








key: cord-349445-yh6ndtgm
authors: Mohammed El Tabaa, Manar; Mohammed El Tabaa, Maram
title: Targeting Neprilysin (NEP) pathways: A potential new hope to defeat COVID-19 ghost
date: 2020-05-27
journal: Biochem Pharmacol
DOI: 10.1016/j.bcp.2020.114057
sha: 
doc_id: 349445
cord_uid: yh6ndtgm

COVID-19 is an ongoing viral pandemic disease that is caused by SARS-CoV2, inducing severe pneumonia in humans. However, several classes of repurposed drugs have been recommended, no specific vaccines or effective therapeutic interventions for COVID-19 are developed till now. Viral dependence on ACE-2, as entry receptors, drove the researchers into RAS impact on COVID-19 pathogenesis. Several evidences have pointed at Neprilysin (NEP) as one of pulmonary RAS components. Considering the protective effect of NEP against pulmonary inflammatory reactions and fibrosis, it is suggested to direct the future efforts towards its potential role in COVID-19 pathophysiology. Thus, the review aimed to shed light on the potential beneficial effects of NEP pathways as a novel target for COVID-19 therapy by summarizing its possible molecular mechanisms. Additional experimental and clinical studies explaining more the relationships between NEP and COVID-19 will greatly benefit in designing the future treatment approaches.

Coronavirus disease 2019 (COVID- 19) is an infectious viral disease that is caused by a newly discovered coronavirus, namely severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) [1] . It is a virus belonging to order Nidovirales of family Coronaviridae, which are singlestranded RNA viruses [2] and broadly distributed in both humans and other mammals [3] .

Majority of the people infected with 2019 novel coronavirus (2019-nCoV) may recover without requiring special treatment [4] , except the elderly people and those with some medical problems such as hypertension, diabetes [5] and chronic respiratory disease [6] . Such patients are more liable to be infected with COVID-19 and might develop a fatal pneumonia with clinical presentation greatly resembling that caused by the previous beta-coronavirus SARS-COV appeared in 2003; severe acute respiratory syndrome (SARS) [7] .

In such cohort, patients firstly complain of fever, dry cough, and at late stage, may suffer from dyspnea that makes them in a desperate need of intensive care unit (ICU) admission and oxygen therapy [8] . However, the time between ICU admission and ARDS development is recorded to be as short as 2 days [9] , being the reason for the high mortality rate associated with COVID-19 at this stage [10] .

Till present, no COVID-19-specific vaccines or medications are available, although some national medical authorities recommend testing the efficacy of antiviral medication in especially sever clinical trials [11] . In addition, several medical researchers suggest starting the supportive and symptomatic treatment till the new medications are developed [12, 13] .

Early evidences have shown that the pathogenicity for COVID-19 may be enhanced with increased the body susceptibility to induce a phenomenon called cytokine storm, in which the immune system gears up by overreacting and producing more inflammatory mediators to fight the infection [14] . As a result, a severe inflammatory reaction is produced accompanied with significant damage, including organ failure [15, 16] . receptors [27] ; disrupting, of course, the normal physiological function of ACE-2/Ang (1-7)/MasR axis of the renin-angiotensin system (RAS) pathway [28] .

Therefore, researchers suggested that the use of angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs), may show a positive trend towards the severe inflammatory reactions and endothelial dysfunction caused by stimulating the function of ACE/Ang II/AT-1 axis and thereby, towards the bad pulmonary effects associated with the COVID-19 infection [29, 30] . However, no clinical trial, till this time, has been proved its efficacy in preventing or even reducing the COVID-19 severity [31, 32] .

Pursuing clinical trials with the absence of whole data describing the structure of COVID-19

virus and its related mechanisms may lead to unsatisfied outcomes. As well, understanding such data will greatly help in determining the most appropriate effective treatment protocols.

Consequently, the first step to prevent and slow down the disease progression should involve the deduction of proper pathophysiology of that novel viral disease.

Identifying ACE-2 as a viral entry receptor will emphasize on the important role of classical RAS pathway in COVID-19 pathophysiology, however, neither the link between ACE-2 and other RAS components nor their exact roles in the COVID-19 pathogenesis have been neatly studied till now.

One RAS component, namely neprilysin (NEP), has been established to potentiate the physiological beneficial role ascribed to the ACE-2/ang (1-7)/MasR axis; by an alternative pathway [33] . Nowadays, NEP has emerged as a pharmaceutical target for many drugs; especially those used in treating cardiovascular diseases and Alzheimer's disease (AD) [34, 35] . Considering the respiratory system, NEP was reported to play a vital role in protecting lungs from inflammation and fibrosis [36] [37] [38] . A long time ago, mentioned that rats infected with common respiratory tract pathogens, such as parainfluenza virus type-1, rat coronavirus, and Mycoplasma pulmonis showed low NEP activity; resulting in an increase in their susceptibility to inflammatory responses [39] . However, the precise NEP's role against life-threatening lung injuries has not been investigated yet.

Consequently, this current review aims to examine the cellular signaling pathways involving NEP in COVID-19 pathogenesis and to summarize the evidences supporting the potential beneficial effects of NEP as a novel target for therapy.

All previous and recent studies agreed with the fact that the surface of all human pathogenic coronaviruses is covered with crown like projections called spike (S) glycoproteins; giving the viruses their name [40] . In addition to S protein, another three main structural proteins have been recognized in SARS-CoV-2, namely envelope (E), nucleocapsid (N) and membrane (M) proteins [41] , Figure (1) .

Specifically, S proteins are very important for SARS-CoV-2 infection to get started [42] . They possess two functional subunits by which the virus can enter into its target host cells involving; S1 subunit, which enables it to bind with receptors on the host cell surface and S2 subunit, that allows the virus to fuse into the cellular membrane [43] .

Unlike other coronaviruses, several experimental analyses proved that SARS-CoV-2 does not use the common known viral entry receptors, such as aminopeptidase N (APN) [41] and dipeptidyl peptidase 4 (DPP4) [44] , but, instead, can utilize ACE-2 receptor [27] .

Additionally, it was revealed that transmembrane protease serine 2 (TMPRSS2) is very critical for the host cell entry of SARS-CoV-2 [45] and its plasma membrane fusion [46] resembling SARS-CoV [47] . Firstly, the virus starts its destructive journey with binding of S1 subunit to ACE-2 enzyme receptor on the cell membrane surface, which in turn activates TMPRSS2.

Activation of TMPRSS2 is followed by cleavage of both virus's S1 subunits from its S2 subunits and so of the ACE-2 receptors. Secondly, activated TMPRSS2 can also act on the S2 subunit, activating it through prompting an irreversible conformational change that will facilitate the virus-cell fusion [48, 49] .

Within this view, understanding the precise involvement ACE-2, as a member of pulmonary RAS pathway, in COVID-19 pathophysiology may open new therapeutic possibilities for management.

For years, RAS was depicted as a hormonal circulating system involved in fluid and electrolyte balance, systemic vascular resistance and blood pressure regulation [50, 51] . However, a wealth of data showed that lung epithelial cells, fibroblasts and alveolar macrophages could also express the major constituents of the RAS [52, 53] supporting the existence of a "local" pulmonary RAS that can be differentiated from the "systemic" circulating RAS [54] .

As regards "local" RAS in the lung, it has been reported to involve multiple cellular mechanisms affecting the vascular permeability, fibroblast activity and alveolar epithelial cells [55, 56] . By the time, it is well recognized that activating pulmonary RAS can influence the pathogenesis of lung injury in different lung diseases such as pulmonary hypertension, acute respiratory distress syndrome (ARDS), asthma and pulmonary fibrosis [54] . As a consequence, pulmonary RAS has been described to participate in disease process or play a protective role against tissue injury [57] and thus, modulating RAS in the lung can successfully play a good role in the treatment of inflammatory lung disease [52, 58] .

The functional steps of RAS was firstly initiated by hepatic synthesis of a plasma globulin called renin substrate (or angiotensinogen) which could be enzymatically converted through renin secreted by juxtaglomerular cells of the kidney, into the biologically inactive decapeptide, namely angiotensin (Ang) I [59] . Subsequently, RAS exhibits two main axes based on two distinct enzymes responsible for cleavage of Ang I into angiotensin (Ang) II or Ang 1-7 [51] ,

First axis involves generation of Ang II as the main effector via the angiotensin converting enzyme (ACE) and named the classical vasopressor axis ACE/ Ang II/ Ang II type 1 receptor (AT1) [60] . For the second axis, angiotensin converting enzyme II (ACE-2) was identified as a depressor for RAS activation through producing Ang 1-7 [61] . Henceforth, this axis ACE-2/ Ang 1-7/ Mas-1 has become an important area of scientific research interest [62] .

The ACE/Ang II/AT-1 axis has been well documented to drive a set of deleterious reactions in the lung through generating Ang II, the principal effector of this classical axis, involved in RAS mediated vasoconstriction, sodium retention, fluid overload, inflammation and fibrosis [63, 64] .

In addition, ACE has been reported to evoke bradykinin and substance P degradation, two local pro-inflammatory and protussive peptides which can stimulate cough reflex and nitric oxide (NO) release [65, 66] .

