J Biol Regul Homeost Agents. 2020 Mar 31;34(2). doi: 10.23812/Editorial-Conti-2. [Epub ahead of print]
How to reduce the likelihood of coronavirus-19 (CoV-19 or SARS-CoV-2) infection and lung inflammation mediated by IL-1.
- 1 Postgraduate Medical School, University of Chieti, Chieti, Italy.
- 2 Department of Biomedical Sciences and Specialist Surgery, Section of Ophthalmology, University of Ferrara, Ferrara, Italy.
- 3 Specialization School in Oral Surgery, Vita-Salute San Raffaele University, Milan, Italy.
- 4 School of Pharmacy, University of Camerino, Camerino, Italy.
- 5 Clinica dei Pazienti del Territorio, Fondazione Policlinico Gemelli, Rome, Italy.
- 6 Medical Center “Mai più Dolore”, Pescara, Italy.
- 7 Department of Medical, Oral and Biotechnological Sciences, University of Chieti, Chieti, Italy.
- 8 University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA.
- 9 Department of Microbiology and Infectious Diseases, School of Veterinary Medicine, Aristotle University of Thessaloniki, Macedonia, Greece.
SARS-CoV-2, also referred to as CoV-19, is an RNA virus which can cause severe acute respiratory diseases (COVID-19), with serious infection of the lower respiratory tract followed by bronchitis, pneumonia and fibrosis. The severity of the disease depends on the efficiency of the immune system which, if it is weak, cannot stem the infection and its symptoms. The new CoV-19 spreads in the population at a rate of 0.8-3% more than normal flu and mostly affect men, since immune genes are more expressed on the X chromosome. If CoV-19 would spread with a higher incidence rate (over 10%), and affect the people who live in closed communities such as islands, it would cause many more deaths. Moreover, people from the poorest classes are most at risk because of lack of health care and should be given more assistance by the competent authorities. To avoid the aggravation of CoV-19 infection, and the collapse of the health system, individuals should remain at home in quarantine for a period of approximately one month in order to limit viral transmission. In the case of a pandemic, the severe shortage of respirators and protective clothing, due to the enormous demand and insufficient production, could lead the CoV-19 to kill a large number of individuals. At present, there is no drug capable of treating CoV-19 flu, the only therapeutic remedies are those aimed at the side effects caused by the virus, such as inflammation and pulmonary fibrosis, recognized as the first causes of death. One of the COVID-19 treatments involves inhaling a mixture of gaseous hydrogen and oxygen, obtaining better results than with oxygen alone. It was also noted that individuals vaccinated for viral and/or bacterial infectious diseases were less likely to become infected. In addition, germicidal UV radiation “breaks down” the oxygen O2 which then aggregate into O3 (ozone) molecules creating the ozone layer, capable of inhibiting viral replication and improving lung respiration. All these precautions should be taken into consideration to lower the risk of infection by CoV-19. New anti-viral therapies with new drugs should also be taken into consideration. For example, microbes are known to bind TLR, inducing IL-1, a pleiotropic cytokine, highly inflammatory, mediator of fever and fibrosis. Therefore, drugs that suppress IL-1 or IL-1R, also used for the treatment of rheumatoid arthritis are to be taken into consideration to treat COVID-19. We strongly believe that all these devices described above can lead to greater survival and. therefore, reduction in mortality in patients infected with CoV-19.
