Discussion
Neuropeptides are a kind of special information substances, which
generally refer to the endogenous active substances that exist in
nervous tissues and participate in the function of the nervous system.
It is characterized by low content, high activity, extensive and complex
effects, and regulates a variety of physiological functions in the body,
such as pain, sleep, emotions, learning and memory, and even the
differentiation and development of the nervous system itself are
regulated by neuropeptides. Neuropeptides not only exist in the nervous
system, but also widely exist in various systems throughout the body,
playing various roles such as neurohormones, neurotransmitters,
neuromodulators, and cytokines, and playing important regulatory roles
in various physiological functions at various stages of biological
development7. In recent years, with the development of
molecular biology technology, the research of neuropeptides is making
rapid progress with each passing day.
The novel coronavirus may invade sensory neurons and glial cells of the
vagus nerve, inducing the release of neuropeptides and inflammatory
mediators. Epithelial cells and inflammatory cells (such as macrophages,
neutrophils, lymphocytes, etc.) involved in COVID-19 infection and
recognition can release a variety of cytokines and inflammatory
mediators8. Neuropeptides and neuroinflammatory
mediators can further recruit and activate immune cells, cause lung and
airway inflammation, and enhance cough sensitivity. The nerve-phagocytic
nature of the novel coronavirus leads to the release of various
inflammatory mediators such as histamine, triggering neurogenic
inflammation, and directly or indirectly stimulating nerve receptors,
resulting in increased cough sensitivity9. COVID-19
infection can induce eosinophilic bronchitis or airway
hyperresponsiveness, a subacute stage of eosinophilic bronchial
inflammation, or cough-variant asthma. At present, a large number of
studies have found that local glucocorticoids can reduce bronchial
inflammation caused by COVID-19 infection or the subacute stage of
variant asthma, mainly through a wide range of effects on structural
cells and inflammatory cells, and multi-target blocking airway
inflammation. It also reduces neuroreceptor sensitivity by reducing
neurogenic inflammation. This suggests that the abnormal release of
neuropeptides plays a major role in the pathogenesis of COVID-1910,11.
ACE2 is distributed in almost all immune cells and endothelial cells,
and its loss in these two cells will lead to the weakening and failure
of many important organs in the body12. COVID-19 has a
high affinity with ACE2 receptors, and ACE2 is highly expressed in some
COVID-19 infections with chronic underlying diseases and elderly people,
suggesting that more ACE2 is needed to counteract the adverse effects of
angiotensin II13,14. The number of ACE2 receptors is
related to age and body health. Studies have shown that the expression
of ACE2 in children’s nasal epithelial cells is low. In this study, the
expression of ACE and ACE2 in children’s COVID-19 group was not high.
There was no significant correlation with the expression of
LDH/N%/L%/CRP, an inflammatory indicator of the disease, similar to
foreign studies, which may be one of the reasons why children are more
tolerant to COVID-19 and have a lower incidence of severe diseases.
ASCL1, a key transcription factor in the development of autonomic
ganglia that is overexpressed in fibroblasts, has not been detected in
COVID-19-infected patients. Studies have shown that specifically
knocking out the ASCL1 gene in asthmatic mice can restrict nerve
conduction in lung tissue. At the same time, the levels of inflammatory
cells such as Th2, eosinophil, and ILC2 cells were significantly lower
than those of wild-type mice, and the expressions of IL-5 and IL-13 were
also significantly lower than those of the control group. It is
suggested that ASCL1 plays an important role in airway neuroendocrine
regulation. In particular, it plays an important role in the occurrence
of human wheezing. In this study, the expression level of ASCL1 was
negatively correlated with N% and CRP, suggesting that ASCL1 may play a
certain role in the inflammation of COVID-19. Further studies on the
mechanism of action and larger samples will be discussed in the future.
Gastrin-releasing peptide (GRP) is a neuropeptide widely available in
the central nervous system. It has a high affinity with GRP receptor
(GRPR) and its expression in different brain regions can participate in
different functions. Such as itch, sighing, fear memory, and so on.
Recent studies have shown that GRP is significantly elevated in children
with asthma, and the use of GRP blockers and GRP antibodies can prevent
the abnormal increase of airway reactivity in asthmatic mouse models
stimulated by OVA, reduce the number of macrophages and granulocytes in
bronchoalveolar lavage fluid, and reduce the levels of IL-5, IL-13, and
other cytokines. In this study, there was no statistically significant
difference in GRP/VIP expression between COVID-19 infection and
non-COVID-19 infection. These results suggest that GRP/VIP has different
roles in asthma and COVID-19 infection, so its expression level may be
conducive to distinguishing acute asthma attacks or asthma combined with
COVID-19 infection.
VIP is distributed in the nerve endings of the bronchial smooth muscle
near the human lung and around the submucosal glands of the lung and
bronchus. The enzymes released by inflammatory cells in children with
asthma will degrade and destroy VIP, which is conducive to cholinergic
nerve action and leads to bronchospasm. Therefore, VIP mainly acts as an
inhibitory neurotransmitter in the body.
SP is the most abundant sensory neuropeptide in the lung. When SP is
released from the sensory nerve by the axonal reflex after inhalation of
stimuli, it can induce bronchoconstriction by binding to the specific
opposite receptors in the lung, resulting in wheezing. At the same time,
SP is involved in the occurrence of lung immune regulation and
inflammatory response, and SP has a chemotactic effect on T cells,
mononuclear macrophages, and eosinophils15,16.
SP level in the sputum of
asthmatic patients and chronic bronchitis patients is significantly
higher than that of the control group, and SP level in asthmatic
patients induced sputum is positively correlated with eosinophils
level17. SP has not been studied in children with
COVID-19 infection. Cough and wheezing are usually one of the main
symptoms in children infected with COVID-19. The specific mechanism of
cough and wheezing remains unclear. Non-specific inflammation of the
lung interstitial is the main pathophysiological change.
In this study, the expression of neuropeptide-related molecules in
COVID-19-infected patients and their correlation with inflammatory
indicators were preliminarily analyzed. It was found that, unlike
adults, ACE and ACE2 expression was not high in children with COVID-19.
The level of neuropeptide ASCL1 in children with COVID-19 was lower than
that in non-COVID-19 children, which may indicate that the expression
level of ASCL1 may be decreased in COVID-19 patients. At the same time,
the expression level of ASCL1 is negatively correlated with N% and CRP,
suggesting that ASCL1 may play a certain role in COVID-19 inflammation.
Limited by the size of the sample size, this project failed to conduct
large-sample and multi-center clinical studies. However, we have
provided a new research entry point for COVID-19 infection, focusing on
the level of neuropeptides. We will further explore the role of
neuropeptides in lung diseases caused by COVID-19 infection through in
vivo and in vitro experiments to provide accurate treatment for COVID-19
Therapy provides a new theoretical basis.
Acknowledgments Not applicable.
Funding This work was supported by the Basic and Applied Basic
Research Foundation of Guangdong Medical Research Foundation (grant
number A2023345), Zhong Nanshan Medical Foundation of Guangdong Province
(grant number 202102010343) and the Science and Technology Program of
Guangzhou (grant number
202102010276).