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Chest pain in patients with COPD: the fascia’s

subtle silence
This article was published in the following Dove Press journal:
International Journal of COPD

Bruno Bordoni 1 Abstract: COPD is a progressive condition that leads to a pathological degeneration of the
Fabiola Marelli 2,3 respiratory system. It represents one of the most important causes of mortality and morbidity
Bruno Morabito 2–4 in the world, and it is characterized by the presence of many associated comorbidities. Recent
Roberto Castagna 2 studies emphasize the thoracic area as one of the areas of the body concerned by the presence
of pain with percentages between 22% and 54% in patients with COPD. This article analyzes
1
Foundation Don Carlo Gnocchi
IRCCS, Department of Cardiology, the possible causes of mediastinal pain, including those less frequently taken into consideration,
Institute of Hospitalization and Care which concern the role of the fascial system of the mediastinum. The latter can be a source
with Scientific Address, Milan, Italy; of pain especially when a chronic pathology is altering the structure of the connective tissue.
2
CRESO, School of Osteopathic
Centre for Research and Studies, We conclude that to consider the fascia in daily clinical activity may improve the therapeutic
Gorla Minore, Italy; 3CRESO, School approach toward the patient.
of Osteopathic Centre for Research
Keywords: COPD, diaphragm, thoracic pain, fascia, muscle pain
and Studies, Fano, Italy; 4Department
of Radiological, Oncological and
Anatomopathological Sciences,
Sapienza University of Rome, Introduction
Rome, Italy COPD is a worsening/degenerative condition that leads to a pathological degeneration
of the respiratory system.1 It represents one of the most important causes of mortality
and morbidity in the world, and it is characterized by the presence of many associated
comorbidities. The World Health Organization (WHO) estimated a current mortality
rate of ~64 million people per year, and in 2030 COPD will represent the third cause
of mortality in the world.2 Approximately 51% of patients with COPD reportedly
have at least a comorbidity, although the precise relation between COPD and these
comorbidities is not entirely clear.1–3 This pathological scenario is associated with a
decrease in survival rates and with more frequent hospitalization.3
There is a strong relation between the presence of pain perceived by the patient
and the presence of comorbidities.3 This clinical picture worsens where the patient
suffers from anxiety or depression or from other preexisting pathologies.3,4 The pain
experienced by patients with COPD is stronger than the one perceived by those without
a respiratory pathology or by patients with other chronic diseases. The former is only
comparable to the pain observed in oncologic patients at the terminal stage.3,5 The most
common causes of pain are arthritis, osteoporosis, systemic myopathy and costochon-
dritis. Pain is generally localized in the trunk, the neck, the lumbodorsal area and the
Correspondence: Bruno Bordoni inferior limbs.3 Female patients allegedly report to experience a stronger pain.5
Foundation Don Carlo Gnocchi IRCCS, Recent studies emphasize the thoracic area as one of the body areas concerned by the
Department of Cardiology, Institute
of Hospitalization and Care with presence of pain, with percentages between 22% and 54% in patients with COPD.5,6
Scientific Address, S Maria Nascente, This article analyzes the potential causes of mediastinal pain, that is, gastroesopha-
Via Capecelatro 66, Milan 20100, Italy
Tel +39 2 34 9630 0617
geal reflux disease (GERD), a loss of elasticity of the parietal pleura, the visceral pleural
Email [email protected] receptors (VPRs) and vagal receptors, bronchial spasm or edema or a pathological

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Figure 1 Chest CT on axial planes. Chest CT usually shows emphysema which can be centrilobular, panlobular or paraseptal; the first one is the most common type of
emphysema (A), usually related to smoking status and more marked in the upper lobes; the parenchymal destruction is centered around the terminal bronchiole, representing
the center of the secondary pulmonary lobule. Other findings include bronchial wall thickening (B), air trapping and narrowing of the trachea in the coronal plane.
Abbreviation: CT, computed tomography.

