dioxide-dissociation curve is steep and relatively linear,
compensation for decreased carbon dioxide exchange in one portion of the lung can be
counterbalanced by increased excretion of carbon dioxide in another area of the lung.
In contrast, shunting of venous blood has a substantial effect on arterial blood oxygen content
and partial pressure. Blood leaving an unventilated area of the lung has an oxygen content that
is less than the normal content (indicated by the square). In the healthy area of the lung, the
increase in ventilation above normal raises the partial pressure of oxygen in the alveolar gas
and, therefore, in the arterial blood. The oxygen-dissociation curve, however, reaches a plateau
at the normal alveolar partial pressure, and an increase in blood partial pressure results in a
negligible increase in oxygen content. Mixture of blood from this healthy portion of the lung
(with normal oxygen content) and blood from the abnormal area of the lung (with decreased
oxygen content) produces a composite arterial oxygen content that is less than the normal
level. Thus, an area of healthy lung cannot counterbalance the effect of an abnormal portion of
the lung on blood oxygenation because the oxygen-dissociation curve reaches a plateau at a
normal alveolar partial pressure of oxygen. This effect on blood oxygenation is seen not only
in shunting but in any abnormality that results in a localized reduction in blood oxygen
content.
Mismatching of ventilation and blood flow is by far the most common cause of a decrease in
partial pressure of oxygen in blood. There are minimal changes in blood carbon dioxide
content unless the degree of mismatch is extremely severe. Inspired air and blood flow
normally are distributed uniformly, and each alveolus receives approximately equal quantities
of both. As matching of inspired air and blood flow deviates from the normal ratio of 1 to 1,
alveoli become either overventilated or underventilated in relation to their blood flow. In
alveoli that are overventilated, the amount of carbon dioxide eliminated is increased, which
counteracts the fact that there is less carbon dioxide eliminated in the alveoli that are relatively
underventilated. Overventilated alveoli, however, cannot compensate in terms of greater
oxygenation for underventilated alveoli because, as is shown in the oxygen-dissociation curve,
a plateau is reached at the alveolar partial pressure of oxygen, and increased ventilation will
not increase blood oxygen content. In healthy lungs there is a narrow distribution of the ratio
of ventilation to blood flow throughout the lung that is centred around a ratio of 1 to 1. In
disease, this distribution can broaden substantially so that individual alveoli can have ratios
that markedly deviate from the ratio of 1 to 1. Any deviation from the usual clustering around
the ratio of 1 to 1 leads to decreased blood oxygenation—the more disparate the deviation, the
greater the reduction in blood oxygenation. Carbon dioxide exchange, on the other hand, is not
affected by an abnormal ratio of ventilation and blood flow as long as the increase in
ventilation that is required to maintain carbon dioxide excretion in overventilated alveoli can
be achieved.
A fourth category of abnormal gas exchange involves limitation of diffusion of gases across
the thin membrane separating the alveoli from the pulmonary capillaries. A variety of
processes can interfere with this orderly exchange; for oxygen, these include increased
thickness of the alveolar–capillary membrane, loss of surface area available for diffusion of
oxygen, a reduction in the alveolar partial pressure of oxygen required for diffusion, and
decreased time available for exchange due to increased velocity of flow. These factors are
usually grouped under the broad description of “diffusion limitation,” and any can cause
incomplete transfer of oxygen with a resultant reduction in blood oxygen content. There is no
diffusion limitation of the exchange of carbon dioxide because this gas is more soluble than
oxygen in the alveolar–capillary membrane, which facilitates carbon dioxide exchange. The
complex reactions involved in carbon dioxide transport proceed with sufficient rapidity to
avoid being a significant limiting factor in exchange.
Robert A. Klocke
Citation Information
Article Title: human respiratory system
Website Name: Encyclopaedia Britannica
Publisher: Encyclopaedia Britannica, Inc.
Date Published: 01 December 2023
URL: https://www.britannica.comhttps://www.britannica.com/science/human-respiratory-system
Access Date: January 02, 2024

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1/2/24, 9:52 PM human respiratory system -- Britannica Online Encyclopedia

The design of the respiratory system

The upper airway system comprises the nose and the

Morphology of the upper airways

Morphology of the lower airways

Behind the shieldlike thyroid cartilage, the vocal cords

The trachea and the stem bronchi

Structural design of the airway tree

The hierarchy of the dividing airways, and partly also of

The intrapulmonary conducting airways: bronchi and bronchioles

The gas-exchange region

Blood vessels, lymphatic vessels, and nerves

Central organization of respiratory neurons

Neurally, inspiration is characterized by an augmenting discharge of medullary neurons that

Muscle and lung receptors

The lung–chest system

The role of muscles

The respiratory pump and its performance

Hemoglobin is a protein made up of millilitre of blood. The quantity of oxygen bound to

Temperature changes affect the oxygen-dissociation curve similarly. An increase in

Transport of carbon dioxide

Gas exchange in the lung

Abnormal gas exchange

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