Relevance of angiotensin-(1-7) and its receptor Mas in pneumonia caused by influenza virus and post-influenza pneumococcal infection

Melo, Eliza Mathias; Sarto, Juliana Del; Vago, Juliana P.; Tavares, Luciana P.; Rago, Flávia; Gonçalves, Ana Paula; Machado, Marina Amaral de Ávila; Aranda-Pardos, Irene; Valiate, Bruno Vinicius Santos; Cassali, Geovanni Dantas; Pinho, Vanessa; Sousa, Lirlândia P.; A-González, Noelia; Campagnole‐Santos, Maria José; Bäder, Michael; Santos, Robson Augusto Souza; Machado, Alexandre Vaz; Ludwig, Stephan; Teixeira, Mauro Martins

doi:10.1016/j.phrs.2020.105292

Cited by 17 publications

(23 citation statements)

References 52 publications

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“…coli– induced peritonitis replicated the findings from the LPS-induced pleurisy, supporting the important role of MasR inducing the CCL2-mediated migration of macrophages during the resolution phase of infection and clarifying its importance for macrophage phagocytosis of bacteria by aiding the resolution of infections. Recently, we have also shown that Ang-(1-7) decreases viral burden in the lungs during influenza A infection, without acting directly on the viral killing/inhibition ( 71 ). Here, in agreement with this previous study, we have shown that Ang-(1-7) did not present a direct antimicrobial effect to E .…”

Section: Discussionmentioning

confidence: 99%

Angiotensin-(1-7)/MasR axis promotes migration of monocytes/macrophages with a regulatory phenotype to perform phagocytosis and efferocytosis

Zaidan¹,

Tavares²,

Sugimoto³

et al. 2022

JCI Insight

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Nonphlogistic migration of macrophages contributes to the clearance of pathogens and apoptotic cells: critical steps for the resolution of inflammation and return to homeostasis. Angiotensin-(1-7) [Ang-(1-7)] is an heptapeptide of the Renin-Angiotensin system that acts through Mas receptor (MasR). Ang-(1-7) has recently emerged as a novel pro-resolving mediator, yet Ang-(1-7) resolution mechanisms are not fully determined. Herein, Ang-(1-7) stimulated migration of human and murine monocytes/macrophages in a MasR, CCR2 and MEK/ERK1/2-dependent manner. Pleural injection of Ang-(1-7) promoted nonphlogistic mononuclear cell influx alongside increased levels of CCL2, IL-10 and macrophage polarization towards a regulatory phenotype. Ang-(1-7) induction of CCL2 and mononuclear cell migration was also dependent on MasR and MEK/ERK. Noteworthy, MasR was upregulated during resolution phase of inflammation and their pharmacological inhibition or genetic deficiency impaired mononuclear cell recruitment during self-resolving models of LPS pleurisy and E. coli peritonitis. Inhibition/absence of MasR was associated with reduced CCL2 levels, impaired phagocytosis of bacteria, efferocytosis and delayed resolution of inflammation. In summary, we have uncovered a novel pro-resolving feature of Ang-(1-7), namely the recruitment of mononuclear cells favoring efferocytosis, phagocytosis and resolution of inflammation. Mechanistically, cell migration was dependent on MasR, CCR2 and the MEK/ERK pathway.

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Section: Discussionmentioning

confidence: 99%

Angiotensin-(1-7)/MasR axis promotes migration of monocytes/macrophages with a regulatory phenotype to perform phagocytosis and efferocytosis

Zaidan¹,

Tavares²,

Sugimoto³

et al. 2022

JCI Insight

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“…We have previously hypothesized that inflammation was a major contributor to tissue dysfunction and death associated with viral and bacterial infections (Boff et al, 2020;Costa et al, 2022;de Araújo et al, 2022;Fagundes et al, 2012;Garcia et al, 2010;Machado et al, 2020;Melo et al, 2021;Sousa et al, 2013;Tavares, Melo, et al, 2022). Formal demonstration of this hypothesis in humans was brought about by the COVID-19 (Coronavirus Disease 19) pandemic in which studies clearly showed the central contribution of excessive inflammation to end-organ damage and death associated with infection.…”

Section: Resolution Pharmacology and Its Potential As A Therapy For I...mentioning

confidence: 99%

“…The underlying mechanisms by which Ang-(1-7) exerts its antiinflammatory and pro-resolving effects are multifaceted. Figure 2 de Carvalho Santuchi et al, 2019;Magalhaes et al, 2018;Melo et al, 2021;Pan et al, 2021).…”