adaptation of the diaphragm and from its innervating system. can suffer from adhesions with the visceral pleura and
Furthermore, this article considers the other possible sources from scarring processes caused by a chronic inflammatory
of mediastinal pain that are related to the fascial system, environment. In patients with COPD, the presence of inflam-
which is an integral part of the somatic and visceral thoracic matory cytokines, such as transforming growth factor-beta,
area: the muscular and fascial system of the rib cage, the weakens the immune system, favoring adhesions and scars
movement and shape of the rib cage and the endothoracic in the pleurae (parietal and visceral).10 In the animal model,
and visceral fascia (Figure 1A and B). pleural adhesions determine the creation ex novo of nervous
and vascular structures, suggesting that these adhesions can
Thoracic pain: non-fascial causes be a source of pain.11 The creation of pleural adhesions
GERD and scars further reduces the lung expansion in patients
Thoracic pain can have multiple, isolated or concomitant, with COPD.9
causes. The presence of GERD and/or hiatal hernia is a
comorbidity often found in patients with COPD. This can be VPRs
due to the peripheral sensitization provoked by the constant Another source of thoracic pain can be the visceral pleura.
stimulation of inflammatory mediators (pepsin, bile, ATP, The VPRs are myelinated sensitive nervous fibers that derive
cytokines, hydrochloric acid and histamine), which lower from the spinal roots of the upper dorsal tract, which could
the vagal and nociceptive afferential threshold. This reduc- reach the lungs through the sympathetic trunks.12 The VPRs
tion increases the permeability to cations of pain receptors, are connected to the elastic fibers of the pulmonary paren-
with the appearance of primary hyperalgesia. With time, chyma, and they are thought to be able to translate mechanical
other nociceptors will activate, including acid-sensing ion or pain stimuli in electric signals.8 If the mechanical envi-
channels, transient receptor potential V1 and P2X purinocep- ronment is altered or overstimulated, these receptors will
tors (ATP-gated ion channel).7 This symptomatological activate rapidly.13 The overstretching of the visceral pleura
scenario can lead to phenomena such as secondary hyperal- caused by a chronic overinflation of the lungs, for example,
gesia and allodynia, with central sensitization caused by the could stimulate these receptors.
persistent involvement of medullary neurons and cerebral
areas, and the subsequent involvement of the psychoneuroim- Vagal receptors
mune system.7 We invite the reader, if interested, to reread There are at least seven different vagal receptors in the
the article by Boeckxstaens and Rohof.7 pulmonary area, such as high-threshold A-delta receptors
and bronchial and pulmonary C-fiber receptors, which are
Loss of elasticity of the parietal pleura considered as nociceptors.12 These receptors may send painful
Thoracic pain in patients with COPD can also derive from the sensations because of an altered mechano-metabolic envi-
loss of elasticity of the parietal pleura, which is innervated ronment. The inflammation of bronchial pathways causes
by somatic fibers (intercostal nerves), and sympathetic and the production of free radicals (reactive oxygen species)
vagal fibers and contains nociceptors.8,9 The parietal pleura (H2O2, isoprostanes and nitrotyrosine residues), which can

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Dovepress Chest pain in patients with COPD