Specifically, pulmonary vascular inflammation contributes to a phenomenon called ACE "shedding," in which endothelial surface-bound ACE is released into the interstitium resulting in significant increase in the level of Ang II [67] , which explains the detection of higher Ang II level in COVID-19 patients than normal [68] .

Several studies declared that Ang II could act through two distinct G protein-coupled receptors (GPCR) subtypes, angiotensin II receptor type 1 (AT1R) and type 2 (AT2R), that were found to be expressed in human lung tissue; proving the local generation of Ang II in lung [65, 69] .

The majority of actions evolved by Ang II could be mediated by AT1 receptor via enhancing many complex intracellular signaling pathways including MAPK/ERK, PLCb/IP3/diacylglycerol, tyrosine kinases, and NF-kB [70] . Activating AT1 receptor had been shown to further stimulate monocytes, macrophages and vascular smooth muscle cells to produce the proinflammatory cytokines such as TNF-α and IL-6 [71] [72] [73] . On the contrary, AT2

receptor was documented to have a number of counterregulatory interactions against lung tissue injury via inhibiting inflammation, and fibrosis [74, 75] .

In addition to the known Ang II effects on promoting vasoconstriction, and pro-inflammatory cytokine release, there is also an increasing evidence that Ang II could induce vascular endothelial dysfunction [76, 77] , promoting the activation and aggregation of platelets and thereby, pro-thrombotic milieu [78] .

Ang II could be associated with noticeable rise in the plasma level of endothelin-1 (ET-1) [79] , which is a peptide secreted mainly from vascular endothelial cells (ECs), and basically works through the endothelin type A receptor (ETA) in vascular smooth muscle cells and the endothelin type B receptor (ETB) in ECs [80] . Consequently, ET-1 is described as the most potent bronchoconstrictor [81] and vasoconstrictor in the airways [82] . Practically, ET-1 acts as a key player of angiotensin II-induced endothelial dysfunction and platelets activation via inducing IL-6 release [83, 84] , which was documented to be correlated directly with the extent of endothelial dysfunction [85] .

Endothelial dysfunction is generally characterized by an imbalance between endotheliumdependent relaxing and contracting factors, attributed to reduced production/availability of nitric oxide (NO); namely endothelium-derived relaxing factor (EDRF) [86, 87] . NO acts as a potent endogenous vasodilator that could prevent platelet aggregation and leukocyte adhesion to ECs [88, 89] . Since IL-6 would inactivate endothelial nitric oxide synthase (eNOS), it could disrupt NO production [90] , decreasing its level and inducing a state of oxidative stress that may lead to Ang II-induced impairment in endothelial responses [91] Postulating impaired endothelium functions as a principal factor in the pathogenesis of heart failure, hypertension and diabetes, it will be expected to classify the patients of such diseases as high risk groups for COVID-19 development [92] [93] [94] .

Furthermore, platelets activation and aggregation may be noticed as a result of inflammatory reactions aggravated by endothelial dysfunction, leading to imbalance between coagulation and fibrinolysis [87] . It is clearly evident that continuing release of IL-6 can enhance hepatic thrombopoietin (TPO) mRNA expression resulting in thrombopoiesis stimulation and increase in circulatory platelets' numbers, known as (inflammatory thrombocytosis). Within this context, ET-1 can also mediate the synthesis of platelet activating factor (PAF), a potent phospholipid mediator of platelet activation and aggregation, that may activate platelets to stick together and aggregate. As a result, a platelet plug is formed as an initiator for blood clotting and intravascular thrombus formation [88, 89] , which is considered as a starting point for developing stroke [95] .

Even though the high incidence of inflammatory thrombocytosis in COVID-19 patients, the laboratory results of severe cases showed the opposite; suffering from thrombocytopenia [23] .The possible explanation is the depletion of both platelets and megakaryocytes as a result of multiple blood clots formed at the injured site, leading to less platelet production with more consumption as the disease severity increases [96] .

Interestingly, endothelial dysfunction and platelet activation can successively together worsen the severity of COVID-19 infection. As known, both ET-1 and activated platelets, associated with endothelial dysfunction, [97] could promote leukocytes rolling, adherence to endothelium, activation and migration into the inflammatory sites, sharing in enhancement of leukocytes recruitment [98, 99] . In addition, endothelial dysfunction can drive the fibrotic consequences following SARS-CoV-2 infection, developing pulmonary fibrosis as a result of releasing transforming growth factor-β1 (TGF-β1), the main fibrogenic cytokines implicated in pulmonary fibrosis, which could be induced by ET-1 action [100, 101] .

Taken into consideration the numerous harmful effects possibly induced by Ang II during COVID-19 pathogenesis, we found that most novel studies aim to use the anti-hypertensive drugs which act either by inhibiting the ACE activity or by blocking AT1 receptor, suggesting that action may mitigate the disease severity in COVID-19 patients.

On the other side, it has been proposed that enhancing the counter regulatory axis composed by ACE-2/Ang (1-7)/MasR axis may be the most helpful.

ACE-2/Ang (1-7)/MasR axis, the depressor arm of RAS, was identified to mitigate the deleterious actions mediated by ACE/ Ang II/ AT1 [51] . Within this axis, ACE-2 competes with ACE by hydrolyzing Ang I into the nonapeptide angiotensin (Ang 1-9) which is further cleaved by the action of ACE into heptapeptide angiotensin (Ang 1-7), thus decreasing the amount of Ang I available for Ang II generation by ACE [102, 103] . To the same extent, ACE-2 could also hydrolyze Ang II converting it into Ang (1-7) [104, 105] .

Until the year 2000, ACE has emerged as the key enzyme in the pulmonary RAS, but this was challenged by the discovery of its homologue; ACE-2 [106] which was found out to be broadly expressed in almost all types of lung cells, within the vascular endothelial and smooth muscle cells, types I and II alveolar epithelial cells and bronchial epithelial cells [107, 108] .

ACE-2 could negatively regulate the RAS in the lung through reducing Ang II/AT1 receptor signaling and activating the counterregulatory Ang (1-7)/ Mas receptor pathway [54] . That finding was compatible with the animal studies showed that the use of RAS inhibitors could effectively relieve the symptoms of acute severe pneumonia and respiratory failure [109] .

Consequently, the increased ACE-2 was addressed as a target for protection from predisposition to inflammatory lung diseases such as, acute respiratory distress syndrome (ARDS) [108, 110] .

Concerning COVID-19 pathogenesis, binding of SARS-CoV-2 to ACE-2 resulted in exhaustion of ACE-2, breaking the balance of the RAS system within the lung and then, exacerbation of pulmonary inflammatory reactions [109, 111] .

Being ACE-2 receptors widely expressed on vascular endothelial cells (EC) within the lungs [112] , SARS-coV-2 can exploit them to induce and diffuse inflammatory cascades within endothelial cells disrupting their function; evidenced by the existence of viral elements and inflammatory cells within endothelial cells [113] .

Thus, distributing ACE-2, as the main functional receptor for SARS-CoV-2, within human tissues will be the determinator for spreading of viral infection within the lung and other organs [108, 114] . Both alveolar and bronchial membranes were reported to highly express ACE-2 , which may explain the higher tendency of SARS-CoV-2 virus to harmfully affect lower airways than the upper ones [110, 115] . However, recent reports indicate that few COVID-19 patients may also develop some signs and symptoms of upper respiratory tract infection (e.g. rhinorrhea, sneezing, or sore throat) [7, 17, 116] .

Furthermore, it was reported that ACE-2 is also expressed in many epithelial cells of other organs than lung including kidney, blood vessels, intestine [110] and brain [117] . The fact which may explain the existence of some extra-pulmonary co-morbidities as myocardial dysfunction [30] and acute kidney injury (AKI) [118] , gastrointestinal manifestations (diarrhea, vomiting or abdominal pain) [119] , neurologic manifestations (altered mental status or seizures) [120, 121] .

Therefore, increased ACE-2 may be useless by promoting viral entry into lung cells, potentiating its devastating effect and enhancing mortality [122] . Consistent with these findings, suggesting ACE-2 activators such as, Diminazene aceturate (DIZE) [65] , 4-[2-(4carbamimidoyl phenyl) imino hydrazinyl] benzene carboximidamide and Xanthenone (XNT) [54] for counteracting COVID-19 pathogenesis will be in vain.

As a consequence, in order to diminish SARS-CoV-2 entry and its subsequent lung injury, pulmonary ACE-2 activity should be reduced. However, at the same time, reduced ACE-2 activity may contribute to worsening of the lung inflammation, by unopposed angiotensin II accumulation [31] and forcing the RAS to continuously increase the expression of cytokines [123] .

Simultaneously, a previous data indicated that the decrease in the ACE-2 activity in a rat model of ARDS was paralleled by low amounts of Ang-(1-7) [124] , which has been reported to play a beneficial role against pulmonary inflammation and fibrosis [125, 126] . In this context, another study stated that treatment with protease-resistant, a cyclic form of Ang (1-7) (cAng 1-7), could restore the ACE-2 activity; attenuated the inflammatory response; decreased lung injury and improved lung function [124, 127] . That confirms the positive relationship between Ang 1-7 and preserving the depressor role of ACE-2/Ang (1-7)/MasR axis in pulmonary RAS.

