COVID-19: excessive neuropeptide secretion by neuroendocrine cells in the lungs can lead to fluid buildup and poor oxygenation


COVID-19 has put a spotlight on the pulmonary and nervous systems, but there is still much to learn about how they interact. Researchers at University of California San Diego School of Medicine recently explored this relationship in the context of a childhood lung disease, but their findings may also apply to COVID-19 symptoms.

In a study published March 17, 2022, in the journal Developmental Cell, scientists show that excessive neuropeptide secretion by neuroendocrine cells in the lungs can lead to fluid buildup and poor oxygenation; blocking the neuropeptides may be an effective treatment.

Neuroendocrine cell hyperplasia of infancy (NEHI) is a lung disease affecting infants in which lung size and structure appear normal but blood-oxygen levels are consistently low. There is no disease-specific treatment available for NEHI, and most children require supplemental oxygen for many years.

The defining feature of NEHI is an increase in the number of pulmonary neuroendocrine cells (PNECs), a type of lung cell with many neuronal properties. These cells serve as a gateway between the nervous system and the lung, taking in signals about the air environment and directing the lung to respond. But until now, physicians did not know how these cells contribute to the disease, or if they merely proliferate in response.

Excess neuropeptides disrupt lung function in infant disease and COVID-19

In the new study, a team led by senior author Xin Sun, Ph.D., professor of pediatrics at UC San Diego School of Medicine and the Division of Biological Sciences, confirmed that a developmental increase in PNECs is what drives NEHI, and revealed how these neuron-like cells can disrupt lung function.

Using the first genetically engineered mouse model of NEHI, Sun’s team found that the overabundance of PNECs leads to excess secretion of their neuropeptide products. This includes calcitonin gene-related peptide (CGRP), a potent vasodilator.

In healthy lungs, oxygen and carbon dioxide move between the lung epithelium and the blood vessel endothelium in a process known as gas exchange. In NEHI, increased CGRP signals trigger a molecular sequence that weakens the seal between endothelial cells, making the blood vessels more permeable. This allows fluid to leak out of the blood vessels and into the lung, covering cells under a layer of liquid. Gasses then have to pass through this additional fluid layer, which disrupts the gas exchange process and lowers blood oxygenation.

“We were surprised to find that neuropeptides can play such a major role in gas exchange,” said Sun. “Researchers are just starting to appreciate the relationship between the nervous system and the lungs, but the more we understand it, the more we can modulate it to treat disease.”

First author Jinhao Xu, a Ph.D. student in the UC San Diego Division of Biological Sciences, showed that blocking CGRP signals with receptor antagonists could protect the endothelial barrier and improve oxygenation in NEHI mice. These findings suggest that neuropeptides may be a promising therapeutic target for conditions marked by excess lung fluid.

One such condition is acute respiratory distress syndrome (ARDS), a lung condition with multiple causes, including SARS-CoV-2 infection. In patients with COVID-19-associated ARDS, excess fluid is the primary cause of death.

Through collaborations with other UC San Diego School of Medicine faculty, the researchers were able to obtain lung tissue samples from COVID-19 patients. They found the samples also had an increased proportion of CGRP-secreting PNECs, suggesting the same mechanism may contribute to the excess fluid in COVID-19 lungs.

Sun notes that several CGRP and CGRP-receptor antagonists have already been approved by the U.S. Food and Drug Administration for the treatment of migraines, so future clinical trials could evaluate their potential to improve lung function.

“This study was a community effort between many researchers and physicians at UC San Diego,” said Sun. “Through these collaborations, we were able to take our work from the bedside to the bench. Our next steps are to help close this loop and bring our findings back to the patients.”

COVID-19 infection and stress
When severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reaches the oropharynx, there is an innate immune inflammatory response, and the patient develops fever, headache, sore throat, cough, malaise, myalgia, arthralgia, anosmia, ageusia, and occasional diarrhea [14].

The next stage is the invasion of the virus into the lungs, heart, and other tissues [5]. This process is permitted by ACE-2 receptors [15]. Various autopsy studies have confirmed the hyperinflammatory response and the activation of the coagulation cascade [16,17]. In relation to the immune response, a recent study shows that the degree of COVID-19 infection is inversely correlated with interferon I and directly with the overproduction of proinflammatory cytokines such as IL-1 and IL-6.