be found in patients with COPD and which may activate inhalation or the flowing of blood.15 The baroreceptorial
these receptors.13 afferences are gathered by the nucleus of the solitary tract
(NTS), which modulates the efferential intervention to the
Bronchial spasm vagal system and the sympathetic inhibitory efference on a
When there is a constriction, a spasm or an edema, the spinal level in the proximity of the nucleus ambiguus, of the
bronchial pathways can be a source of thoracic pain. This dorsal motor nucleus and of the ventrolateral rostral area of
happens because of the activation of the abovementioned the medulla oblongata.16 The afferences influence different
vagal receptors.13 It is important to remember that, in the areas of the central nervous system, with a general inhibitory
presence of COPD, the mechanical bronchial tension can effect. The NTS is interconnected with the reticular forma-
radically change, because of the remodeling of the inner tion, sending information to the anterior, lateromedial and
bronchial structure caused by constant inflammation. The prefrontal insulae and to the anterior cingulate cortex; the
epithelium can generate fibroblasts, creating a pathological thalamus, the hypothalamus and the periaqueductal gray area
bronchial fibrosis.14 receive baroreceptorial signals from the NTS.16 In a healthy
The intrapulmonary epithelium is innervated by a group context, the diaphragm stimulates the baroreceptors to raise
of pulmonary neuroendocrine cells (PNECs), which can be the pain threshold, favoring, with its movements, the upward
activated by mechanical stimuli such as stretching or meta- venous and lymphatic return.4,15 This modulation of pressure
bolic changes.12 We still know little about PNECs, but they influences the redistribution of blood, which is probably the
could probably play a role in the sensation of pain.12 action that determines the response of the baroreceptors and
the perception of pain.4,15 Chronic and acute pain can alter the
A pathological adaptation of the diaphragm functions of the baroreceptors, just like an altered function
and from its innervating system and position of the diaphragm can negatively influence the
The limitation of the progressive air flux in patients affected baroreceptorial system.4,15 This creates a vicious circle, and
by COPD determines a pathological adaptation of the dia- it becomes difficult to understand the cause and the effect.
phragm, even though these changes are still not entirely
understood. The respiratory district changes position, The vagus nerve and the perception
influencing negatively patients’ tolerance for exercise. of pain
The diaphragmatic dome is lower in inhaling attitude.4 The afferences of the vagus nerve are generally able to inhibit
Contractile strength diminishes, with metabolic and electric the activity of the second order of medullary neurons in the
alterations. The muscle thickness increases, particularly in spinothalamic and spinoreticular tracts and in the trigeminal
the left side, with diminished mechanical excursion.4 This nuclei.4,15 Recent scientific evidence, however, highlights the
increase is probably due to the shortening of the fibers. There ability to transport painful afferences from the vagus nerve,
is a decrease in the presence of fibers of the anaerobic type particularly visceral pain to supraspinal centers.4,15 This
(type II) and an increase in aerobic fibers (type I), a circum- happens also because of the retrograde transport of inflam-
stance which becomes increasingly relevant as the pathology matory biochemical substances that travel through the nerve.
advances. The increase in the oxidative capacity, though, The nerve itself cooperates in the creation and the mainte-
does not coincide with the improvement of the diaphragmatic nance of pain memory at a central level, also modulating the
function. The percentage of myosin drops, with an altered descending inhibitory pathway that leads back to the noci-
sarcomeric organization, further decreasing the expression ceptive medullary areas.4,15 We have no precise information
of contractile strength.4 Phrenic activity is altered, probably on these and descending mechanisms (probably involving
because of the strain caused by the chronic lowering of the the NTS, the parabrachial nuclei, the periaqueductal gray
diaphragm, producing neuropathy.4 The diaphragm influ- area, the hypothalamus, the limbic area, the magnus raphe
ences the perception of pain and the emotional state of the nucleus and the locus coeruleus), but we can state that the
individual. This event seems to mirror the intervention of vagal tone has an important influence on the perception of
the baroreceptors.4 pain.15 We know that the compression of the vagus nerve can
The baroreceptors located in the carotid body and in the alter its function and ability to transport, just like the dysfunc-
area of the aortic arch, in the adventitia of the vessels, are tion of a peripheral nerve, mimicking the nerve entrapment
structures that activate particularly, thanks to mechanical syndrome.17 We can suppose that an anomalous tension of
stimuli, for instance, when the vessels are stretched during the diaphragm in the area of the vagal passage could induce