Hence, these data will attract the attention to the pivotal role of Ang (1-7) in COVID-19 pathophysiology and therapy.

Ang (1-7) is a biologically active metabolite of the RAS that had become a peptide of interest in the last decade, because of its effective role in activating a number of crucial events for the homeostasis of normal physiological functions [128] . It was reported that Ang (1-7) could exert various effects, which are greatly in opposition to those of AT-1 receptor activation such as vasodilator, anti-inflammatory, anti-hypertrophy, anti-proliferative, anti-fibrosis and antioxidant effects [54, 129] .

Clinical and epidemiological studies have revealed the existence of a powerful link between the vasodilator effect of Ang 1-7 and its higher plasma levels in females; making them less liability to hypertension than males [130, 131] . Several mechanisms have been attributed to Ang 1-7 in lowering blood pressure which can be explained as follows (i) Triggering eNOS to stimulate the release of NO, which could play a critical role in promoting the relaxation of blood vessels and inhibiting the platelet aggregation [132, 133] (ii) Inducing natriuresis/diuresis [134] , and (iii) Activating peroxisome proliferator activator receptors (PPARs), which in turn supports the availability of NO [135] .

Interestingly, Ang 1-7 was documented to directly blunt the activation of pro-inflammatory signaling pathways induced by the Ang II-associated phosphorylation of MAPKs and NF-kB signaling [136, 137] , suggesting also the anti-hypertrophic effects of Ang 1-7 through normalization of MAPKs activity [130] . Moreover, Ang (1-7), by counteracting the Ang II effects, could also preserve the endothelial function through increasing nitric oxide bioavailability and inhibiting oxidative stress [138] .

Taken together, Ang 1-7 could also reduce lung injury by suppressing the expression of fibrogenic molecules such as TGF-β1 [139] , which acts as a key mediator involved in pulmonary fibrosis [140] .

Moreover, several researches have pointed out the antioxidant role of Ang 1-7 [54, 130] that might be established by; (i) limiting the activation of NADPH oxidase, which is a membranebound enzyme complex involved in triggering ROS production through generating superoxide radicals [141] , and/or (ii) normalizing the expression of antioxidant enzymes such as catalase and heme oxygenase-1 (HO-1) [130] , as well as the nuclear factor erythroid 2-related factor 2 (Nrf2), that acts as an emerging regulator of cellular resistance to oxidants [142] .

Other observation and experimental evidence suggested that endogenous ACEIs effects of Ang

(1-7) can be mediated by its unique membrane bound G protein-coupled receptor known as Mas (MasR) [143] , which was revealed to be found in the thin areas of the bronchial epithelium and smooth muscle [144] . MasR could direct the Ang 1-7 biological responses via the MasR/cAMP/protein kinase A (PKA) signaling [145] , which was previously validated by administrating AVE 0991 (a nonpeptide mimetic of Ang 1-7 as a specific ligand (agonist) for

MasR [130] .

Subsequently, attention should be drawn to specifically trigger the Ang (1-7) as a potential therapeutic agent able to mitigate the lung injury in patients with COVID-19 infection, without increasing ACE-2 activity.

There are different formulations of Ang 1-7 are being developed e.g. AVE-0991 [146] , HPβCD/Ang 1-7 [147] , CGEN-856 [148] , NorLeu3-A [149] and cyclic Ang 1-7 [150] and used to demonstrate its therapeutic potential in numerous animal models of human diseases, including hypertension, heart failure, stroke, diabetes mellitus, atherosclerosis, renal disease and pulmonary arterial hypertension [130, 145, 151] . However, therapeutic attempts and clinical trials are still underway because of Ang (1-7) rapid in vivo degradation by ACE [130] .

On the other hand, previous studies emphasized that Ang (1-7) could induce vasodilatation in rats of Mas-deficient vessels [152] and in rats pretreated with A779 (MasR blocker) [153] . The former observed data suggested that Ang (1-7) might also interact with an additional specific receptor other than MasR to elicit vasodilatation [154] . Indeed, Ang (1-7) have been shown to stimulate also the bradykinin (BKs) pathway via preventing the BK hydrolysis [155] .

BKs are one of the formed kinins that can play significant roles in regulating tissue injury, inflammatory responses and vascular permeability [156] . They have a little direct impact on the activation and recruitment of inflammatory cells, but they could work indirectly through stimulating the airway epithelial cells and lung fibroblasts through producing a wide array of cytokines, including IL-6, IL-1, IL-8, granulocyte colony stimulating factor (G-CSF), GM-CSF and macrophage chemoattractant protein-1 (MCP-1) [157] [158] [159] [160] . BK action was mediated by G-coupled receptors, namely BK receptor (BR) [156] that amazingly found to be interacted with the Mas receptors in order to regulate the vasodilator effect of the Ang (1-7) [161] .

At the same time, it was found that the reduction in ACE-2 mRNA expression within the lungs of STZ diabetic rats was linked with an increase in circulating Ang II, but without any significant change in the production of Ang (1-7) [162, 163] , ensuring that pulmonary ACE-2

was not the only enzyme responsible for Ang (1-7) production, but there might be another enzyme contributing to its synthesis.

By the time, the classical view of RAS has been further expanded and become well established than previously conceived. As a consequence, it was discovered that there was another alternative pathway by which Ang (1-7) is produced, instead of that based on ACE-2. That way was disclosed to degrade Ang I directly into Ang (1-7) by another RAS member, called NEP.

NEP (neutral endopeptidase or neprilysin, previously known as CD10) is a member of transmembrane zink-metalloendopeptidase that particularly highly expressed in both kidney and lung [164] [165] [166] . NEP was also found in a number of other tissues, as epithelia of breast, prostate, stomach and in the central nervous system [167] [168] [169] . NEP had been also shown to be present in a soluble circulating form (cNEP) within several body fluids including urine, cerebrospinal fluid and plasma [170] .

Although NEP can discriminately hydrolyze a broad spectrum of physiologically relevant substrates, it was found to possess an obvious substrate specificity. Classically, NEP exhibits a size-related specificity that enables it to hydrolyze only peptides with a small molecular weight generally at or below 3,000 Dalton [171] . As well, NEP has been also described to show a distinction between substrates being cleaved 'in vitro' and that being cleaved 'in vivo'. Initially, NEP was reported to specifically cleave more than 7 peptides 'in vivo' including natriuretic peptides (NPs) (Atrial natriuretic peptide (ANP), C-type natriuretic peptide (CNP), and B-type natriuretic peptide (BNP)), BKs, neuropeptides (substance P, enkephalins), Gastrin,

Chemotactic peptide formyl-Met-Leu-Phe (fMLP), versus 26 peptides 'in vitro' such as IL-lβ,

Oxytocin, Gastrin-releasing peptide (GRP), ET-1, Ang I and II……etc [172] [173] [174] . By time, more substrates had been proposed with varying levels of 'in vitro' and/or 'in vivo' proof of cleavage. Among that, GRP, ET-1, Ang I which have been proved to be additionally metabolized 'in vivo' by NEP [162, 175, 176] , emerging the evidence that NEP could play an important role in many physiological and pathological conditions [177] , Table 2 For CVS patients, NPs were known to be of therapeutic importance in lowering blood volume by inducing natriuresis, in which excess sodium can be excreted in urine with accompanying water by the renal tubules [35] . Previous clinitcal trials proved that administering synthetic NPs might be associated with some limitations especially on the long run [178, 179] , that pushed them to depend on using Neprilysin inhibitors (NEPi) such as (thiorphan or candoxatrilat) to prolong and potentiate the beneficial effects of vasoactive/NPs via inhibiting endogenous NPs degradation [180] .

NEPi have been used for decades to treat acute diarrhea [181] . However, they are now developed and emerged as a pharmaceutical target for different CVS diseases. NEPi have been used mainly in people with congestive heart failure and a reduced left ventricular ejection fraction (LVEF) [182] . However, using NEPi (e.g. candoxatril) solely for hypertension treatment was ineffective, because NEPi could inhibit Ang II degradation, increasing its associated simultaneous detrimental effects. Therefore, combining NEPi either with ACEi (e.g.

omapatrilat) or ARBs (e.g. LCZ696) become a necessity to overcome this limitation [183, 184] .

Another critical aspect for the pharmacological role of NEPi was achieved in treating diabetes via inhibiting the breakdown of some substrates known to modulate glucose metabolism, such as incretin glucagon-like peptide-1 (GLP-1), NPs and BKs [185] .

Within the brain, NEP had also proved to hold a great beneficial role in the neurological disorders such as Alzheimer's disease (AD) on both in vitro and in vivo studies [186] [187] [188] .

Multiple lines of evidence highlighted the presence of many amyloid plaques in the form of βamyloid (Aβ) peptide in the brains of AD patients with dementia [189] . It was worthy mentioned that NEP was one of the major Aβ peptide-degrading enzymes in the brain, whose expression was documented to be lower in the brain of AD patients [190] supporting the role that NEP can play in the prevention and treatment of AD.

In addition to the above mentioned, NEP seems to play a protective role in the pathogenesis of lung injury since significant decrease in the NEP enzymatic activity in the lung of mice with ALI was associated with inactivation of the tachykinins degradation pathway and consequently, reducing uncontrolled inflammation in ALI/ARDS and in other neurogenic respiratory diseases [37, 191, 192] .

of both respiratory bronchioles and alveoli [193, 194] , resulting in excessive production of GRP [195] .