Coronaviruses are a family of common RNA viruses that can cause seasonal colds and even serious infections of the lower respiratory tract followed by bronchitis and pneumonia (1). Acute respiratory viral diseases are caused by respiratory tract infections that afflict the world community globally and cause about 4 million deaths per year, of which about 40% are caused by coronavirus (2). Severe acute respiratory syndrome is given by coronavirus-19 (SARS-CoV-2 also referred to as CoV-19), a family of common RNA viruses that can provoke seasonal colds, and even serious infections, followed by bronchitis and pneumonia, particularly in vulnerable subjects (3). Many inflammatory phenomena with severe pneumonia can occur with the flu, which can be avoided through vaccinations by effectively reducing the number of deaths (4). In patients with COVID-19 the blood test shows very high IL-6, as well as ferritin and the number of neutrophils (neutrophilia), while there is a significant decrease in the number of lymphocytes (lymphopenia) and platelets (thrombocytopenia) with a clotting defect (unpublished data). Furthermore, anti-CoV-19 antibodies appear in the blood after 5-10 days and the search for these antibodies can reveal whether the analyzed subject has come into contact with the virus in the past. The severity of the disease depends on the efficiency of the immune system, which in a healthy subject allows to respond better to antibiotics and anti-inflammatories in order to obtain a better prognosis (5). The new CoV-19 spreads in the population at a rate of 0.8-3% more than normal influenza. If CoV-19 would spread with a higher incidence rate (over 10%), and affect the people who live in closed communities such as islands, it would cause many more deaths. This is because the inhabitants of islands, often far from societies with greater communication, have less contact with the various strains of coronavirus. The immune system of the islanders who have never come into contact with coronaviruses does not have an effective immune response, therefore they would be more affected by the disease (COVID-19). When the Spanish pandemic occurred in 1918, the mortality rate of the people living on the islands was many times higher than that of the Americans. The new coronavirus is similar to, or perhaps more lethal than, the Spanish flu, and could cause genocide in closed communities (6). Therefore, various international health organizations and competent authorities should provide medical assistance to these communities in order to avoid a tragedy. In case of an irrepressible pandemic occurring, each community would benefit from a large and efficient hospital for infectious diseases or suitable environments for hospitalizations. In addition, in the case of a pandemic, the severe shortage of respirators and protective clothing, due to the enormous demand and insufficient production, could lead the CoV-19 to kill a large number of individuals (7). For example, people from the poorest classes are most at risk for lack of health care and should be given more assistance by the competent authorities. To avoid the aggravation of CoV-19 infection, individuals should remain at home for a period of approximately one month in order to limit viral transmission from man to man (8). At present, there is no drug capable of treating CoV-19 flu, the only therapeutic remedies are those aimed at the side effects of the virus, such as inflammation and pulmonary fibrosis, recognized as the first causes of death (9). Many therapeutic solutions have been proposed to date: transfusion of plasma containing antibodies from individuals with COVID-19; use of monoclonal antibodies against CoV-19; anti-SARS drugs used against malaria, and others, but they are all to be checked carefully.
Some hospitals have treated COVID-19 pneumonia with a mixture of gaseous hydrogen and oxygen. In 1875, it was discovered that the mixture of hydrogen and oxygen could be used for severe pneumonia, although the specific mechanism to date is still unclear. At present, patients with coronavirus-19 pneumonia are treated with high flow pure oxygen (without adding hydrogen), although the effect of O2 when associated with hydrogen may give better results (10). The production of mucus in these patients reduces the absorption of oxygen, while with a mixture of oxygen and hydrogen the bronchioles and the alveoli of the lungs are further expanded, optimizing the absorption of oxygen (11). Hydrogen is used as a catalyst to accelerate the binding of hemoglobin with oxygen and the release of hemoglobin with carbon dioxide (12). It has recently been noted that there is a low incidence rate of CoV-19 in individuals who have had recent bacterial or viral vaccinations (13).
