Ventilation of the lungs provides O2
for the tissues and removes CO2. Breathing must therefore be closely matched to metabolism for adequate O2
delivery and to prevent a build-up of CO2. A central pattern generator located
in the brain stem sets the basic rhythm and pattern of ventilation and controls
the respiratory muscles. It is modulated by higher centres and feedback from sensors,
including chemoreceptors, and lung mechanoreceptors (Fig. 29a). The
neural networks are complex, as breathing must be coordinated with coughing, swallowing
and speech, and are not fully understood.
The brain stem and central pattern
generator
The brain stem includes diffuse groups
of respiratory neurones in the pons and medulla that act together
as the central pattern generator (Fig. 29a); it is unclear whether there is a single
pacemaker region. Some neurones only show activity during inspiration or expiration,
and these exhibit reciprocal inhibition, i.e. inspiration inhibits expiration and vice versa. The medulla contains dorsal and ventral respira-
tory groups that receive input from the chemoreceptors and lung receptors and
drive the respiratory muscle motor neurones [inter-costals, phrenic (diaphragm),
abdominal]. The medullary respiratory groups also provide ascending input to and
receive descending input from the pneumotaxic centre in the pons, which is
critical for normal breathing. The pneumotaxic centre receives input from the hypothalamus and higher centres, coordinates medullary homeostatic functions with factors
such as emotion and temperature, and affects the pattern of breathing. Voluntary
control is mediated by cortical motor neurones in the pyramidal tract, which
by-passes the respiratory neurones in the brainstem.
Chemoreception
Chemoreceptors detect arterial Pco2, Po2 and pH – Pco2 is the most
important. Alveolar Pco2 (PAco2) is normally ∼5.3 kPa (40 mmHg), and PAo2
normally 13 kPa (100 mmHg). An increase in PAco2 causes ventilation to rise in an
almost linear fashion (Fig. 29d). Increased acidity of the blood (e.g. lactic acidosis in severe exercise) causes the
relationship between Pco2 and ventilation to shift to the left, and decreased acidity
causes a shift to the right. Conversely, Po2 normally stimulates ventilation only
when it falls below ∼8 kPa (∼60 mmHg) (Fig. 29e). However, when a fall in Po2
is accompanied by an increase in Pco2, the resultant increase in ventilation is
greater than would be expected from the effects of either alone; there is thus a
synergistic (more than additive) relationship between Po2 and Pco2 (Fig.
29e).
The central chemoreceptor comprises
a collection of neurones near the ventrolateral surface of the medulla, close to
the exit of the cranial nerves IX and X (Fig. 29b). It responds indirectly to
blood Pco2, but does not respond to changes in Po2. Although CO2 can easily
diffuse across the blood–brain barrier from the blood into the cerebrospinal
fluid (CSF), H+ and HCO3 cannot. As
a result, the pH of the CSF around
the chemoreceptor is determined by the arterial Pco2 and CSF HCO −, according to
the Henderson–Hasselbalch equation (Fig. 29b). A rise in blood Pco2 therefore makes
the CSF more acid; this is detected by the chemoreceptor, which increases ventilation
to blow off CO2. The central chemoreceptor is responsible for ∼80% of
the response to CO2 in humans. Its response is delayed because CO2
has to diffuse across the blood–brain barrier.
As the blood–brain barrier is impermeable to H+, the central chemoreceptor is not
affected by blood pH.
The peripheral chemoreceptors are
located in the carotid and aortic bodies (Fig. 29c). The carotid bodies are
small distinct structures located at the bifurcation of the common carotid arteries,
and are innervated by the carotid sinus nerve and thence the glossopharyngeal
nerve. The carotid body is formed from glomus (type I) and sheath (type
II) cells. Glomus cells are chemoreceptive, contain neurotrans-mission-rich dense
granules and contact carotid sinus nerve axons. The aortic bodies are located
on the aortic arch and are innervated by the vagus. They are similar to carotid
bodies but functionally less important. Peripheral chemoreceptors respond to changes
in Pco2, H+ and, importantly, Po2.
They are responsible for ∼20% of the response to increased Pco2.
Lung receptors
Various types of lung receptor provide
feedback from the lungs to the respiratory centre. In addition, pain often
causes brief apnoea (cessation of breathing) followed by rapid breathing, and mechanical
or noxious stimulation of receptors in the trigeminal region and larynx
causes apnoea or spasm of the larynx.
Stretch receptors. These are located in the bronchial walls. Stimulation
(by stretch) causes short, shallow breaths, and delay of the next inspiratory cycle.
They provide negative feedback to turn off inspiration. They are mostly slowly
adapting (continue to fire with sustained stimulation) and are innervated by
the vagus. They are largely responsible for the Hering–Breuer inspiratory reflex,
in which lung inflation inhibits inspiration to prevent overinflation.
Juxtapulmonary (J) receptors. These are located on the alveolar and
bronchial walls close to the capillaries. They cause depression of somatic and visceral
activity by producing rapid shallow breathing or apnoea, a fall in heart rate and
blood pressure, laryngeal constriction and relaxation of the skeletal muscles via
spinal neurones. They are stimulated by increased alveolar wall fluid, oedema, microembolisms
and inflammation. The afferent nerves are small unmyelinated (C-fibre) or myelinated
nerves in the vagus.
Irritant receptors. These are located throughout the airways between
epithelial cells. In the trachea they cause cough, and in the lower airways hyperpnoea
(rapid breathing); stimulation also causes bronchial and laryngeal constriction.
They are also responsible for the deep augmented breaths every 5–20 min at
rest, reversing the slow collapse of the lungs that occurs in quiet breathing,
and may be involved in the first deep gasps of the newborn. They are stimulated
by irritant gases, smoke and dust, rapid large inflations and deflations, airway
deformation, pulmonary congestion and inflammation. The afferent nerves are
rapidly adapting myelinated fibres in the vagus.
Proprioceptors (position/length sensors).
These are located in the
Golgi tendon organs, muscle spindles and joints.
They are important for matching increased
load, and maintaining optimal tidal volume and frequency. They are stimulated by
shortening and load in the respiratory muscles (but not the diaphragm). Afferents
run to the spinal cord via the dorsal roots. It should be noted that input from
non-respiratory muscles and joints
can also stimulate breathing.