GRP was known to be one of the Bombesin-like peptides that can be expressed and released by PNECs into the surrounding airway parenchyma in response to various stimuli like hypoxia or irritation [196, 197] to regulate the neutrophil chemotaxis and macrophage infiltration within the lung tissue [198, 199] . GRP could act via stimulating Gastrin-releasing peptide receptor (GRPR) at the surface of macrophages, which in turn, would enhance the release of early inflammatory mediators contributing to the recruitment of neutrophils [200, 201] .

More neutrophil infiltration within the lung is usually associated with high tendency for lung tissue damage [202, 203] , since they would be involved in breakdown of basement membrane integrity within the bronchiolar/alveolar architecture and thereby, diminution of pulmonary function. Moreover, during the deleterious inflammatory reactions, as in pneumonia, neutrophil lifespan is prolonged to generate more superoxide radicals resulting in damage of the surrounding normal tissue [204] .

Interestingly, NEP can play a vital role during lung inflammation through its catabolic effect on (GRP) [205] in addition to its presence on the plasma membrane of neutrophils modulating their chemotactic responsiveness via cleaving the chemotactic peptide formyl-Met-Leu-Phe (fMLP) which resembles an effective chemotactic agonist in response to GRP [206, 207] . Thus, breaking both GRB and fMLP peptide by NEP will cut the way for recruiting more neutrophils into site of injury and consequently, grab the reins.

On the other hand, once neutrophils being activated at inflammatory sites, they could secrete high concentration of several serine proteases into the extracellular environment to degrade host pathogens, recruit more cytokines and stimulate further tissue damage [208, 209] . Cathepsin G was reported to be one of the neutrophil-derived serine proteases that is abundantly found in the azurophil granules and known to degrade both Angiotensinogen and Ang I into Ang II [209, 210] .

So far, NEP can additionally take a part in decreasing the pro-inflammatory, oxidative and profibrotic effects of Ang II by minimizing the release of cathepsin G and consequently, its action on Ang I [211] [212] [213] .

As NEP was reported to have more catalytic activity than ACE-2 in cleaving Ang I into Ang

(1-7), it could also effectively enhance the protective activities associated with Ang (1-7) in the lung [214] . As well, NEP could not affect lung Ang (1-7) metabolism because it was involved in the metabolism of Ang (1-7) within tissues other than pulmonary tissues, as renal cortex. On the other hand, ACE was recorded to be the major enzyme responsible for Ang (1) (2) (3) (4) (5) (6) (7) metabolism in the pulmonary membranes by hydrolyzing it to Ang (1-5), and then, into Ang (3) (4) (5) by the action of aminopeptidases [215] . Besides, NEP shows higher activity than ACE towards BKs degradation, resulting in inhibition of the bradykinin-induced inflammatory cells influx [125, 216] .

Despite multiple data confirming the expected role of NEP in relieving the pulmonary inflammatory response, its effect on reducing exacerbation of acute severe pneumonia in COVID 19 patients has not been highlighted yet.

Hence, the question now, may the reviewed actions of NEP pathways be sufficient to impose a new effective strategy for COVID-19 management as compared to the suggested repurposed drugs?

guidelines only provide supportive care. However, many drugs repurposed based on host response in order to defeat COVID-19, Table 1 [217].

Recently, there is an empirical use of anti-inflammation therapy in critical patients of COVID-19 presented with severe complications in order to prevent further injury and suppress Cytokine storm manifestations as ARDS and other organs damage till even death. Main antiinflammatory medications include, non steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, chloroquine and statins [22] .

Numerous observational data support a strong association between use of NSAIDs in management of lower respiratory tract infections and higher incidence of complications including fulminating pneumonia, pleural effusions and dissemination of infection [218] .

NSAIDs may also induce nephrotoxicity among susceptible covid-19 patient groups and is exacerbated by fever and dehydration [219] . Consequently, some studies recommend avoiding use of NSAIDs e.g. ibuprofen and diclofenac as the first choice for fever control and pain symptoms in COVID-19 infection and using paracetamol instead [220, 221] .

Previous study demonstrated that corticosteroids-treated asthmatic patients showed enhanced NEP expression in their airway epithelium as compared to nonsteroid-treated ones. This fits the hypothesis that the anti-inflammatory effect of corticosteroids within the airways may be partially mediated by upregulating NEP [222] .

Despite of possible benefits gained from the anti-inflammatory effect of corticosteroids, they will be associated with serious impairment in the immune system of severe COVID-19 cases [22] . Corticosteroids may delay the viral elimination and increase susceptibility for the secondary infection resulting in deterioration of the disease especially with immune system impairment [223] . Other side effects associated with corticosteroid treatment include hyperglycemia, central obesity and hypertension which represent an obstacle against their use in people at higher risk for COVID-19 especially diabetic, cardiac and hypertensive patients [217] . Auyeung et al., 2005 reported that there is no survival benefit for treatment of SARS patients with corticosteroids [224] . Another study on corticosteroid therapy of MERS patients has revealed no mortality difference with delayed clearance of MERS-CoV from lower respiratory tract [225] . Moreover, there is no evidence from any clinical trials supporting its administration for COVID-19 [22] .

In order to overcome the immune suppression induced by corticosteroids, a variety of other therapies have been developed to act directly as specific anti-cytokines (e.g. anakinra or tocilizumab) [10] or anti-inflammatory cytokines (e.g. IL-37 or IL-38) [17] without targeting the immune system and have proven to be effective in treating several syndromes that triggered by cytokine storm [123] .

According to previous studies, Chloroquine (CQ) and its less toxic metabolite, hydroxychloroquine (HCQ) possess anti-inflammatory and immunomodulatory benefits by affecting cell signaling in viral infections. CQ/HCQ also exhibit a wide variety of antiviral reactions against several viruses including members of the flaviviruses, retroviruses, and coronaviruses [25] .

CQ and HCQ can prevent the attachment of viral particles to their cell surface receptor, modulate pH in order to inhibit pH-dependent steps of viral replication or interfere with posttranslational modifications (PTMs) of viral proteins [217, 226] .

An enough pre-clinical evidence considering CQ effectiveness for treatment of COVID-19

showed reduction in the pneumonia exacerbation, improving lung imaging findings and high rate of virus nucleic acid test negativity. Accordingly, CQ phosphate in Guidelines (version 6)

for treatment of COVID-19 has been recommended with oral administration twice daily at a dose of 500 mg (300 mg for chloroquine) for adults and no more than 10 days [22] .

However, there is a narrow margin between CQ/HCQ therapeutic and toxic dose. Its poisoning has been favored and life-threatening in patients with cardiac disorders [227] . It is also contraindicated for people with retinopathy, elevated liver enzymes, heart rhythm disorders (as QT prolongation) or allergy to CQ/HCQ [228] . Further, efficiency and safety of CQ/HCQ for COVID-19 is still unclear and needs a confirmation depending on more preclinical and clinical trials [229] .

Statins are the widely used cholesterol lowering drugs, that were also reported to improve endothelial functions via lipid-independent mechanisms; mediated by their anti-inflammatory and anti-oxidant properties as well as their ability to restore vascular NO bioavailability [230] .

Because of their immunomodulatory effect, they have also proven to be beneficial as adjuvant therapy in patients with different auto-immune inflammatory conditions (e.g. systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis) [231] . As a consequence, some hospitals included statins in the treatment protocol of COVID-19. Although statin therapy is usually well tolerated, their use in COVID-19 patients may increase the incidence and severity of myopathies and acute kidney injury [232] . Moreover, statin drugs may increase IL-18 levels which can promote severe pneumonia, deteriorating SARS-CoV-2-induced ARDS and mortality, especially in elderly patients who are more likely to use these drugs [233] .

Sex differences in health outcomes following COVID-19 may be attributed to sex-dependent production of steroid hormones. Estrogen has been reported to attenuate inflammation which might protect women compared to men [234] . Estrogen signaling are also known to downregulate MCP-1 expression and promote adaptive T cell response by stimulating neutrophil recruitment [235] .

It has been also reported that SERMs, like Toremifene, exhibits potential effects in blocking various viral infections as SARSCoV and MERSCoV virus [236] through interacting with and destabilizing the virus membrane glycoprotein resulting in inhibition of its replication [237] .

Wang et al., 2020 suggests that treatment with estrogens and estrogen-related compounds as estradiol (E2) could suppress the expression of TMPRSS2 in the lung resulting in decreased mortality to SARS-CoV infection [235] .

An estrogen receptors/RAS interaction has been demonstrated in several studies. E2 was detected to drive RAS to increase Ang-(1-7) production through estrogen receptor (ER α) mediated stimulation of ACE1 and ACE2 mRNA expression and activity. A sex difference has been revealed in the expression of RAS components [238] .

There is a controversy about the role of RAS blockers including, ACE inhibitors and/or angiotensin II type 1 receptor blockers (ARBs) in treating COVID-19 and their exact roles still remain unclear [28, 32, 239] .

