**6. Annexin A1 and Lung Diseases**

Endogenous glucocorticoids are proresolving intermediaries, a model of which is the endogenous glucocorticoid-regulated protein annexin A1. Because silicosis is an occupational lung disease typified by persistent inflammation and fibrosis, models regarding this illness have been studied to test the therapeutic properties of the ANXA1 on experimental silicosis [66]. The authors have demonstrated that the therapeutic administration of N-terminal peptide of ANXA1 (Ac2-26) in ischemia–reperfusion-provoked lung injury might substantially attenuate the lung edema and proinflammatory cytokine production, thus reducing oxidative stress, apoptosis, neutrophil infiltration and lung tissue injury, perhaps via the activation of the N-formyl peptide receptor [66].

A similar result was published in an experimental study made with animals affected by bleomycin-induced lung fibrosis that were treated with an ANXA1 peptido-mimetic, administrated prophylactically (from day 0 to 21) or therapeutically (from day 14 onward), which improved signs of both inflammation and fibrosis [71]. Together these data show a pathophysiological relevance for ANXA1 in lung inflammation and in fibrosis, and may open up a new approach for the pharmacological handling of pneumonia and lung fibrosis. Currently, the resolution of inflammation, once considered to be a passive process, has recently been revealed to be an active and precisely controlled process. In the resolution stage of acute inflammation, new mediators, including lipoxins and resolvins, which are members of the specific proresolving mediators of inflammation, are released [72].

Acute lung injury and the more severe forms of acute respiratory distress syndrome, ALI/ARDS, are relatively common syndromes in seriously ill patients and are related with a high rate of morbidity and mortality. Recently, new evidence has shown that the resolution of inflammation might be an active and highly regulated process. Specific proresolving mediators (SPMs), have been proved to produce strong immune-resolving effects, such as cell proliferation, migration and the clearance of apoptotic cells and microorganisms. Therefore, the effective and timely control of inflammation could be the key step to maintain effective host defense and the restoration of homeostasis. Therefore, this reveals a new mechanism for pulmonary edema fluid reabsorption in which SPMs, amongst them annexin A1, might offer new chances to design "reabsorption-targeted" treatments with high levels of precision in controlling acute lung injury [73]. It is also widely acknowledged that to survive, edema fluid should be removed for patients with ALI/ARDS [74].

Moreover, lung endotoxemia is characterized by neutrophil accumulation, enlarged vascular permeability and parenchymal damage. In relation with toxic problems, it has been proposed that the molecular reactions stimulated by ANXA1 peptidomimetic Ac2-26 lead to the control of leukocyte activation/migration and both cytokine production and lung injury that are generated by lipopolysaccharides [75]. It was also published that ANXA1 may accelerate the resolution of inflammation in acute radiation-induced lung damage through the inhibition of IL-6 and myeloperoxidase inflammatory cytokines, demonstrating that ANXA1 may have a therapeutic role as treatment target for acute-radiation lung damage [76].

Moreover, it is well known that pattern recognition receptors (PRRs) are key elements in the innate immune response. FPR2/ALXR, a receptor modulated for specialized proresolving mediators of inflammation, amongst them annexin A1, has been shown to be one of the receptors implicated in inflammation process control. This has encouraged the research community to search for and develop new anti-inflammatory/proresolution small molecules to control inflammation through the activation of FPR2/ALXR [44].

We believe that the protective function of the ANXA1-FPR2 signaling axis recently described in viral infections it is very important [60]. The formyl peptide receptor (FPR) 2 is a pattern recognition receptor that, in addition to proinflammatory, pathogen-derived compounds, also recognizes the anti-inflammatory endogenous ligand annexin A1 (ANXA1), and it has been shown that ANXA1, via FPR2, controls inflammation and bacterial dissemination during pneumococcal pneumonia by promoting host defenses, suggesting ANXA1-based peptides as a novel therapeutic strategy to control pneumococcal pneumonia [77].

In this context, it has been described that mice with the influenza A virus (IAV) infection in the murine model treated with ANXA1 displayed significantly attenuated pathology upon a subsequent IAV infection with significantly improved survival, impaired viral replication in the respiratory tract and less severe lung damage.

#### **7. COVID-19: The Magnitude of the Problem**

Most countries in the world are suffering a significant spread of SARS-CoV-2, causing pandemic effects. The clinical presentation of the SARS-CoV-2 infection varies from asymptomatic or with light symptoms to clinical situations characterized by respiratory insufficiency requiring mechanical ventilation and intensive care, to multiorgan dysfunction syndrome with signs and symptoms such as sepsis, septic shock and multisystem failure. It also is true, unfortunately, that all the countries in the world do not have the capacity to solve this problem due to the lack of therapeutic measures that could have the appropriate impact. The problem is massive. Therefore, there is a great need to contemplate new methods to improve patients' biological resistance to SARS-CoV-2 by using mesenchymal stromal/stem cells [78]. We know that SARS-CoV-2 invade cells through the ACE2 receptor widely expressed in human cells, including the alveolar epithelium and the capillary endothelium. The MSCs are ACE2 negative. So, the transplanted cells are unable to participate in the spread of the infection.

For the healthcare services, the two key imperative necessities in the SARS-CoV-2 infection are to hinder and reduce infection rates, and to decrease the death rate of those infected. The accumulating epidemiological analyses, connected with country-based mitigation strategies, and with estimations that about 80% COVID-19 patients have mild or asymptomatic disease, 14% severe disease, and 6% are critically ill, support a permanent need for the treatment of SARS-CoV-2 infection and COVID-19 pneumonia in the long term.

According to preliminary estimates of severity that were based on a recent analysis of data from EU/EEA countries and the UK available in the *European Surveillance System TESSy* and online country reports (for countries whose data were incomplete or missing in *TESSy*) and summarized by the *European Centre for Disease Prevention and Control* (*ECDC*), we know that amongst all the cases of patients affected, hospitalization has occurred in 32% of cases reported from 26 countries, and cases with severe illness (requiring ICU and/or respiratory support) have accounted for 2.4% cases reported from 16 countries. Moreover, amongst hospitalized cases, severe illness was reported in 9.2% of hospitalized cases in 19 countries and death occurred in the 11% of the hospitalized cases in 21 countries. The age-specific hospitalization rates amongst all cases showed elevated risk amongst those aged 60 years and over. Finally, a strong estimate for the COVID-19 case death rate is still lacking and theoretically biased by partial outcome data and differences in testing policies and procedures.

The number of people affected worldwide is progressive and continuously growing, and SARS-CoV-2 has infected more than 24.5 million people and killed more than 830,000 people in

different countries, areas or territories with cases (ECDC on 28 August 2020). The worldwide lethality (average) is ≈3.38% with a range of 0.1% to 14.0% depending on the country.

The magnitude of the problem is enormous and terrifying.
