LitCovid-sentences  

PMC:7408073 / 82306-95875 JSONTXT 11 Projects

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Id Subject Object Predicate Lexical cue
T403 0-2 Sentence denotes 7.
T404 3-112 Sentence denotes Monitoring ACE/ACE2 Activity in COVID-19 in Order to Determine a Rationale Use of the Specific RAS Inhibitors
T405 113-220 Sentence denotes There is currently no specific pharmacotherapy to combat SARS-CoV-2 infection and its pathological effects.
T406 221-616 Sentence denotes Actually, the use of plasma from convalescent COVID-19 patients or of SARS-CoV-2-specific neutralizing antibodies has been shown to be a promising option for the treatment of critically COVID-19 patients [32,33,34,35,36,37,172,173]; however, it has some limitations that might be overcome by vaccine strategies or by the production of specific anti SARS-Co-V-2 therapeutic monoclonal antibodies.
T407 617-793 Sentence denotes Despite the promising data that demonstrate vaccine protection against SARS-CoV-2 in nonhuman primates [174], we cannot be sure to get a vaccine against SARS-CoV-2 (see [175]).
T408 794-1044 Sentence denotes Indeed, animals immunized with inactivated SARS-CoV vaccines developed a severe (asthma-like) lung eosinophilic immunopathology when challenged with SARS-CoV, further indicating a central role of eosinophil “balanced numbers” in this pathology [176].
T409 1045-1228 Sentence denotes Vaccines might generate antibodies against viral ligand/ACE2 complex that finally blocks ACE2 activity during SARS-CoV infection and consequent downstream asthma-like events/symptoms.
T410 1229-1540 Sentence denotes On the other hand, fatal outcomes in SARS-CoV infection correlated with a cytokine storm involving elevated Th2 serum cytokines (including IL-4, IL-5 and IL-10), suggesting that an increase of Th2 cytokines possibly mediated by virus-specific CD4 T cells might be crucial in the severe forms of infection [110].
T411 1541-1955 Sentence denotes In addition to cytokine profile (such as IL-10), eosinopaenia, tachycardia, normo/hypotension (although COVID-19 and hypoxia increase Ang II and many patients are “hypertensive” and/or receiving anti-hypertensive medications) and hypoxia in SARS-CoV-2 patients are compatible with downstream events stemming from both an excessive ACE2 pathway upregulation and activation of positive feedback loops (see Figure 2).
T412 1956-2152 Sentence denotes ACE2 and (anti-inflammatory) IL-10 hyperproduction may ultimately trigger subsequent compensatory (and deleterious) responses, leading to both renin/ACE and pro-inflammatory cytokine upregulation.
T413 2153-2272 Sentence denotes In line with this hypothesis, a longitudinal study showed that IL-6 increases late during the COVID-19 progression [3].
T414 2273-2569 Sentence denotes Altogether these data imply not only that the ACE2 is the “vehicle” of viral entry into the host cells, but also that virus-dependent and virus-independent mechanisms may sustain activation of both arms of the RAS and of the inflammatory system, finally promoting SARS-induced multi-organ injury.
T415 2570-2880 Sentence denotes Unfortunately, complete analysis of circulating levels of ACE/ACE2 proteins and activities, together with ACE and ACE2 substrates and products i.e., Ang I, Ang 1–9, Ang II, Ang (1–7) and Ang (1–5), des-Arg(9)-bradykinin and the inactive metabolite bradykinin (1–7) is lacking to address the current hypothesis.
T416 2881-3064 Sentence denotes The required data could be obtained from blood sample analyses, however, it is important to consider that:(1) Organ-specific local microenvironment might not reflect the systemic one;
T417 3065-3301 Sentence denotes (2) S1-sACE2 and SARS-CoV-2-sACE2 complexes, formed by viral-induced ACE2 shedding or by subsequent binding of sACE2 with viral particles or S1 fragments in the circulation, might not be detectable by some anti-ACE2 antibodies in ELISA.
