20 de março de 2020 às 16:18
Beneficial Effects of ACE2/ANG-(1-7)/MAS Axis In Lung Disease
Giselle Santos Magalhaes1,2, Maria da Gloria Rodrigues-Machado2, Daisy Motta-Santos1, Maria Jose Campagnole Santos 1, Robson A Souza Santos1
1Department of Physiology and Biophysics, National Institute of Science and Technology in Nanobiopharmaceutics (INCT-Nanobiofar); 2Medical Sciences Faculty of Minas Gerais, Post-Graduate Program in Health Sciences, Minas Gerais, Brazil.
Corresponding author: Robson A S Santos (Department of Physiology and Biophysics; National Institute of Science and Technology in Nanobiopharmaceutics. Federal University of Minas Gerais. Av. Antonio Carlos, 6627 – ICB; 31270-901, Belo Horizonte, MG, Brazil).
Because of the harmful role of ACE2 in mediating the entry of SARs-COV-2 into lung cells and the derived misunderstandings that this may cause, it is important to advance some thoughts on the complex relationship between the renin-angiotensin system (RAS), lung diseases and COVID-19.
Experimental and clinical evidences indicate that activation of the lung renin-angiotensin system is involved with the pathophysiology of pulmonary inflammation, mainly due to a prolonged and inappropriate increase in angiotensin converting enzyme (ACE)/angiotensin (Ang) II/AT1 receptor axis activity (4,19). However, the axis comprised by ACE2/Ang-(1-7)/Mas receptor axis, recognized as a counterregulator pathway in the RAS, exhibits anti-inflammatory and pro-resolving effects in lung diseases (19,21).
In acute respiratory distress syndrome (ARDS), an imbalance between ACE and ACE2 activity has been demonstrated, with an increase in ACE activity, and this increase has been shown to correlate with the degree of lung injury (22). On the other hand, it was found that ACE2 mRNA, protein, and enzymatic activity were highly downregulated in lung injuries of patients and experimental animals (11). Decreased ACE2 expression was observed in severe acute respiratory syndrome (SARS), in which the coronavirus pathogen (SARS-CoV) triggers severe pneumonia and acute lung failure, often lethal (13).
Kuba et al. demonstrated that ACE2 is the receptor for SARS-CoV entry in the cells, and both SARS-CoV infections and the spike protein of the SARS-CoV reduce ACE2 expression, contributing to the severity of pulmonary pathology. In contrast, recent study has also shown that after SARS-CoV-2 infection, ACE2 expression increased dramatically and remained high for at least 48 hours, suggesting that increased expression of ACE2 could prolong life cycle, improve replication and mediate the penetration of the virus into the host cell, which in turn could result in a greater leukocyte migration and increased production of inflammatory mediators (7). All of these effects are important mechanisms for the deterioration of lung function. In keeping with these observations, it was suggested that blockade of ACE2 would be a possible supplementary therapeutic approach for COVID-19 (5,7). However, injection of SARS-CoV spike into mice aggravated acute lung failure in vivo by increasing pulmonary Ang II levels and AT1 receptor activation (13). Therefore, the balance between ACE/Ang II/AT1 and ACE2/Ang-(1-7)/Mas axis and, probably increasing the activity of the second one, seems to be important in order to defeat the disease.
In 2005, Imai et al. reported that lack of ACE2 expression (knockout mice, ACE2−/Y) precipitated severe ARDS, suggesting that ACE2 could present an important role in mitigating ARDS (8). In this study, elastance of the respiratory system and pulmonary edema were significantly higher in ACE2−/Y mice subjected to a model of sepsis. In addition, it was observed thickening of the alveolar wall, edema and pulmonary congestion, infiltration of inflammatory cells and hyaline membrane in these mice. After 6 hours of observation, all WT animals were alive and only 2 out of 10 animals in the ACE2−/Y group survived. Moreover, intraperitoneal injection of recombinant human ACE2 protein (rhuACE2) in ACE2−/Y mice subjected to ARDS prevented the increase in respiratory system elastance and pulmonary edema. In contrast to ACE2−/Y mice, ACE knockout animals (ACE−/−) were protected against ARDS induced by acid aspiration and ACE inactivation in ACE2−/Y animals attenuated ARDS. Likewise, pharmacological inhibition or genetic deletion of AT1a (AgTr1a−/−) receptors significantly attenuated pulmonary dysfunction and edema (8). It is interesting to note that ACE inhibition or blockade of AT1 receptor favors an increase in Ang-(1-7) levels in rats and humans (12,19).
Bone marrow-derived mesenchymal stem cells (MSCs) with ACE2 overexpression were used as a vehicle for gene therapy in ARDS mice induced by lipopolysaccharide (LPS) (6). In animals that received these cells, pulmonary overexpression of ACE2 was associated with improved lung histopathology, decreased neutrophils and inflammatory mediators in the lung, decreased Ang II and increased ACE2 and Ang-(1-7) pulmonary levels (6). In addition, in another study, attenuation of lung inflammatory response and tissue injury induced by pulmonary ACE2 overexpression was abolished by an ACE2 inhibitor (14). On the other hand, ACE2 knockdown caused a marked deterioration of lung injury and increased cytokine secretion in rats that received LPS injection (14). Altogether, these findings suggest that ACE2 in the lung prevents LPS-induced lung injury and inflammation. Moreover, it has been shown that pretreatment with either A779, a selective antagonist of Ang-(1-7)/ Mas receptor, or an ACE2 inhibitor significantly inhibited the protective effects of ACE2 on LPS-induced lung injury (14). This result also suggests that the protective action of ACE2 on lung injury in ARDS is mediated by Ang-(1-7).