Section: Gilz and Bacterial Infectionsmentioning

confidence: 99%

“…Importantly, the success of Ang-(1-7) treatment was directly linked to the presence of the Mas receptor, because the absence of this receptor worsened the infection, leading to 100% mortality(Melo et al, 2021). These findings highlight the importance of the RAS system in viral infection pathogenesis and suggest that modulation of this system, such as restoring the balance between AngII and Ang-(1-7) or administering Ang-(1-7), may have therapeutic potential in mitigating the inflammatory response and improving outcomes in severe viral infections.10.3 | Ang-(1-7) and bacterial infectionsIn the context of bacterial infection, treatment with Ang-(1-7) has shown promising benefits in reducing lung bacterial load, sepsis and mortality associated with pneumococcal infection following Influenza A virus infection(Melo et al, 2021). Another significant finding of Ang-(1-7) is its ability to restore the phagocytic capacity of neutrophils in mice with experimental Type 2 Diabetes Mellitus, enabling them to effectively phagocytose bacteria such as S. aureus, which are known to cause lung infections(Soto et al, 2019).…”

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confidence: 99%

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Resolution pharmacology and the treatment of infectious diseases

Costa,

Resende,

Melo

et al. 2024

British J Pharmacology

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Inflammation is elicited by the host in response to microbes, and is believed to be essential for protection against infection. However, we have previously hypothesized that excessive or misplaced inflammation may be a major contributor to tissue dysfunction and death associated with viral and bacterial infections. The resolutive phase of inflammation is a necessary condition to achieve homeostasis after acute inflammation. It is possible that targeting inflammation resolution may be beneficial for the host during infection. In this review, we summarize the evidence demonstrating the expression, roles and effects of the best described pro‐resolving molecules in the context of bacterial and viral infections. Pro‐resolving molecules play a pivotal role in modulating a spectrum of pathways associated with tissue inflammation and damage during both viral and bacterial infections. These molecules offer a blend of anti‐inflammatory, pro‐resolving and sometimes anti‐infective benefits, all the while circumventing the undesired and immune‐suppressive unwanted effects associated with glucocorticoids. Whether these beneficial effects will translate into benefits to patients clearly deserve further investigation.

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“…Angiotensin-converting enzyme 2 ( ACE 2) compensates the vasoconstrictive axis of the RAS by cleaving Ang II to form Ang(1–7) [ 10 ]. Ang(1–7) has demonstrated vasodilatory [ 11 ], anti-inflammatory [ 10 , 12 ], anti-fibrotic [ 10 , 13 ], and anti-proliferative effects [ 12 , 14 , 15 ] in experimental models. Failure of the RV is associated with increased activation of the RAS in experimental studies [ 16 , 17 ], and increased circulating Ang II concentrations have been observed in humans with ARDS [ 18 ], thus implicating Ang II in disease pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Study to Explore the Association of the Renin-Angiotensin System and Right Ventricular Function in Mechanically Ventilated Patients

Mekontso-Dessap

Hanrott

Powley

et al. 2022

JCM

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Background: Right ventricular (RV) dysfunction is associated with pulmonary vasoconstriction in mechanically ventilated patients. Enhancing the activity of angiotensin-converting enzyme 2 (ACE2), a key enzyme of the renin-angiotensin system (RAS), using recombinant human ACE2 (rhACE2) could alleviate RAS-mediated vasoconstriction and vascular remodeling. Methods: This prospective observational study investigated the association between concentrations of RAS peptides (Ang II or Ang(1–7)) and markers of RV function, as assessed by echocardiography (ratio of RV to left ventricular end-diastolic area, interventricular septal motion, and pulmonary arterial systolic pressure (PASP)). Results: Fifty-seven mechanically ventilated patients were enrolled. Incidence rates of acute cor pulmonale (ACP) and pulmonary circulatory dysfunction (PCD) were consistent with previous studies. In the 45 evaluable participants, no notable or consistent changes in RAS peptides concentration were observed over the observation period, and there was no correlation between Ang II concentration and either PASP or RV size. The model of the predicted posterior distributions for the pre- and post-dose values of Ang II demonstrated no change in the likelihood of PCD after hypothetical dosing with rhACE2, thus meeting the futility criteria. Similar results were observed with the other RAS peptides evaluated. Conclusions: Pre-defined success criteria for an association between PCD and the plasma RAS peptides were not met in the mechanically ventilated unselected patients.

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Relevance of angiotensin-(1-7) and its receptor Mas in pneumonia caused by influenza virus and post-influenza pneumococcal infection

Cited by 17 publications

References 52 publications

Angiotensin-(1-7)/MasR axis promotes migration of monocytes/macrophages with a regulatory phenotype to perform phagocytosis and efferocytosis

Angiotensin-(1-7)/MasR axis promotes migration of monocytes/macrophages with a regulatory phenotype to perform phagocytosis and efferocytosis

Resolution pharmacology and the treatment of infectious diseases

Study to Explore the Association of the Renin-Angiotensin System and Right Ventricular Function in Mechanically Ventilated Patients

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