T418 3302-3525 Sentence denotes Therefore, since the complexes might prevent/mask sACE2 antibody recognition but not the enzymatic activity, sACE2 detection (and its real concentration) by ELISA in blood samples of COVID-19 patients might not be reliable;
T419 3526-3822 Sentence denotes (3) In order to evaluate circulating ACE/ACE2 activity, we can determine it by adding fluorogenic (RAS) substrates to plasma samples without (thus considering also the endogenous ACE2 inhibitor present in plasma [116]) or with adding ZnCl2, which is able to induce ACE/ACE2 maximal activity [96];
T420 3823-3974 Sentence denotes (4) circulating concentrations ACE/ACE2 substrates/products likely depend on the:(a) level of ACE/ACE2 pathway activity and availability of substrates;
T421 3975-4108 Sentence denotes (b) level of expression of the respective receptors (AT1R, AT2R and MasR) that bind and remove ligand products away from circulation.
T422 4109-4331 Sentence denotes For example, Ang (1–7) concentration in blood by ACE2 pathway upregulation is dependent both on the increase of the (antagonistic) Ang II (and its precursor, Ang I) and on MasR expression on surface of cells in the organs.
T423 4332-4573 Sentence denotes To this regard, the detection of inactive metabolites, such as bradykinin (1–7), in COVID-19 patients and comparison with its concentration in healthy subjects could be the most indicative and reliable markers of ACE2 activity in the plasma.
T424 4574-4977 Sentence denotes Of interest, a report that described the ex vivo effect of human rACE2 on the levels of several endogenous Ang peptides in plasma samples, thus mimicking an acute increase of systemic ACE2 activity in plasma [115] showed a strong reduction of Ang II (as expected), a moderate reduction of Ang I and a significant (more than five-fold) increase of Ang (1–9), Ang (1–7) and (ACE-produced) Ang (1–5) [115].
T425 4978-5100 Sentence denotes Therefore, Ang (1–5) may also be an interesting surrogate marker of ACE-ACE2 combined activity in COVID-19 patients [115].
T426 5101-5621 Sentence denotes At the present time, it has been reported that plasma levels of Ang II in SARS-CoV-2 infected patients are markedly elevated as compared with healthy subjects (interquartile range between 260–360 pg/mL and 65–120 pg/mL, respectively) and linearly associated to viral load and lung injury [177]; unfortunately, nobody has tested the levels of Ang (1–7), Ang (1–9), Ang (1–5) and bradykinin (1–7), some of which might be at high levels as well, thus justifying both normo/hypotension and eosinopaenia in COVID-19 patients.
T427 5622-5805 Sentence denotes More information on the RAS peptides in plasma of Acute Respiratory distress syndrome, a COVID-19-like disease, (and pulmonary arterial hypertension) is instead available (see Box 6).
T428 5806-5889 Sentence denotes Box 6 Acute Respiratory distress syndrome and hyperactivation of the RAS pathways.
T429 5890-6016 Sentence denotes The main clinical feature of ARDS patients is the progressive deterioration of lung function leading to progressive hypoxemia.
T430 6017-6203 Sentence denotes ARDS can be induced by different causes such as ZnCl2 aspiration, sepsis, trauma, acute pancreatitis, or pneumonias following virus infections such as SARS-CoVs or human influenza virus.
T431 6204-6340 Sentence denotes ACE insertion/deletion polymorphisms correlated with severity of ARDS in humans, suggesting that the RAS could have a role in ARDS [44].
T432 6341-6519 Sentence denotes In animal models, ACE2 protected from acute lung by inhibiting Ang II/AT1R activity [15], for this reason the use of recombinant ACE2 in ARDS has been proposed and pursued [134].
T433 6520-6850 Sentence denotes Clinical trials with recombinant human ACE2 started in healthy volunteers in 2009 (ClinicalTrials.gov number, NCT00886353 [178]), then it was tested in ARDS (ClinicalTrials.gov number, NCT01597635 [134]), PAH (ClinicalTrials.gov number, NCT01884051 [108]) and finally in COVID-19 patients (ClinicalTrials.gov number, NCT04287686).