Several studies have shown that treatment with Ang-(1-7) or Mas receptor agonist activates an anti-inflammatory response in different pathophysiological conditions (19,21). More recently, we have also described that pro-resolving mechanisms are triggered by Ang-(1-7) in acute and chronic inflammatory processes (1,15). Ang-(1-7) can be formed in the circulation or in different tissues, preferably by ACE2 and exerts its actions, in large part, through activation of G-protein-coupled receptor Mas (18,19). In the lung, Mas receptor is expressed in the epithelium and airway smooth muscle, alveolar cells, vascular smooth muscle cells and endothelium (17,23). Mas receptor has also been identified in cells of the immune system, such as, dendritic cells, lymphocytes, macrophages, eosinophils, neutrophils and alveolar macrophages, indicating a cellular mechanism for immune actions by Ang-(1-7) (1,15,19,21).
In models of pulmonary inflammation, such as asthma, lung fibrosis, ARDS and pulmonary emphysema, administration of Ang-(1-7) decreased cytokine/chemokine synthesis, migration of inflammatory cells to the lung and improved of pulmonary function (2,3,11,15,17,19,20,21,24). Ang-(1-7) treatment improved arterial oxygenation, decreased inflammatory response and reduced collagen deposition in the lungs of murine ARDS models (3,11,24) suggesting that the inhibitory effect of Ang-(1-7) in the recruitment of inflammatory cells observed in the acute phase may be related to the reduction in fibrosis in the later phase. In addition, anti-inflammatory effects were also observed after treatments with the ACE inhibitor, captopril and/or the receptor antagonist, losartan (9,10). The effects of these treatments may also be partially related to an increase in Ang-(1-7) levels in the lung (12,19). In another example of chronic lung inflammation, such as asthma, treatment with Ang-(1-7) was shown to reduce eosinophils count in the lung, to reduce the production of inflammatory mediators, to decrease activation of signaling pathways related to the production of cytokines, chemokines and survival of inflammatory cells (15,17). These anti-inflammatory effects were accompanied by reduced collagen deposition, mucus production and improved lung function (15,17).
An important step in the immune response is the resolution of the inflammation. Resolution is an active phenomenon that aims to stop inflammation and restore tissue homeostasis (1,15). We have recently demonstrated that Ang-(1-7) is a pro-resolutive mediator (1,15). We found that treatment with Ang-(1-7) at the peak of pulmonary eosinophilic inflammation induced eosinophil apoptosis, inhibited signaling pathways related to cytokine production and inflammatory cell survival, and reduced molecules related to maintenance of the Th2 immune response (15). In addition, Ang-(1-7) reduced the expression of genes involved in collagen expression in the lung (15). We have also observed similar results in a model of neutrophil-induced inflammation, arthritis (1). In this condition, blocking the Mas receptor delayed natural resolution, emphasizing that the ACE2/Ang-(1-7)/Mas axis plays an important physiological role in resolving inflammation (1). Similar results were observed in studies of pulmonary inflammation in progress in our laboratory. Moreover, in FVBN mice, a strain resistant to the asthma model, genetic deletion of the Mas receptor worsened pulmonary inflammation and remodeling when these animals were subjected to ovalbumin-induced asthma (16). Therefore, in addition to the therapeutic administration of Ang-(1-7), results from our group strongly suggest that absence or malfunction of the ACE2/Ang-(1–7)/Mas pathway intensifies inflammation, affects its resolution and contributes to the impaired function of the inflamed tissue.
Our findings are in line with those of other groups and strengthen the evidence that the ACE2/ Ang-(1-7)/ Mas axis has a physiological role in the immune response. Deletion of ACE2 or Mas receptor worsened pulmonary inflammation and remodeling in different lung diseases. Therapeutic administration of Ang-(1-7) reduced inflammation, induced resolution, prevented and mitigated pulmonary remodeling and promoted a faster and more complete restoration of pulmonary homeostasis. The harmful role of ACE2 in mediating the entry of SARs-COV-2 into lung cells is a relevant issue and needs to be studied in detail. However, as the RAS axis with anti-inflammatory and pro-resolving role is impaired by the binding of SARs-COV-2 to ACE2, the strategy to inhibit ACE2 needs to be rethought, specially when seeking more efficient therapeutic treatment. Inhibiting ACE2 will significantly decrease Ang-(1-7) levels and/or increase Ang II, contributing to the aggravation of pulmonary inflammation and the course of the disease. Thus, after the onset of the infection, activation of the Mas receptor or administration of Ang-(1-7) or Mas analogs can be important additive measures to control the inflammatory response mediated by SARS-CoV-2 in the lung.
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