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the compression of the nerve, negatively affecting its anti- Thoracic pain: possible fascial
nociceptive and anti-inflammatory ability.17 somatic causes
The muscular system of the rib cage is an integral part of the
The phrenic nerve and the perception fascial continuum.26 At present, there is no univocal definition
of fascia, probably because of the scientific imprint of each
of pain
professional who tries to create a single point of view.27 From
The phrenic nerve is a mixed nerve, able to send efferences
a macro-anatomic perspective, the fascial tissue is equally
to the diaphragm and to receive a lot of visceral information,
distributed throughout the entire body, creating various
as well as information from the lungs, the pericardium, the
layers at different depths and forming a three-dimensional
vena cava, the Glisson’s capsule and the peritoneal subdia-
metabolic and mechanical matrix.28 The fascial organization
phragmatic area.18 Considering the pathological condition
that covers the contractile part of the muscle can be defined
of the phrenic nerve in patients with COPD (neuropathy
as the myofascial system.26 The fascia allows the muscles
and constant nerve stretching), its anastomoses with the
to act in synergy, thanks to the fact that the fascial tissues
vagus nerve at the level of the ansa cervicalis and the
connect all the muscular districts.26
relation with the NTS, we could suppose that there are
phrenic, somatic and visceral nociceptive afferences.17–19
Through the spinothalamic tract and near the medullary The movement and shape of the rib cage
segment C2–C3, the phrenic afferences overlap with visceral The movement and shape of the rib cage are altered in patients
and trigeminal vagal afferences, precisely in the dorsal with COPD. The anteroposterior axis of the chest is some
areas of the laminae I–IV.20,21 Phrenic afferences transport centimeters longer than in healthy patients, particularly in the
mechanical (proprioceptive and mechanoreceptors) and lower area, taking a rounder form.29 During forced breathing,
nociceptive information, not only from the diaphragm but however, patients have less rib mobility than people who are
also from the viscera that they meet on their path.21,22 not affected by chronic respiratory disorders.29 Sternocostal
The difficulty of the inspiratory muscle to bear protracted and costovertebral joints become stiffer, with a reduced
solicitations puts the respiration in a context of fatigue.5,23 ability to move; we can often notice a hyperkyphosis ten-
Diaphragmatic fatigue in patients with COPD is more prob- dency of the thoracic spine in patients who are in an advanced
ably related to the central nervous system.24 Regardless of stage of the disease.30 Costal biomechanics changes, alter-
the cause that leads to diaphragmatic fatigue, in the presence ing the physiologic movement during inhalation. Lower
of contractile difficulty, the phrenic afferences of type IV lateral ribs paradoxically tend to move inwards (Hoover’s
transport nociceptive and somatic information.25 sign) during inhalation.31 A paradox movement of the lower
Thoracic pain in patients with COPD can also originate sternum during inhalation can also occur.32 Joint stiffness and
from cardiac pathologies, often connected to the presence of altered costal dynamics could be related to the somatic fascial
chronic respiratory disorders.5 system (thoracic rib muscles) (Figure 2A and B).

Figure 2 Chest X-ray in PA (A) and LL (B) projections. Chest X-ray has poor sensitivity to detect COPD; possible findings include prominence of the hilar vessels and
decreased peripheral bronchovascular markings, flattened diaphragm due to hyperexpansion and hyperkyphosis and increased lung lucency (especially seen in the retrosternal
region in LL projection) and bullae (round focal lucency over 1 cm).
Abbreviations: PA, posterior–anterior; LL, latero-lateral.