This study was conducted in patients with mild/moderate, severe, and critical disease [18]. In each of these stages, the viral infection and immune/inflammatory response stimulate the stress response systems, a fundamental part of the immune–neuroendocrine system, such as the following:

  • the hypothalamic–pituitary–adrenal (HPA) axis;
  • the hypothalamic–pituitary–thyroid (HPT) axis,
  • the hypothalamic–pituitary–gonadal (HPG) axis,
  • the prolactin axis (HP-PRL), and
  • the sympathetic and parasympathetic nervous system [19].

In fact, this type of integral response has been observed in infections of different types, such as viral, bacterial, and parasitic. Therefore, this response can be similar in patients infected with COVID-19. Viral infections engage in a very particular manner of infecting the human body, every virus has a different way of doing this; however, each mechanism ends in the relationship with the neuroendocrine system [20].

Consequently, the COVID-19 infection undoubtedly causes emotional, physical, and biological stress, leading to the to stress response systems. In fact, several studies demonstrated that approximately 60% of patients during the COVID-19 pandemic exhibited anxiety, stress, and depression [21].

COVID-19 and the immune–neuroendocrine system
At the beginning of the COVID-19 infection, the innate and adaptative immune systems are activated, releasing proinflammatory cytokines. Multiple evidence indicates that pro-inflammatory mediators activate the neuroendocrine system. Viral interaction has been studied for many years [20]. However, there is scarce evidence of this interaction with the COVID-19 infection. Next, we will update the interaction between viral infection and the immune–neuroendocrine system (Fig. 1 ).

Fig. 1
Fig. 1
Interaction between viral infection and the immune–neuroendocrine system.

Hypothalamic–pituitary–adrenal axis
The first axis that is activated after a viral infection and stress situation is the hypothalamic–pituitary–adrenal (HPA) axis. The proinflammatory cytokines released by this viral infection cross the Blood Brain Barrier (BBB), arrive at the hypothalamus, activating neurons of the organum vasculosum of the laminae terminalis (OLVT) and of the paraventricular nucleus (PVN), stimulating the release of the corticotrophin-releasing hormone (CRH) [22], activating the anterior pituitary gland and consequently releasing the adrenocorticotropic hormone (ACTH), ending with the release of corticoids by the adrenal glands [23,25].

These corticoids yield negative feedback on immune cells, which suppress the synthesis and release of the cytokines TNF-α, IL-1β, and IL-6 [23]. Another function of glucocorticoids is to change from Th1- to Th2-type immune responses, thus counterbalancing damage to the tissues [24].

The HPA axis has receptors at every level for cytokines and it was demonstrated that this axis can also synthesize the latter [25]. Cytokines cross the BBB, which is an integral part of the immune–neuroendocrine system [26]. There are several identified ways as to how cytokines cross the BBB as follows: stimulating afferents pathways that project to the nucleus tractus solitarius, activating norepinephrine in the PVN; crossing the BBB at damaged regions; exerting a direct effect on CRH in the medium eminence, and inducing/releasing secondary messengers and crossing the BBB by active transport [24]. The BBB is injured by the TNF-α and IL-6 participating in neuroinflammation. TNF-α allows depolarization of the BBB endothelial cells and IL-6 production with the consequent stimulation of immune–neuroendocrine system [26].

A clear example of this relationship is the existing between HIV-1 and the HPA axis, in which the levels of cortisol have been observed as increased and, in several cases, adrenal insufficiency has also been observed [27]. Despite high cortisol levels, ACTH levels are low; this can indicate that some cytokines by themselves can stimulate the synthesis of glucocorticoids [28].

Anosmia and ageusia demonstrate the direct involvement of SARS-CoV-2 and cytokines on the central nervous system (CNS). In this respect, histological studies obtained on the olfactory epithelium have shown that TNF-α levels were significantly high in patients infected with COVID-19 compared to those of a control group [29].

Early studies found on tonsilitis a local production of proinflammatory cytokines and its relationship with catecholamine receptors [30]. Based on these findings, an immune–neuroendocrine interaction has been proposed. In fact, the SARS-CoV-2 virus is neurotropic [26].

COVID-19 infection alters the stress response system, and this alteration contributes to the worsening of elderly patients or those with an autoimmune disease. In fact, patients severely infected with COVID-19 exhibited significantly lower cortisol levels than severely infected non-COVID-19 patients [31].