T434 6851-6949 Sentence denotes Despite its safe use, no conclusive evidence in support of its use in these diseases was reported.
T435 6950-7266 Sentence denotes Of interest, in the plasma samples from ARDS patients, levels of Ang I have been shown to be significantly increased in non-survivors (interquartile range 1990–16950 pg/mL) compared to survivors (interquartile range 730–5660 pg/mL) [92], suggesting a marked increase of renin activity in non-surviving ARDS patients.
T436 7267-7721 Sentence denotes Unfortunately, no comparisons of the two ARDS groups with healthy subjects (interquartile range 35–66 pg/mL, markedly lower than both patient groups [179]) were reported; this is important to consider since the plasma concentrations of the RAS peptides may significantly differ depending on method of detection (ELISA versus vs. mass spectrometry) and, in particular, on protocol of determination (endogenous versus equilibrium Ang peptide levels [179]).
T437 7722-7855 Sentence denotes Endogenous RAS peptide concentrations can be evaluated collecting and stabilizing blood samples with a RAS enzyme inhibitor cocktail.
T438 7856-8068 Sentence denotes Differently, heparinized plasma samples can be incubated at 37 °C to induce ex vivo equilibrium, which unveils the presence of renin, ACE and/or ACE2 activity in the plasma (equilibrium Ang peptide levels) [179].
T439 8069-8156 Sentence denotes This last protocol usually gives significantly higher levels of the RAS peptides [179].
T440 8157-8684 Sentence denotes For example, in healthy subjects, the normal ranges (interquartile ranges) of endogenous RAS peptides, Ang I, Ang II, Ang (1–7), Ang (1–9) and Ang (1–5) were 12–24 pg/mL, 1–12 pg/mL, <2 pg/mL, <4 pg/mL and < 1 pg/mL, respectively, differently the normal range after ex vivo equilibrium of the same peptides were 35–66 pg/mL, 110–200 pg/mL, < 2 pg/mL, < 4 pg/mL and < 1 pg/mL, respectively [179], indicating the presence of renin and ACE (but no ACE2) activity (as highlighted by Ang peptide increases upon ex vivo equilibrium).
T441 8685-8887 Sentence denotes Similarly, another report that evaluated Ang II and Ang (1–7) in healthy males showed normal endogenous ranges ~ 14.5 pg/mL and 0.9 pg/mL, respectively, and an Ang (1–7)/Ang II ratio ~ 0.06 ratio [180].
T442 8888-9150 Sentence denotes Moreover, Ang (1–7), Ang I, Ang (1–9) and Ang (1–7)/Ang II ratio were significantly higher in ACEI-treated hypertensive patients compared to healthy subjects [180], suggesting that inhibition of ACE predisposes to upregulation of the ACE2/Ang (1–7)/MasR pathway.
T443 9151-9372 Sentence denotes Notably, two different reports that evaluated the RAS peptides in ARDS patients using the similar method of detection (high performance liquid chromatography plus mass spectrometry) showed significantly different results.
T444 9373-9505 Sentence denotes One report showed that Ang II ranged (interquartile range) between 120–630 pg/mL (non-survivors) and 70–2220 pg/mL (survivors) [92].
T445 9506-9790 Sentence denotes A second report showed significantly lower values of Ang II, (interquartile range) between 40–150 ng/mL (non-survivors with placebo) and 5–20 pg/mL (survivors with placebo) (see Supplementary Data [134]), suggesting that they used different protocols of the RAS peptide determination.
T446 9791-9944 Sentence denotes Nevertheless, both Ang (1–7) and Ang (1–7)/Ang II ratios found in ARDS patients of both reports [92,134] were significantly higher than healthy subjects.
T447 9945-10137 Sentence denotes One report showed that Ang (1–7) ranged (interquartile range) between 2.5–10 pg/mL (see Figure 2B of [134]), Ang II between 5–20 pg/mL (see Figure 2 of [134]) and Ang (1–7)/Ang II ratio ~ 0.5.