Their use has been suggested to be of a value through increasing ACE-2 that may have a protective effect against virus-induced lung injury by preserving ACE-2 in competition with SARS-CoV-2 entry into the cells [28] . Another mechanism by which ACE-2 can prevent lung damage and attenuate the pulmonary fibrosis, will be via enhancing the ACE-2/Ang-(1-7)/Mas axis to increase the production of ang (1-7), which in turn can counteract the activity of the ACE/AngII/AT1R axis [137] .

On the other hand, it was known that ACE inhibitors could block the breakdown of bradykinin increasing its level and then, promoting its associated inflammatory reactions resulting in more deterioration in the health state [240] . Additionally, it has been expected that patients receiving ARBs may show upregulation in the membrane bound ACE-2 facilitating the coronavirus entry and worsen then its course [241] .

The suggested explanation may be attributed to the increase in angiotensin II level that probably pushes it to act as an increased substrate loaded on the ACE enzyme, resulting in shifting a part of Ang II to be converted by the action of ACE2 into Ang (1-7) , that may be associated with ACE-2 upregulation [32] .

Other agents acting on the RAS, such as beta-blockers and direct renin inhibitors (DRI) to lower AngI formation and thereby, AngII and Ang (1-7). However, till now, no one discussed their impact on the severity and prognosis of COVID-19 [28] .

On the contrary, lacking Ang (1-7) will be of negative effect on lung health. So, there is an urgent need to suppose a pathway that can ensure the increase of Ang (1-7) level without upregulating ACE-2. That effect may be attained by keeping ACE activity to enhance the pulmonary metabolism of Ang (1-7) and at the same time, shifting the RAS system away from ACE/Ang II/AT-1 axis to avoid its associated inflammatory and oxidative activities. We suggest that NEP may achieve this complicated equation.

Based on previous literature that addressed several beneficial and protective effects displayed by NEP during lung injury, we postulate that increasing NEP activity may mitigate COVID-19

pathogenesis. Lung of COVID-19 patients showed pneumocyte hyperplasia with inflammatory cellular infiltration [242] , confirming the release of excessive GRP into the surrounding airway parenchyma as a result of PNECs hyperplasia [193, 194, 196, 197] .

Considering the documented links between high GRP level and both neutrophil chemotaxis and infiltration as well as reduction in food and water intake [243] , it is not surprising to detect high neutrophil count [244] and anorexia in severe COVID-19 patients [245] .

Thus, we expect that GRP is the first spark in initiating neutrophils recruitment as well as cytokine storm, which are the main pillars in COVID-19 pathophysiology. Our suggested hypothesis herein depends on two main aspects, Figure (3 

NEP may abrogate GRP-induced neutrophil chemotaxis via cleaving GRP and degrading fMLP peptide that can modulate the chemotactic responsiveness of neutrophils. On the other aspect, NEP may withstand the potent cytokine storm, which was prescribed to be one of causes for lung damage progression and death in COVID-19 patients.

We suggest that NEP can diminish the release of inflammatory cytokines that may increase sensitivity of target cells for further stimulation by SARA-CO-2 virus [246, 247] . Thus, NEP can improve lung histopathology and enhance tissue survival through two mechanisms:

Firstly, interfering with Ang II formation via preventing the proteolytic cleavage of angiotensinogen and Ang I into Ang II by neutrophil-derived Cathepsin G [209] [210] [211] that is expected to be released continuously in response to uncontrolled neutrophil activation associated with COVID-19 patients and via regenerating the synthesis of endogenous Ang (1-7), expected to be minimized because of ACE-2 exhaustion by SARA-CO-2 virus [109] . Ang

(1-7) by itself may protect against pulmonary fibrosis through reducing TGF-β1 expression [139] .

Secondly, breaking BKs and thereby, inhibiting its role in activation and recruitment of the inflammatory cells.

However, recorded findings suggest that lung damage caused by COVID-19 is induced by an alternative mechanism rather than hyperinfammatory injury. It likely seems that endothelial activation and associated pulmonary intravascular coagulopathy are the contributing factors in COVID-19 pathogenesis [18] .

Within this context, NEP may exert a critical role in suppressing ET-1 that mediates angiotensin II-induced endothelial and platelets dysfunction. Yet, NEP may minimize the chance for Ang II formation, which was reported to be a potent stimulator of ET-1 in endothelial cells [248] .

Even, NEP can additionally degrades ET-1, preventing its associated inflammatory injury and eventual fibrotic cascade in the lung [81, 175] .

Furthermore, we speculate that NEP may be helpful in dealing with individuals at high risk groups for COVID-19 that exhibit many obstacles in their management. NEP may regulate blood pressure in cardiovascular and hypertensive patients indirectly via decreasing both blood and tissue levels of Ang II by: (i) increasing Ang I substrate availability a result of inhibiting cathepsin G-mediated neutrophil release, and (ii) augmenting the rate of Ang I conversion into

Ang (1) (2) (3) (4) (5) (6) (7) , that previously reported to exert a stimulatory effect on ANP secretion via MasR [249] .

For diabetic patients, we demonstrate that NEP may regulate pancreatic RAS flux to improve glycemic conditions. In response to NEP-mediated degradation 'in vitro', NEP may evoke the insulin secretory ability of Ang (1-7) via hydrolyzing it into the biologically active Ang (1) (2) dipeptide in pancreatic islets [33, 250] .

Numerous 'in vivo' and 'in vitro' experiments have been made to increase NEP expression. One study speculated that dexamethasone could enhance NEP expression in airway epithelial cells via promoting its transcription and synthesis [251] . Another prior finding demonstrated that Valproic acid could reduce plaque formation and improve learning deficits via up-regulating NEP in APP/PS1 transgenic mice [252] . Recently, serotonin and its derivatives were explored to ameliorate symptoms of AD induced in mouse via enhancing NEP up-regulation [253] .

Several lines of evidence identified that hormones such as androgens [254] and estrogen [255] could also positively regulate NEP expression, suggesting that decline in levels of androgen or estrogen associated with aging would accompany by decrease in NEP synthesis, which may be an important factor for increasing the risk of COVID-19 infection among elderly.

On the other hand, several findings investigated the up-regulating effect of some natural products on NEP expression such as Apigenin, Luteolin, and Curcumin, (-)-Epigallocatechin-3-gallate as well as Resveratrol [256] [257] [258] . In China, Naoerkang (NEK), a traditional Chinese herbal medicine, improved the ability of learning and memory in rats model of AD by increasing NEP expression in their hippocampal tissues [259] .

However, some scientists aimed to produce recombinant NEP (r NEP) instead, as Park et al.,

2013 who prepared recombinant soluble NEP from insect cells to be intracerebrally injected into AD mice [238] .

Therefore, we finally suggest that therapeutic strategies aimed to increase NEP expression and/or activity may be of great benefit for prevention and treatment of COVID-19.

Despite the high widespread of COVID-19 contagion worldwide, there is no specific efficient treatment that has been proved till now. Several pharmacological interventions for COVID-19

have been suggested targeting the host's immune response. Following SARS-coV-2 exposure, there is an overproduction of GRP within lung tissue resulting in increased release of inflammatory cytokines such as IL-1β, IL-6, TNF-α, VEGF, GM-CSF and MCP-1. Such cytokines are widely known to enhance neutrophil infiltration which, in turn, induce lung inflammation and respiratory distress as reported in COVID-19 infected patients. As well, cytokines release is also presumed to develop SARS-coV-2 -associated pulmonary fibrosis.

Novel findings define COVID-19 as one of the pulmonary diseases associated with endothelial and platelets dysfunction. Now, it is definitely known that viral invasion can be mediated by one of the RAS signaling system components, namely ACE-2. Hence, COVID-19 occurrence and progression can be attributed to imbalance in the pulmonary RAS signaling resulting from SARS-coV-2-induced ACE-2 drain. Interestingly, the decrease in ACE-2 activity will be accompanied with a decrease in the generation of Ang1-7 which was known to be the light side of RAS. Regarding the data emphasized on the protective role of Ang (1-7) in lung injury, it may be recommended as a COVID-19 therapy, but because of its short half-life, Ang (1-7)

exhibits a limitation for its use. Since NEP is a more potent alternative way than ACE-2 for producing Ang1-7, it is suggested to assess the possible beneficial role of NEP in COVIDinduced lung injury. Few studies have discussed NEP-mediated protective pathways in experimental models of lung injury and fibrosis, however its actual role as a lung protective therapy has not been yet recognized. NEP has been involved in degradation of many peptides that may be incorporated in COVID-19 pathophysiology. So, we expect that NEP can effectively interfere with the chemotactic responsiveness and recruitment of neutrophils by degrading both fMLP peptide and GPR, respectively. Furthermore, we suggest that NEP can minimize cytokine storm associated with SARS-coV-2 invasion through inhibiting Ang II formation by neutrophil-derived Cathepsin G and directing Ang I for generating Ang (1-7) which can in turn suppress TGF-β1 expression and its fibrogenic action, protecting against fibrosis. Degrading both BKs and ET-1 by NEP may be associated with low IL-6 levels, which will be beneficial for stabilizing endothelium and restoring its function. In addition to its catabolic properties, we postulate that NEP may possess an advantage for COVID-19 high risk patients through modulating blood pressure and glucose homeostasis. Practically, numerous invivo and in-vitro experimental manipulations were made to upregulate NEP expression either by using drugs (Dexamethasone and Valproic acid), hormones (Androgens and Estrogen) or natural substances (Apigenin, Luteolin, Curcumin and (-)-Epigallocatechin-3-gallate).