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Somatic fascial system (group II and IV, respectively, myelinated and non-myelinated)
One of the causes of thoracic pain in patients with COPD that gather nociceptive information by mechanical, chemical
can be related to costal muscles, which face an alteration of and thermal stimuli. These somatic afferences travel inside
their physiologic length (shortening or lengthening) caused intercostal nerves, bringing information to the lamina I in the
by the change of costal biomechanics, influenced in turn by medullary dorsal area, from where they will travel through
lung movements.9,29,33 the spinothalamic tract to the central nervous system, the
There are different muscles that operate on the ribs and that nucleus submedius, the anterior paraventricular nucleus,
take part in the respiratory acts, whose behavior is not always the posterolateral ventral nuclei of the thalamus, the anterior
easy to determine. Externally, the intercostal muscles are cingulate cortex, the primary and secondary somatosensory
covered by the deep fascia originating from the deep cervical cortex, the prefrontal cortex and the insular cortex.43–45
fascia, while, internally, they are covered by the endothoracic A constant stimulation of the nociceptive system will
fascia. Laterally, these muscles form two thin layers between cause a plastic change in the peripheral and central nervous
the intercostal spaces: one is located more externally, forming structures, creating the mechanism known as sensitization.16
the external intercostal contractile districts, while the other is The latter manifests itself as a lowering of the threshold of
located internally, forming the internal intercostal muscles.34 activation of spinal neurons (allodynia). In chronic condi-
Behind these muscles and near the vertebrae, the external tions, the pathways of nociceptive excitation activate even
intercostal muscles form the levator doral muscles, while the when the original stimulus has ceased (hyperalgesia),
external intercostal muscles form the subcostal muscles.34,35 often causing a similar response also by the neighbor-
In the abdomen, between the sternum and the costochondral ing tissues which have not been necessarily damaged
joint, the external intercostal muscles form a fibrous aponeu- (secondary hyperalgesia).16
rosis or anterior intercostal membrane, while the internal
intercostal muscles form the intercostal parasternal muscles.34 The deep fascia
The latter are covered by the triangularis sterni muscle or The deep fascia that covers externally the intercostal muscles
transversus thoracis muscle.36 The intercostal muscles that we and the endothoracic fascia that covers the inside of the rib
described are innervated by the respective intercostal nerves.34 cage could be sources of chronic pain. The deep fascia origi-
The description of the respiratory footprint of these nates from the deep cervical fascia.46,47 Thanks to studies on
muscles lies outside the context of this article (on this point, other fascial areas of the human body (lower limbs, abdomen,
we refer the reader to the article by De Troyer et al).34 trunk and cervical tract), we know that the fascial tissue can be
To understand how costal muscular districts act, it is innervated by spinal nerves and/or by the sympathetic system.
important to remember the multiple vectors of the contractile These fibers are able to transport nociceptive afferences.48–50
fibers and the disposition of each rib: the muscular moment In the fascia that covers intercostal muscles and in the pectoral
changes depending on the costal disposition (Hamberger fascia, there are nervous fibers that respond to the mechanical
mechanism).34 We know that the costal position changes in and nociceptive stimuli (polymodal receptors with fibers of
patients with COPD, so we can deduce that the costal con- type C), which are activated by the stretching of the rib cage.51
tractile apparatus is in an unfavorable and non-physiologic We know that the rib cage suffers from a biomechanical
biomechanical situation.34,37 limitation and that costal muscles tend to become fibrotic.
The muscular respiratory disadvantage increases the We know that the fascial tissue is in close proximity to the
risk of hospitalization.37 Costal muscles work harder, and muscles (deep fascia and epimysium) and that it can suffer
weakness, fatigue and inflammation appear.37–39 The level of from the same non-physiologic adaptation of the contractile
inflammatory cytokines found in costal muscles is linked to districts (and vice versa).28,50,52 We know that the nociceptors
the seriousness of COPD.40 Muscles suffer from hypotrophy that are in the fascia have a lower threshold of activation if
with an increase in the amount of fat inside contractile fibers. the fascial tissue is less compliant (greater stiffness).52 We can
This sarcopenia correlates with the severity of COPD.41 suppose that the deep fascia covering externally the ribs is
During intense exercise, costal muscles suffer from a reduc- one of the causes of thoracic pain.
tion of blood perfusion, mirroring the inability of the circula-
tory system to satisfy the needs of the peripheral muscles.42 The endothoracic fascia
Costal muscles can be a source of chronic pain. The The endothoracic fascia derives from the deep cervical fascia
contractile and connective tissues have nervous terminals and delimits the internal costal area, covering the intercostal