Another study evaluated adrenocortical function in a group of patients with COVID-19 in which the study’s findings suggest an inadequate response of the HPA axis [32]. In support of these findings, an autopsy study of COVID-19 patients revealed enlarged hematomas, diffuse bleeding, thrombus, necrosis, and the inflammatory infiltrate of adrenal glands. Taken this evidence together, COVID-19 has a devastating effect on the hypothalamic–pituitary–adrenal axis, that is, the principal stress response system [33].

Hypothalamic–pituitary–gonadal axis
The relation between this axis and the immune response can be sustained by certain facts, such as that the gonadotropin releasing hormone (GnRH),produced by immune cells; estrogens stimulate the immune response, and androgens inhibit this response [34]. Experimental models revealed that male rodents had a worse outcome after a Hepatitis B infection due to the immunosuppressive activity of testosterone. Another example was that after an Influenza A virus infection, female mice had a greater inflammatory response than males [35]. These examples clearly demonstrate the relation between these two systems, and this has also been studied for the SARS-COV 2 infection. It was observed that men present more complications than women, this due to the levels of androgens, particularly in the expression of a gene, TMPRSS2, whose transcription is regulated by androgen receptors [36]. With regard to ACE2 receptors and SARS-CoV-2 interaction, estrogens and androgens increase their expression [37]. It was evidenced that the hypothalamic–pituitary–gonadal axis can be directly affected by COVID-19, destroying Sertoli cells and Leydig cells, causing a worsening of spermatogenesis and a decrease in testosterone levels [38]. Several investigations have shown the involvement of the COVID-19 infection in the ovarian reserve and can affect the reproductive function of fertile women. Therefore, the latter will be monitored when COVID-19 occurs in women of reproductive age [39].

This evidence indicates the involvement of COVID-19 infection with the HPG axis. The consequence of this damage needs to be studied in the post COVID-19 stage.

Hypothalamic–pituitary–thyroid axis
The HPT axis has a clear relation with the immune system, and low levels of T3 and T4 were found in some infections [40]. An example is HIV infection where prior to the use of antiretroviral therapies, there were several patients with sub-clinical hypothyroidism and low levels of T4 [41]. During the cytokine storm for COVID-19, thyrotoxicosis and low free T3 concentrations have been described. Infection by SARS-COV-2 can destroy thyroid follicular cells and could be the reason for the thyrotoxicosis [42]. Affectation of the HPT axis can take place in two ways: by direct interaction between the SARS-CoV-2 and the thyroid glands, or by means of the hyperinflammatory response. In either situation, thyroiditis occurs. This is probably due to the high number of ACE-2 receptors that exist in the thyroid glands [43]. The description is of interest of some cases of Graves disease and thyroiditis in post-COVID-19 vaccinated patients [44,45].

Hypothalamic–pituitary–aprolactin axis
Prolactin is a lactotrophic hormone that possesses immunostimulatory properties, and it is synthetized and secreted by different cells or tissues, including immune system cells [[46], [47], [48]]. In fact, the prolactin gene in humans is located on the short arm of chromosome 6, near the major histocompatibility complex (MHC) [49].

It is well known that prolactin stimulates the innate and adaptive immune responses. Prolactin is produced by the T-lymphocytes, which are considered proinflammatory cytokines. In this regard, it was demonstrated that the hypoprolactinemic state is associated with the risk of infections and death. It has been proposed that drugs such as Domperidone/Metoclopramide (which are dopamine antagonists) can enhance PRL levels and, in this manner, the hyperprolactinemic state can increase the protective effect against COVID-19 infection [48]. In contrast, a hyperprolactinemic state has been demonstrated in systemic lupus erythematosus and other associated autoimmune diseases to increase active disease [50]. Recently, there was the first case of a COVID-19-positive patient in her third trimester of pregnancy who developed a pituitary apoplexy. This patient presented low TSH levels and high prolactin levels. It is probable that this axis is affected by COVID-19 [51].

COVID-19, immune-neuroendocrine system and age
The involvement of the immune–neuroendocrine system during the battle against SARS-CoV-2 has not been clearly described; however, we do know that the disease drastically disrupts its components, particularly in older adults. To effectively eliminate SARS-CoV-2, the immune–neuroendocrine system must recognize, alert, destroy, and clear the virus [9]. This entity causes the activation of the immune–neuroendocrine system. Dysregulation of the stress system leads to communication between the brain and the HPA axis for the adaptation of the organism [64].