Infectious viral diseases that affect animals, but can also be accidentally transmitted to humans through direct contact with the animal, can be characterized by fever, pneumonia, fibrosis and many other pathophysiological effects, which are much milder in cases in which the subjects have already had bacterial infections. In fact, it has been noted that individuals affected by bacterial infections with production of exotoxins seem to be able to create COV-19-inhibiting antibodies, hindering their harmful effects, but these results are still under study (14). If these biological effects are effective, the vaccine for these infections should be used to prevent COVID-19. What has just been described would represent an indirect therapeutic intervention capable of avoiding the onset of pneumonia and pulmonary fibrosis. In the battle against the new coronavirus, healthcare professionals wear protective clothing that must comply with some basic rules to avoid creating gaps in protection and serious inconvenience to healthcare professionals (15). For example, wearing protective masks may cause suffocation and anoxia and often the masks are not sufficiently protective; furthermore, they also cause anaerobic metabolism increase and oxygen free radical production. In addition, wearing protective clothing for a long time, without having the time to replace them, can lead to urinary retention, which causes excessive expansion of the bladder of medical personnel with serious inconvenience at work (16). Excessive sweating can also be a problem as it causes the loss of water and electrolytes. Lack of oxygen, urine retention, sweating, physical stress, pressure of work rhythms and fear of infectious diseases can cause alteration of the sympathetic nervous system, affecting the health of medical personnel. Therefore, to avoid the drawbacks described, it would be necessary to speed up the work shift program of the clinicians who are in the front line. In the pandemic phase, if individuals are not isolated for about one month in quarantine, the health system could collapse and the mortality rate would increase dramatically (17), and even a large number of medical personnel could become infected in hospital settings. Moreover, COV-19 can nest in the protective clothing of healthcare professionals, with infectious potential. In addition, UV ultraviolet rays, commonly used in medical research laboratories to avoid germ contamination of cell cultures, should be taken into consideration (18). In this regard, it has been thought that if UV sterilizing lamps are installed in infectious risk environments, CoV-19 infections may be less frequent. Furthermore, since the entire body of the healthcare professional is covered with protective clothing, there is no risk of harmful UV radiation for the operator. At the moment, many hospital environments are almost completely devoid of UV lamps that can counteract the spread of the virus (19). Germicidal UV radiation is absorbed by oxygen (O2) with breakage of the covalent bond creating the ozone layer, i.e. air containing ozone (O3) capable of inhibiting viral replication and improving lung respiration (20). Ozone generators are also available on the general market and are not expensive, therefore infectious risk environments should make use of them. In irradiated environments for at least one day, a large amount of ozone is formed in the air which, if breathed into the lungs by health workers and held for about a minute, can represent an effective weapon to contrast COVID-19. If this practice is repeated several times, the new CoV-19 can be inactivated by ozone (21). It is reasonable to think that in rooms equipped with an air purifier, or well-ventilated, and equipped with UV, the internal infection rate is significantly lower than that found in rooms that do not have it. These are all precautions that should be taken into consideration to lower the risk of infection. All these measures, designed to counter the advance of the virus, could be decisive and helpful. Currently, many countries are devastated by CoV-19 infection and inflammation, and the population is exhausted and eagerly awaits the resolution of the COVID-19. Therefore, the discovery of new effective therapeutic weapons, including vaccine and pro-inflammatory cytokine inhibitors are strongly needed (22).
The interleukin (IL)-1 family has recently expanded and comprises 11 members including IL-1. There are two molecules of IL-1 divided into IL-1a (also referred to as IL-1F1) and IL-1b (also referred to as IL-1F2) associated mostly with innate immunity (23). This article only takes into account IL-1b which will simply be called IL-1. IL-1 is a pleiotropic cytokine, active in different biological processes, mainly in inflammation, immunity and hematopoiesis. IL-1 binds IL-1R receptor, and IL-1R2 in a similar manner – a reaction which allows it to recruit the co-receptor IL-1R3 (23). These processes lead to the recruitment of MyD88 and activation of phosphorylation with the production of the pro-inflammatory pathways and formation of cytokines that induce other cytokines, amplifying the inflammatory state in many diseases including COVID-19 (24). The activation of Toll Like