However, others directed their efforts towards preparing the recombinant NEP (r NEP).

Because most pre-clinical and clinical studies within the medical field are interested in studying NEP inhibitors, there is a little data concerning use of NEP as a therapeutic agent. Consequently, its associated adverse effects have not yet been studied well. Finally, we hope our hypothesis will be somewhat enough to direct a future work towards the therapeutic role of NEP in modulating COVID-19 pandemic and to target the subsequent therapies for enhancing NEP activity in COVID-19 patients.

The authors declare no conflict of interest. The authors and their institutions are the only responsible for the financial support and the content of this work in the submitted manuscript.

All other authors have no conflict of interests to disclose. [28, 272, 273] 

Asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): Facts and myths

Features, evaluation and treatment coronavirus (COVID-19), in: StatPearls

Clinical features of patients infected with 2019 novel coronavirus in

Coronavirus: covid-19 has killed more people than SARS and MERS combined, despite lower case fatality rate

Clinical Characteristics of Covid-19 in China

Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study

Coronavirus infections: (2020)

SARS-CoV-2 and Coronavirus Disease 2019: What We Know So Far, Pathogens

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

COVID-19: consider cytokine storm syndromes and immunosuppression

Correspondence Use of antiviral drugs to reduce COVID-19

Therapeutic options for the 2019 novel coronavirus (2019-nCoV)

Drug treatment options for the 2019-new coronavirus (2019-nCoV)

Molecular immune pathogenesis and diagnosis of COVID-19

Cytokinstormer ved covid-19?

Clinical features and outcomes of 221 patients with COVID-19 in

Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies

Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation

The pulmonary endothelium in acute respiratory distress syndrome: Insights and therapeutic opportunities

Elsayegh, Brain , Behavior , and Immunity COVID-19 presenting as stroke

Comparative study of the lymphocyte change between COVID-19 and non-COVID-19 pneumonia cases suggesting uncontrolled inflammation might not be the main reason of tissue injury

The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The experience of clinical immunologists from China

Platelet-to-lymphocyte ratio is associated with prognosis in patients with Corona Virus Disease-19

Associations between immune-suppressive and stimulating drugs and novel COVID-19-a systematic review of current evidence

Effects of chloroquine on viral infections: an old drug against today's diseases

COVID-19 Drug Therapy-Potential Options

COVID-19: Epidemiology, Evolution, and Cross-Disciplinary Perspectives

COVID-19 and the Renin-Angiotensin System

SARS-CoV2: should inhibitors of the renin-angiotensin system be withdrawn in patients with COVID-19?

COVID-19) and Cardiovascular Disease: A Viewpoint on the Potential Influence of Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers on Onset and Severity of Severe Acute Respiratory Syndrome Coronavirus 2 Infec

Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19

Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic?

-7)'s Ability to Enhance Insulin Secretion via Its Proteolytic Activity to Generate Angiotensin-(1-2)

Neprilysin inhibition: a new therapeutic option for type 2 diabetes?

PIONEER-HF: a new frontier in the role of neprilysin inhibition in the management of heart failure with reduced ejection fraction

Intrinsic defence capacity and therapeutic potential of natriuretic peptides in pulmonary hypertension associated with lung fibrosis

Expression of neutral endopeptidase activity during clinical and experimental acute lung injury

Decreased neprilysin and pulmonary vascular remodeling in chronic obstructive pulmonary disease

Neutral endopeptidase and neurogenic inflammation in rats with respiratory infections

Structure, function, and evolution of coronavirus spike proteins

Insights into the recent 2019 novel Coronavirus (SARS-CoV-2) in light of past human coronavirus outbreaks

Pre-fusion structure of a human coronavirus spike protein

Genotyping coronavirus SARS-CoV-2: methods and implications, ArXiv Prepr

Receptor usage of a novel bat lineage c betacoronavirus reveals evolution of Middle East respiratory syndrome-related coronavirus spike proteins for human dipeptidyl peptidase 4 binding

Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells

Design of potent membrane fusion inhibitors against SARS-CoV-2, an emerging coronavirus with high fusogenic activity

Efficient activation of the severe acute respiratory syndrome coronavirus spike protein by the transmembrane protease TMPRSS2

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV

RAS inhibition in hypertension

Three key proteases--angiotensin-Iconverting enzyme (ACE), ACE2 and renin--within and beyond the renin-angiotensin system

The pulmonary renin-angiotensin system

Attenuates Bleomycin-Induced Lung Fibrosis in Mice

A Comprehensive Review

The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice

Angiotensin-converting enzyme 2 in lung diseases

Clinical relevance of local renin angiotensin systems

Angiotensinconverting enzyme 2 inhibits lung injury induced by respiratory syncytial virus

An ACE in the hole: Alternative pathways of the renin angiotensin system and their potential role in cardiac remodeling

Renin-angiotensin system revisited

The ACE2/Angiotensin-(1-7)/MAS Axis of the

Role of angiotensin II receptor subtypes on the regulation of aldosterone secretion in the adrenal glomerulosa zone in the rat

Angiotensin II revisited: New roles in inflammation, immunology and aging

Targeting the renin-angiotensin system as novel therapeutic strategy for pulmonary diseases

Targeting the 'Janus face'' of the B2-bradykinin receptor

Responses of serum and lung angiotensin-converting enzyme activities in the early phase of pulmonary damage induced by oleic acid in dogs

Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury

Intrapulmonary activation of the angiotensinconverting enzyme type 2/angiotensin 1-7/G-protein-coupled Mas receptor axis attenuates pulmonary hypertension in Ren-2 transgenic rats exposed to chronic hypoxia

A century old renin-angiotensin system still grows with endless possibilities: AT1 receptor signaling cascades in cardiovascular physiopathology

Activation of human peripheral monocytes by angiotensin II

Angiotensin II induces interleukin-6 transcription in vascular smooth muscle cells through pleiotropic activation of nuclear factor-kappa B transcription factors

Angiotensin II type 1 receptor antagonist decreases plasma levels of tumor necrosis factor alpha, interleukin-6 and soluble adhesion molecules in patients with chronic heart failure

The selective angiotensin II type 2 receptor agonist, compound 21, attenuates the progression of lung fibrosis and pulmonary hypertension in an experimental model of bleomycin-induced lung injury

AT2 receptor and tissue injury: Therapeutic implications topical collection on mediators, mechanisms, and pathways in tissue injury

Angiotensin II Regulates Vascular and Endothelial Dysfunction: Recent Topics of

Angiotensin II Type-1 Receptor Signaling in the Vasculature

Angiotensin II-induced vascular endothelial dysfunction through RhoA/Rho kinase/p38 mitogen-activated protein kinase/arginase pathway

Angiotensin II, platelets and oxidative stress

Role for endothelin-1 in angiotensin II-mediated hypertension

The role of endothelin-1 and endothelin receptor antagonists in inflammatory response and sepsis

Role of endothelin-1 in lung disease

A novel potent vasoconstrictor peptide produced by vascular endothelial cells

Endothelin-1 induces interleukin-6 release via activation of the transcription factor NF-κB in human vascular smooth muscle cells

Effects of angiotensin II and endothelin-1 on platelet aggregation and cytosolic pH and free Ca2+ concentrations in essential hypertension

Fernández-Real, Serum interleukin-6 correlates with endothelial dysfunction in healthy men independently of insulin sensitivity, Diabetes Care

Endothelial Derived Relaxation Factor (EDRF)

Endothelial dysfunction and vascular disease

Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium

Nitric oxide: An endogenous modulator of leukocyte adhesion

Interleukin-6 inhibits endothelial nitric oxide synthase activation and increases endothelial nitric oxide synthase binding to stabilized caveolin-1 in human vascular endothelial cells

Interleukin-6 Induces Oxidative Stress and Endothelial Dysfunction by Overexpression of the Angiotensin II Type 1 Receptor

Endothelium as a therapeutic target in heart failure

Endothelium-dependent contractions and endothelial dysfunction in human hypertension

Endothelial dysfunction in diabetes

Molecular mechanisms of thrombus formation in ischemic stroke: Novel insights and targets for treatment

Analysis of the level of selected parameters of inflammation, circulating immune complexes, and related indicators (neutrophil/ lymphocyte, platelet/lymphocyte, CRP/CIC) in patients with obstructive diseases, Cent

Endothelium-derived endothelin-1, Pflugers Arch

Interleukin-6 stimulates thrombopoiesis through thrombopoietin: Role in inflammatory thrombocytosis

Endothelin stimulates plateletactivating factor synthesis by cultured rat Kupffer cells

Stimulation of Transforming Growth Factor-β1-Induced Endothelial-To-Mesenchymal Transition and Tissue Fibrosis by Endothelin-1 (ET-1): A Novel Profibrotic Effect of ET-1

Personal View Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy

Angiotensin-Converting Enzyme 2 (ACE2) and ACE Activities Display Tissue-Specific Sensitivity to Undernutrition-Programmed Hypertension in the Adult Rat