T448 10138-10306 Sentence denotes Moreover, in the report in which the elevated concentrations of Ang I and Ang II indicate an ex vivo equilibrium of the RAS peptides, the increase was even more marked.
T449 10307-10625 Sentence denotes In that report, Ang (1–7) (< 1pg/mL in healthy subjects) ranged between 80–1070 pg/mL and Ang (1–7)/Ang II ratio (~ 0.06 in healthy subjects) ranged between 0.24–1.82 [92], suggesting that ACE2 activity (and ACE2 presence in plasma samples) was significantly increased in ARDS patients as compared to healthy subjects.
T450 10626-10807 Sentence denotes In line with this hypothesis, there was the determination of Ang (1–9), whose production from Ang I exclusively depends on ACE2 (which also compete with ACE for the same substrate).
T451 10808-11209 Sentence denotes In normal healthy subjects, it was reproducibly below the limit of quantification [179,180], differently, both in ex vivo treatments of plasma samples with human rACE2 [115,181] and in ARDS patients, it was markedly increased (Ang (1–9) ranged between 100–3080 pg/mL) [92], suggesting both that the dominating activity of ACE in plasma of healthy subjects is overcome by that of ACE2 in ARDS patients.
T452 11210-11287 Sentence denotes Therefore, Ang (1–9) may represent a good surrogate marker for ACE2 activity.
T453 11288-11496 Sentence denotes Similarly to Ang (1–9), there was the determination of Ang (1–5), whose production depend on both ACE2 [that produces Ang (1–7) from Ang II] and ACE [that produces Ang II from I and Ang (1–5) from Ang (1–7)].
T454 11497-11762 Sentence denotes Ang (1–5) was undetectable in healthy subjects [178,179]; however, it was significantly increased in ARDS patients (interquartile range between 50–730 pg/mL [92]), suggesting that both ACE2 and ACE activity were likely upregulated as compared with healthy subjects.
T455 11763-11886 Sentence denotes The activation for both arms of the RAS needs of the contemporary activation renin, the rate-determining enzyme of the RAS.
T456 11887-12217 Sentence denotes Indeed, analysis of plasma samples (from a healthy subjects), treated ex vivo with recombinant renin, showed an increase of Ang I, Ang II, Ang (1–7) and Ang (1–5), but not Ang (1–9) [115,179,181], further suggesting both the ACE2 specific activity in producing Ang (1–9) and an activation of both arms of the RAS in ARDS patients.
T457 12218-12519 Sentence denotes Finally, in vivo or ex vivo administration of human rACE2 in plasma samples produced an increase not only of Ang (1–9) but also of Ang (1–5) and Ang (1–7) in both healthy subjects [178] and ARDS patients [134], indicating that all three Ang peptides might represent surrogate markers of ACE2 activity.
T458 12520-12821 Sentence denotes Of interest, the mean arterial pressure of ARDS patients was markedly low and significantly lower in non–survivors (mean value 65 mmHg and more likely need vasopressor support) compared to survivors (mean value 71 mmHg) [92], which may likely be a consequence of the above described ACE2 upregulation.
T459 12822-12909 Sentence denotes Interestingly, similar features were also detected in PAH and coronary atherosclerosis.
T460 12910-13138 Sentence denotes In particular, a significant increase of both Ang II and Ang (1–7) peptides was observed in plasma of these patients [108,182] and plasma levels of TNF-α were significantly elevated in the critical coronary artery disease [182].
T461 13139-13358 Sentence denotes Moreover, despite a significant increase of Ang II/Ang (1–7) ratio (that suggested a therapeutic use of recombinant hACE2 in PAH patients) systolic and diastolic blood pressures were in the range of normality [108,182].
T462 13359-13569 Sentence denotes Altogether these observations suggest that Ang peptide ratios are not reliable markers for disease status in these pathologies; rather, increased plasma amounts of each RAS peptide should be careful considered.