Receptor (TLR) receptor by IL-1 can be inhibited by IL-1Ra (IL-1 receptor antagonist, also called IL-1F3). IL-1 is produced by many immune cells including lymphocytes, macrophages and mast cells (MCs), but is also generated by non-immune cells, such as fibroblasts and endothelial cells, that take part in infectious processes (25). IL-1RI, shares a 50% amino acid homologous domain and functional properties with the TLR protein which is made up of 11 members and all share TIR domain, as does the IL-1RI. Many mechanisms can activate TLR which triggers inflammation via microbial product activation including CoV-19 and damage-associated molecular patterns (DAMPs), similar to IL-1 which functions as DAMP. In addition IL-1 can also play a role in acquired immunity (23). Therefore, microbes including CoV-19 and microbial products induce IL-1 via TLR. Drugs that block the IL-1 receptor such as anakinra, approved by FDA for the treatment of rheumatoid arthritis in 2002, are used in therapy for a multitude of inflammatory diseases common to rheumatoid arthritis (23). Indeed, patients with microbial infections treated with anakinra have shown greater survival and therefore reduction in mortality. As IL-1 is an important mediator in CoV-19-induced lung inflammation and fibrosis, suppression of this highly pro-inflammatory cytokine could have an important therapeutic role (26). IL-37 protein is expressed by human blood monocytes from healthy subjects, but also by human macrophages, B cells, plasma cells, T cells, and neoplastic cells (23). The inhibition of IL-1 can also be achieved by using IL-37, a new member of the IL-1 family, and subjects deficient in IL-37 are more likely to encounter inflammatory diseases (27). IL-37 signaling suppresses mTOR with inhibition of phosphorylation and inflammation. IL-37 mRNA is increased in several inflammatory and infectious diseases in proportion to the severity of the disease. In viral infections IL-37 increases in relation to the inflammatory response, and inhibits pro-inflammatory IL-1 family members and IL-6 but, on the other hand, IL-37 leads to unwanted immunosuppression (23).
IL-38 is also a member of the IL-1 family with anti-inflammatory properties. IL-38 is an inhibitor of IL-1-related pro-inflammatory cytokines and is also capable of suppressing IL-6 induced in viral infections such as CoV-19 (23).
Tumor necrosis factor
Tumor necrosis factor (TNF) is a potent pro-inflammatory and pro-apoptotic protein which can be induced by IL-1 (28). Its inhibition alleviates the inflammation and suppresses the production of other pro-inflammatory cytokines induced by this cytokine. TNF is released by several immune and non-immune cells after stimulation with a number of activator compounds such as microbial products and inflammatory cytokines including IL-1 (29). MCs are immune cells and mediators of inflammation which contain TNF preformed in their granules released quickly after activation of IgeRI receptor with appropriate ligands, including IgE. Furthermore, in MCs, TNF can be synthesized de novo after several hours and appears to require mitochondrial translocation. TNF induces endothelial leukocyte adhesion in inflammation by recruiting neutrophils through stimulation of ELAM-1, ICAM-1, VCAM-1 on vascular endothelial cells, contributing to inflammation (30). Moreover, it is known that TNF, as well as IL-1 are capable of inducing the pro-inflammatory cytokine IL-6 (31) in virus-induced diseases, such as COVID-19. In addition to performing the inflammatory function, TNF shares the signaling pathways with IL-1. TNF mediates inflammation in innate and adaptive immune responses by contributing to the recruitment of white blood cells to the sites of inflammation. This suggests that TNF can modulate immunity and inflammation in various pathological states including those caused by CoV-19. TNF and TGFβ1 derived from activated MCs via TLR4 can provoke an augmentation of type-I collagen with the increase of production of fibroblasts by means of the fibrotic phenomenon, as can occur in CoV-19 infection. TNF can increase mortality after microbial infection, improve microbial growth and after inhibition it can decrease inflammation. In this regard, the anti-TNF antibody which is effective in inflammatory monoarthritis by inhibiting this cytokine, may also be helpful in CoV-19-induced TNF-mediated inflammation (32).The administration of a TNF neutralizing antibody could contribute to an improvement of inflammation and greater survival. TNF inhibitors play a role in immunotherapy, alone or in combination with anti-inflammatory or anti-rheumatic drugs. However, since TNF is an immune response mediator of viral infections, the use of anti-TNF inhibitors in CoV-19-infected patients may promote viral reactivation. In conclusion, TNF can strongly contribute to the initiation and amplification of inflammation, and its neutralization can certainly give relief, also in CoV-19 infections. However, anti-TNF therapies are known to increase the risk of numerous infections due to suppression of the immune system involved in the battle against viral diseases including those induced by CoV-19.
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