Coronavirus Disease 2019 (COVID-19) Infection and Renin Angiotensin System Blockers

Hydrolysis of biological peptides by human angiotensinconverting enzyme-related carboxypeptidase

ACE2, angiotensin-(1-7) and Mas receptor axis in inflammation and fibrosis

Angiotensin-converting enzyme 2 autoantibodies: further evidence for a role of the renin-angiotensin system in inflammation

Angiotensinconverting enzyme 2/angiotensin-(1-7)/Mas axis prevents lipopolysaccharide-induced apoptosis of pulmonary microvascular endothelial cells by inhibiting JNK/NF-κB pathways

Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target

Inhibitors of RAS Might Be a Good Choice for the Therapy of COVID-19 Pneumonia

Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2

COVID-19, an emerging coronavirus infection: advances and prospects in designing and developing vaccines, immunotherapeutics, and therapeutics

Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2

Single-cell RNA expression profiling of ACE2 , the putative receptor of Wuhan 2019-nCov

Influenza and SARS-coronavirus activating proteases TMPRSS2 and HAT are expressed at multiple sites in human respiratory and gastrointestinal tracts

SARS-CoV-2 receptor ACE2 and TMPRSS2 are predominantly expressed in a transient secretory cell type in subsegmental bronchial branches

Antihypertensive treatment with ACEI/ARB of patients with COVID-19 complicated by hypertension

Potential pathogenesis of multiple organ injury in COVID-19

Covid-19 and the Digestive System

COVID-19-associated Acute Hemorrhagic Necrotizing Encephalopathy: CT and MRI Features

Frequent Convulsive Seizures in an Adult Patient with COVID-19: A Case Report, Iran. Red Crescent Med

COVID-19 and Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: What Is the Evidence?

The modelling of COVID19 pathways sheds light on mechanisms, opportunities and on controversial interpretations of medical treatments. v2, ArXiv Prepr

Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin-(1-7) or an angiotensin II receptor antagonist

The Angiotensin-Converting Enzyme 2/Angiogenesis-(1-7)/Mas Axis Confers Cardiopulmonary Protection against Lung Fibrosis and Pulmonary Hypertension

Decreased levels of serum Angiotensin-(1-7) in patients with pulmonary arterial hypertension due to congenital heart disease

Reninangiotensin-system, a potential pharmacological candidate, in acute respiratory distress syndrome during mechanical ventilation

Dose-dependent, therapeutic potential of angiotensin-(1-7) for the treatment of pulmonary arterial hypertension

Angiotensin II type 2 receptor (AT2R) in renal and cardiovascular disease

Angiotensin-(1-7): A Novel Peptide to Treat Hypertension and Nephropathy in Diabetes?

Differences in angiotensin (1-7) between men and women

The antithrombotic effect of angiotensin-(1-7) involves mas-mediated NO release from platelets

Angiotensin peptides and nitric oxide in cardiovascular disease

Modulating Role of Ang1-7 in Control of Blood Pressure and Renal Function in AngII-infused Hypertensive Rats

Angiotensin-(1-7) prevents diabetes-induced attenuation in PPAR-gamma and catalase activities

Eosinophilic Inflammation in an Experimental Model of Asthma

Angiotensin-converting enzyme 2/angiotensin-(1-7)/mas axis protects against lung fibrosis by inhibiting the MAPK/NF-κB pathway

-7)-mediated signaling preserves endothelial function through reducing oxidative stress in diabetes

Exogenous angiotensin (1-7) directly inhibits epithelial-mesenchymal transformation induced by transforming growth factor-β1 in alveolar epithelial cells

Bach1 siRNA attenuates bleomycin-induced pulmonary fibrosis by modulating oxidative stress in mice

The Angiotensin-(1-7)/Mas Axis Counteracts Angiotensin II-Dependent and -Independent Proinflammatory Signaling in Human Vascular Smooth Muscle Cells

Angiotensin-converting enzyme 2 attenuates inflammatory response and oxidative stress in hyperoxic lung injury by regulating NF-kappaB and Nrf2 pathways

The Vasoactive Mas Receptor in Essential Hypertension

Angiotensin-(1-7) attenuates airway remodelling and hyperresponsiveness in a model of chronic allergic lung inflammation

Angiotensin-converting enzyme 2 and angiotensin 1-7: Novel therapeutic targets

AVE 0991, a nonpeptide mimic of the effects of angiotensin-(1-7) on the endothelium

vasoactive peptide and its β-cyclodextrin inclusion complexes: complete sequencespecific NMR assignments and structural studies

Vascular relaxation, antihypertensive effect, and cardioprotection of a novel peptide agonist of the MAS receptor

NorLeu3-A(1-7) stimulation of diabetic foot ulcer healing: results of a randomized, parallel-group, double-blind, placebo-controlled phase 2 clinical trial., Wound Repair Regen

Addition of cyclic angiotensin-(1-7) to angiotensinconverting enzyme inhibitor therapy has a positive add-on effect in experimental diabetic nephropathy

Angiotensin-(1-7)/Angiotensin-Converting Enzyme 2/Mas Receptor Axis and Related Mechanisms

Endothelial dysfunction through genetic deletion or inhibition of the G protein-coupled receptor Mas: a new target to improve endothelial function

Role of Mas Receptor Antagonist A799 in Renal Blood Flow Response to Ang 1-7 after Bradykinin Administration

Ovariectomized Estradiol-Treated Rats

Evidence for a new angiotensin-(1-7) receptor subtype in the aorta of Sprague-Dawley rats

Bradykinin Potentiation by Angiotensin-(1-7) and ACE Inhibitors Correlates With ACE C-and N-Domain Blockade

The kinin system--bradykinin: biological effects and clinical implications. Multiple role of the kinin system--bradykinin

Bradykinin induces interleukin-6 production in human airway smooth muscle cells: Modulation by Th2 cytokines and dexamethasone

Release of cytokines from isolated lung strips by bradykinin

Bradykinin stimulates NF-κB activation and interleukin 1β gene expression in cultured human fibroblasts

Bradykinin stimulates lung fibroblasts to release neutrophil and monocyte chemotactic activity

Interaction between bradykinin B2 and Ang

Mas receptors regulates erythrocyte invasion by Plasmodium falciparum

In vivo metabolism of angiotensin I by neutral endopeptidase (EC 3.4. 24.11) in spontaneously hypertensive rats

Activation of the GLP-1 Receptor by Liraglutide Increases ACE2 Expression, Reversing Right Ventricle Hypertrophy, and Improving the Production of SP-A and SP-B in the Lungs of Type 1 Diabetes Rats

Localization of neutral endopeptidase (NEP) mRNA in human bronchi

Increased expression of renal neutral endopeptidase in severe heart failure

Concise review: Neutral endopeptidase (CD10): A multifaceted environment actor in stem cells, physiological mechanisms, and cancer

Antiprogressive effect of neutral endopeptidase 24.11 (NEP/CD10) on cervical carcinoma in vitro and in vivo

On the role of endothelin-converting enzyme-1 (ECE-1) and neprilysin in human breast cancer

CD10 enhances metastasis of colorectal cancer by abrogating the anti-tumoural effect of methionine-enkephalin in the liver

The circulating form of neprilysin is not a general biomarker for overall survival in treatment-naïve cancer patients

Structural Substrate Conditions Required for Neutral Endopeptidase-Mediated Natriuretic Peptide Degradation

11 (enkephalinase) and related regulators of peptide hormones1

Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics

The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment

Role of neutral endopeptidase in the metabolism of endothelin

Neutral endopeptidase 24.11: structure, inhibition, and experimental and clinical pharmacology

Neprilysin Deficiency Is Associated With Expansion of Islet β-Cell Mass in High Fat-Fed Mice

Atrial natriuretic peptide mimetics and vasopeptidase inhibitors

The role of natriuretic peptides in cardioprotection

Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure

Pharmacologic comparison of clinical neutral endopeptidase inhibitors in a rat model of acute secretory diarrheas

Sacubitril/valsartan (LCZ696) in heart failure

The Therapeutic Potential of Candoxatril, a Neutral Endopeptidase Inhibitor, in Humans

The Role of Neprilysin Inhibitors in Cardiovascular Disease

Pharmacological Neprilysin Inhibition Improves Glucose Homeostasis in a Mouse Model of Type 2 Diabetes

Amyloid-beta and Alzheimer's disease: the role of neprilysin-2 in amyloid-beta clearance

Neutral endopeptidase can hydrolyze β-amyloid (1-40) but shows no effect on β-amyloid precursor protein metabolism

Metabolic regulation of brain Aβ by neprilysin

The dark sides of amyloid in Alzheimer's disease pathogenesis

Protective effect of recombinant soluble neprilysin against β-amyloid induced neurotoxicity

Mechanisms of toxic smoke inhalation and burn injury: role of neutral endopeptidase and vascular leakage in mice

Early protection from burn-induced acute lung injury by deletion of preprotachykinin-A gene

Neuroendocrine cell hyperplasia as an unusual form of interstitial lung disease

Diffuse idiopathic pulmonary neuroendocrine hyperplasia, chronic eosinophilic pneumonia, and asthma

Oxygen, gastrin-releasing Peptide, and pediatric lung disease: life in the balance

Increased pulmonary neuroendocrine cells with bombesin-like immunoreactivity in adult patients with eosinophilic granuloma

Pulmonary neuroendocrine cells (PNEC) and neuroepithelial bodies (NEB): Chemoreceptors and regulators of lung development

Functional characterization of pulmonary neuroendocrine cells in lung development, injury,and tumorigenesis

Pulmonary neuroendocrine cells function as airway sensors to control lung immune response

Bombesin-like peptides: Modulators of inflammation in acute lung injury?