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muscles and touching the parietal pleura.53–55 It contains behind the subclavian and the brachiocephalic arteries. This
lymphatic vessels, particularly in the parasternal and para- connection is called interpleural ligament or ligament of
vertebral areas. Especially in the latter, the endothoracic Morosow.62 In the inferior mediastinum, the esophagus (right
fascia comes into contact with spinal nerves and sympathetic side) and the aorta connect with a fascial structure, whose
ganglia. Vessels of the internal mammary artery can be fascial boundaries attach bilaterally to the pulmonary fascia.62
found in the parasternal area of the fascia.55,56 The fibrosis The fascia between the esophagus and the descending aorta
of the different tissues that can be found in patients with is called meso-esophageal fascia, with the presence of vagal
COPD (muscles and pulmonary system) could be noticed terminals. This fascia is connected to the bronchi, to the peri-
in the endothoracic fascia as well, for reasons linked to cardial sac (area of the left atrium) and to the trachea.63,64
anatomic and functional continuity. The fascia influences Among the intrathoracic fasciae, we also have the broncho-
the function of the viscera it wraps around and vice versa.28,57 pericardial or tracheobroncho-pericardial ligament.65 It con-
The fibrosis of the muscles, the fascia or the visceral tissues nects the terminal part of the trachea and the bronchi with
is similar to the wound-healing mechanism, which modifies the pericardium (area of the left atrium), anteriorly.65 The
the mechanical abilities, without necessarily altering their pretracheal fascia, deriving from the deep fascia of the neck,
shape.58 The deep fascia, like the endothoracic fascia, is made originates from the upper boundary of the thyroid cartilage,
up of several layers that slide over one another (a layer defined then covers the trachea anteriorly, touches the posterior part of
as subserous layer of connective tissue is located between the parietal pericardium (the fascia that envelopes the heart)
the endothoracic fascia and the parietal pleura); it is made and joins the endothoracic fascia covering the diaphragm.66
up of structures which render it elastic, for example, elastin, It is probably innervated by the recurrent laryngeal nerve.66
proteoglycans, glycosaminoglycans and hyaluronic acid.58,59 The parietal pericardium is a connective structure; it is the
The different layers will lose the anisotropic ability to slide if fascial system that covers the pericardial sac, connecting the
they lose water and hyaluronic acid (like in fibroses), creating heart and the abovementioned structures with the diaphragm,
greater stiffness and density of the tissue. This happens in the the sternum, some ribs (from the fourth to the sixth one on
fascial tissue of many anatomic areas where there is chronic the left) and the thoracic vertebrae (D10–D11).67 The pari-
pain (back, neck) or in pathologies (diabetes, traumata and etal pleura is innervated by phrenic nerves, the sympathetic
surgery and hormonal variations) and aging.58 The fascial tis- system and the vagus nerve.67
sue that loses part of its ability to slide could create adhesions We have no data on how the fascial web adapts inside the
to the tissues it comes into contact with, further stimulating mediastinum in patients with COPD. We know that the fascia
the nociceptive fascial afferences.49 We have no data on the can lose its elasticity and, probably, negatively influence the
adaptation of the endothoracic fascia in patients with COPD, viscera that it covers or with which it is in contact, altering
but we can suppose, considering scientific elements coming visceral elasticity. This could lead to a change in the move-
from other body areas, that this deep structure could be one ment and shape of the viscera themselves, an event that, as
of the sources of the chronic pain perceived by patients. we know, can occur in the respiratory and cardiac systems
in the presence of chronic pathologies of the airways.68,69
The visceral fascia An anomalous distention of the viscera could activate
The different organs of the mediastinum communicate with nociceptive pathways connected to the cerebellum through
one another, thanks to visceral fascial relations. The visceral mossy and climbing fibers and diffuse monoaminergic and
fascia that covers the organs and connects them with other cholinergic afferents.70 A-delta fibers and C-fibers, afferential
organs is able to stretch and to adapt to the shape and move- nociceptive pathways, activate the previously mentioned
ments of the viscera. In the presence of traumas, infections nervous fibers through postsynaptic connections in the dorsal
or inflammations, the visceral fascia loses its compliance medullary area. Through the spino-olivo-cerebellar pathway,
and adaptability to the viscera, causing reduced movement the nociceptive information reaches the Purkinje cells of the
capability and pain.60 The fascia that envelopes the lung is cerebellum.70 The cerebellum processes this nociceptive
rich in elastic and sympathetic fibers.60 The visceral fascia information through motor efferences.70 This scenario could
that covers the lungs is closely connected to the fascial layer be one of the reasons for the lack of motor coordination found
that envelopes the pericardium (parietal pericardium) and in patients with COPD.71
to the endothoracic fascia.61 In the superior mediastinum, The pain coming from the viscera, caused by the stiffness
the pulmonary visceral fascia connects the two lungs, passing of the visceral fascia, could not only be one of the causes

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of perceived pain but also contribute to the patients’ lack of remains a largely underexplored area in pathologies such as
neuromotor coordination. COPD, even though it would deserve more attention and
The visceral fascial system could be considered as a more extensive research. The focus of this article was to
proprioceptive organ.72 The fascia that envelopes and links hypothesize the possible nociceptive scenarios coming from
the different mediastinal organs is probably a tool that the the fascial tissue, such as the external thoracic fascia and
central nervous system uses to perceive the functional status the costal muscular complex, the endothoracic fascia and
of the organs, just like its position.27 If an alteration of the the fascial connections between the viscera of the thorax.
fascial mechanical tension (stiffness) occurs, the propriocep- In a local and systemic inflammatory environment such as
tive terminals will send nociceptive information, determin- that existing in the presence of COPD or of other mechani-
ing another cause of the mediastinal pain perceived by the cal and morphological alterations of the ribs and sternum, it
patients.27 makes sense to take into consideration the fascial system as
The inflammation itself could cause nociceptive fascial a potential source of pain.
afferences.73 The fascia has endocannabinoid receptors
(CB1 and CB2), which, once activated, are able to eliminate Disclosure
pro-inflammatory cytokines. The presence of an inflamma- The authors report no conflicts of interest in this work.
tion could alter the endocannabinoid receptor response.73
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