The changes in this system over time are attributed to the evolution of humans due to adaptation to its environment and to the balance between aggression vs. tolerance caused by various pathogens. With regard to advanced age, the body’s immuno-neuroendocrine response undergoes a progressive deterioration that is conditioned by an inefficient response to diseases [65].

Following the challenge of the immune system to fight the pathogen, it produces a series of cytokines. In fact, several cytokines were reported in the serum of COVID-19 patients, mainly proinflammatory, such as tumor necrosis factor-α (TNF α), interleukin-1 (IL-1) and IL-6, and type I interferons (IFN-α/β).

Their role, in addition to contributing to the immune response against viral infection such as coronavirus, is responsible for activating the HPA axis, which releases adrenal glucocorticoids, providing negative feedback on immune cells in order to inhibit the synthesis and release of cytokines, thus protecting the host from the devastating consequences of an overactive immune response [66].

Type I Interferon (IFN-1) is essential in antiviral immunity to fight against several infections, as in the case of COVID-19 infection.

In France, a study reported that COVID-19 infection is characterized by a decrease in the circulating IFN in patients of all disease-severity states, rendering us vulnerable to pathogens, which is significantly associated with a prognosis of a fatal outcome. Therefore, these authors propose that a blood IFN deficiency could be a biomarker for severe COVID-19 [18]. Agrawal [67] explained that the production of IFN-1 by dendritic cells constitutes the innate immunity of our human organism, but it is affected in older adults as the advance in age, because the immune system’s capacity to express IFN-1 decreases and deteriorates. Therefore, elderly patients are more susceptible to infections and to more serious conditions compared to the young population, supporting what is observed in elderly patients with COVID-19 [68].

The activation of the HPA axis has been observed in phenomena such as immune/inflammatory processes; therefore, in patients infected with COVID-19, it can alter the HPA axis in two ways, that is, hyperactivated or hypoactivated, mainly due to the dysfunction in negative feedback between the axis and the immune system. The hyperactivation of this axis is mainly attributed to the cytokine- storm mechanism in individuals infected with SARS-CoV-2, related to lung damage and fatality. Similarly, another potential mechanism for SARS-CoV-2 for over activating this axis is the decrease in the angiotensin-converting enzyme 2 levels (ACE2). Contrariwise, the HPA is hypo-activated by TNF-α and Transforming growth factor beta (TGF-β); thus, it is possible that a certain number of cytokines that are elevated in patients with COVID-19 are involved in the hypocortisolism associated with this disease, being the main cause of depression in convalescent patients [69].

To date, it is theorized that the interaction between the Spike protein located in the SARS-CoV-2 membrane and the ACE2 receptor improves the host’s tropism. Chatterjee and colleagues [70] explain that the essential part for the entry of the virus into the host cell, mainly for human respiratory epithelial cells, is the viral–receptor interaction. In elderly patients, low immunity is inversely proportional to the viral load, as well as to the increased expression of the ACE2 receptor in hematopoietic cells, cardiopulmonary tissues, macrophages, and monocytes.

Meftahi et al. [71] propose that several factors may associate “inflame aging” with the cytokine storm in elderly patients with COVID-19; they can uncontrollably turn on the inflammatory machine in the aging, including the alteration of ACE2 receptor expression, excessive reactive oxygen species (ROS) production, senescent adipocyte activity, the alteration of autophagy and mitophagy, and immune-senescence, as well as vitamin D (VD) deficiency. Hence, older persons with severe COVID-19 infection cannot shut down their proinflammatory immune–neuroendocrine response (Fig. 2 ).

Fig. 2
Fig. 2
Presentation of severe COVID-19 infection, according to age group.
A. Severe COVID-19 infection in young people. B. Severe COVID-19 infection in older people.

Nevertheless, there is still much to analyze concerning the participation of the axes of the immune–neuroendocrine system in this new worldwide disease, especially in older adults and patients with rheumatic disease.


More information: Jinhao Xu et al, Excess neuropeptides in lung signal through endothelial cells to impair gas exchange, Developmental Cell (2022). DOI: 10.1016/j.devcel.2022.02.023


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