Gastrin-releasing peptide receptor (GRPR) mediates chemotaxis in neutrophils

Pulmonary neutrophil kinetics

Pulmonary retention of primed neutrophils: A novel protective host response, which is impaired in the acute respiratory distress syndrome

Understanding the roles of cytokines and neutrophil activity and neutrophil apoptosis in the protective versus deleterious inflammatory response in pneumonia

CD10/neutral endopeptidase 24.11 hydrolyzes bombesin-like peptides and regulates the growth of small cell carcinomas of the lung

Neutral endopeptidase 24.11 in human neutrophils: Cleavage of chemotactic peptide

Function of Neutral Endopeptidase on the Cell Membrane of Human Neutrophils

Macrophage phagocytosis of aging neutrophils in inflammation. Programmed cell death in the neutrophil leads to its recognition by macrophages

Neutrophil serine proteases: Specific regulators of inflammation

Neutrophil-derived serine proteases modulate innate immune responses

Rapid conversion of angiotensin I to angiotensin II by neutrophil and mast cell proteinases

Release and degradation of angiotensin I and angiotensin II from angiotensinogen by neutrophil serine proteinases

Angiotensin II generation at the cell surface of activated neutrophils: novel cathepsin G-mediated catalytic activity that is resistant to inhibition

Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism

-7) metabolism in pulmonary and renal tissues

Long-term neprilysin inhibition -implications for ARNIs

COVID-19 Treatment: Close to a Cure ? A Rapid Review of Pharmacotherapies for the Novel Coronavirus

Risks Related to the Use of Non-Steroidal Anti-Inflammatory Drugs in Community-Acquired Pneumonia in Adult and Pediatric Patients

Non-steroidal anti-inflammatory drugs and covid-19

Contentious Issues and Evolving Concepts in the Clinical Presentation and Management of Patients with COVID-19 Infection with Reference to Use of Therapeutic and Other Drugs used in Co-morbid Diseases

Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists

Enhanced Expression of Neutral Endopeptidase (NEP) in Airway Epithelium in Biopsies from Steroid-versus Nonsteroid-treated Patients with Atopic Asthma

The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights

The use of corticosteroid as treatment in SARS was associated with adverse outcomes: a retrospective cohort study

Corticosteroid Therapy for Critically Ill Patients with Middle East Respiratory Syndrome

Chloroquine is a potent inhibitor of SARS coronavirus infection and spread

Of chloroquine and COVID-19

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19

Statins and the endothelium

Immune modulatory effects of statins

Considerations for Statin Therapy in Patients with COVID-19

Are certain drugs associated with enhanced mortality in COVID-19?

Sex differences in clinical findings among patients with coronavirus disease 2019 (COVID-19) and severe condition

Transcriptional Inhibition of Host Viral Entry Proteins as a Therapeutic Strategy for SARS-CoV-2, Preprints

Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection

Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2

Estradiol, acting through ERα, induces endothelial non-classic renin-angiotensin system increasing angiotensin 1-7 production

Renin-Angiotensin System Blockers and the COVID-19 Pandemic: At Present There Is No Evidence to Abandon Renin-Angiotensin System Blockers

Stretch-induced alveolar type II cell apoptosis: role of endogenous bradykinin and PI3K-Akt signaling

Renin-Angiotensin System Blockers and the COVID-19 Pandemic

Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients With Lung Cancer

Gastrin releasing peptide-induced satiety is associated with hypothalamic and brainstem changes in chicks

Neutrophil-to-Lymphocyte Ratio Predicts Severe Illness Patients with 2019 Novel Coronavirus in the Early Stage

Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: a descriptive, crosssectional, multicenter study

Cytokines and inflammatory mediators in cystic fibrosis

Inflammatory mechanisms in the lung

Losartan but not verapamil inhibits angiotensin II-induced tissue endothelin-1 increase role of blood pressure and endothelial function

Angiotensin-(1-7) stimulates high atrial pacing-induced ANP secretion via Mas/PI3-kinase/Akt axis and Na+/H+ exchanger

The sweeter side of ACE2: Physiological evidence for a role in diabetes

Dexamethasone Increases Airway Epithelial Cell Neutral Endopeptidase by Enhancing Transcription and New Protein Synthesis

Valproic acid reduces neuritic plaque formation and improves learning deficits in APPSwe/PS1A246E transgenic mice via preventing the prenatal hypoxia-induced down-regulation of neprilysin

Mensah-Nyagan, 5-HIAA induces neprilysin to ameliorate pathophysiology and symptoms in a mouse model for Alzheimer's disease

Androgens regulate neprilysin expression: Role in reducing β-amyloid levels

Estrogen regulation of the neprilysin gene through a hormone-responsive element

Influence of Selected Natural Products on Neutral Endopeptidase Activity and β-Amyloid Production in SK-N-SH Cells

Possible role of Resveratrol targeting Estradiol and Neprilysin pathways in Lipopolysaccharide model of Alzheimer disease

Epigallocatechin-3-gallate attenuates cognitive deterioration in Alzheimer's disease model mice by upregulating neprilysin expression

Effects of Naoerkang on expressions of β-amyloid peptide 1-42 and neprilysin in hippocampus in a rat model of Alzheimer's disease

Decoding the enigma of antiviral crisis: Does one target molecule regulate all?

Severe acute respiratory syndrome: clinical and laboratory manifestations

Biologics for Targeting Inflammatory Cytokines, Clinical Uses, and Limitations

Side effects of anticytokine strategies

Chloroquine and hydroxychloroquine: Current evidence for their effectiveness in treating COVID-19, Cent. Evidence-Based Med

New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?

The discovery and development of selective estrogen receptor modulators (SERMs) for clinical practice

StatPearls [Internet

Aliskiren, the first direct renin inhibitor: assessing a role in pediatric hypertension and kidney diseases

Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis protects against lung fibrosis by inhibiting the MAPK/NF-kappaB pathway

Efficacy and safety of aliskiren, a direct renin inhibitor, compared with ramipril in Asian patients with mild to moderate hypertension

Interaction between RAAS inhibitors and ACE2 in the context of COVID-19

A blind, randomized comparison of racecadotril and loperamide for stopping acute diarrhea in adults

Racecadotril for childhood gastroenteritis: An individual patient data meta-analysis

Role of neprilysin inhibitors in heart failure

LCZ696 therapy reduces ventricular tachyarrhythmia inducibility in a myocardial infarction-induced heart failure rat model

Angiotensin Receptor Neprilysin Inhibitor Attenuates Myocardial Remodeling and Improves Infarct Perfusion in Experimental Heart Failure

Antihypertensive and antihypertrophic effects of omapatrilat in SHR

Omapatrilat Versus Lisinopril

Effects of Omapatrilat on Blood Pressure and Renal Injury in L-NAME and L-NAME Plus DOCA-Treated Rats

Omapatrilat and enalapril in patients with hypertension: The Omapatrilat Cardiovascular Treatment vs

Enalapril (OCTAVE) trial

Influence of Sacubtril/Valsartan on glycemic control in patients with type 2 diabetes and heart failure with reduced ejection fraction

Angiotensin-neprilysin inhibition confers renoprotection in rats with diabetes and hypertension by limiting podocyte injury

Recombinant soluble neprilysin reduces amyloid-beta accumulation and improves memory impairment in Alzheimer's disease mice

Neutral endopeptidase (EC 3.4.24.11) terminates colitis by degrading substance P

Neutral endopeptidase (EC 3.4.24.11) downregulates the onset of intestinal inflammation in the nematode infected mouse

Effects of recombinant neutral endopeptidase (EC 3.4.24.11) on the growth of lung cancer cell lines in vitro and in vivo

Recombinant human neutral endopeptidase ameliorates pancreatic elastase-induced lung injury

Recombinant human enkephalinase (neutral endopeptidase) prevents cough induced by tachykinins in awake guinea pigs

Tachykinin-induced dyspnea in conscious guinea pigs

blocking its action on its receptors on mast cell, inhibiting release of inflammatory cells and thereby, fibroblasts activation that may participate in the development of lung fibrosis, (iii) degrading endothelin-1 and consequently, inhibiting TGF-β1 release and (iv) stabilizing Ang II-induced endothelial dysfunction as well as suppressing platelet activation and aggregation that initiate blood clot formation

ACE-2 = Angiotensin-converting enzyme 2

Ang (1-7) = Angiotensin

AT-1 = Angiotensin II type 1 receptor

ET-1 = Endothelin-1; fMLP = Formyl Methionyl-Leucyl-Proline

GRPR = Gastrin-releasing peptide receptor

PNECs = Pulmonary neuroendocrine cells; SARS-CoV-2 = Severe acute respiratory syndrome coronavirus-2



