scholarly journals Pharmacological inhibition of the kinin-kallikrein system in severe COVID-19 A proof-of-concept study

2020 ◽  
Author(s):  
Eli Mansour ◽  
Andre C Palma ◽  
Raisa G Ulaf ◽  
Luciana C Ribeiro ◽  
Ana Flavia Bernardes ◽  
...  
Keyword(s):  
Pathological Finding ◽  
Alveolar Cells ◽  
Open Label ◽  
Angiotensin Converting Enzyme 2 ◽  
Pharmacological Inhibition ◽  
Disease Mortality ◽  
Cellular Machinery ◽  
O2 Diffusion ◽  
Disease Recovery ◽  
Blood Eosinophils

Coronavirus disease-19 (COVID-19) can develop into a severe respiratory syndrome that results in up to 40% mortality. Acute lung inflammatory edema is a major pathological finding in autopsies explaining O2 diffusion failure and hypoxemia. Only dexamethasone has been shown to reduce mortality in severe cases, further supporting a role for inflammation in disease severity. SARS-CoV-2 enters cells employing angiotensin converting enzyme 2 (ACE2) as a receptor, which is highly expressed in lung alveolar cells. ACE2 is one of the components of the cellular machinery that inactivates the potent inflammatory agent bradykinin, and SARS-CoV-2 infection could interfere with the catalytic activity of ACE2, leading to accumulation of bradykinin. In this open-label, randomized clinical trial, we tested two pharmacological inhibitors of the kinin-kallikrein system that are currently approved for the treatment of hereditary angioedema, icatibant and inhibitor of C1 esterase/kallikrein, in a group of 30 patients with severe COVID-19. Neither icatibant nor inhibitor of C1 esterase/kallikrein resulted in significant changes in disease mortality and time to clinical improvement. However, both compounds promoted significant improvement of lung computed tomography scores and increased blood eosinophils, which has been reported as an indicator of disease recovery. In this small cohort, we found evidence for a beneficial role of pharmacological inhibition of the kinin-kallikrein system in two markers that indicate improved disease recovery.

scholarly journals Safety and Outcomes Associated with the Pharmacological Inhibition of the Kinin–Kallikrein System in Severe COVID-19

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 309
Author(s):  
Eli Mansour ◽  
Andre C. Palma ◽  
Raisa G. Ulaf ◽  
Luciana C. Ribeiro ◽  
Ana Flavia Bernardes ◽  
...  
Keyword(s):  
Pathological Finding ◽  
Alveolar Cells ◽  
Angiotensin Converting Enzyme 2 ◽  
Pharmacological Inhibition ◽  
Cellular Machinery ◽  
O2 Diffusion ◽  
Small Cohort ◽  
Disease Recovery ◽  
Blood Eosinophils

Background: Coronavirus disease 19 (COVID-19) can develop into a severe respiratory syndrome that results in up to 40% mortality. Acute lung inflammatory edema is a major pathological finding in autopsies explaining O2 diffusion failure and hypoxemia. Only dexamethasone has been shown to reduce mortality in severe cases, further supporting a role for inflammation in disease severity. SARS-CoV-2 enters cells employing angiotensin-converting enzyme 2 (ACE2) as a receptor, which is highly expressed in lung alveolar cells. ACE2 is one of the components of the cellular machinery that inactivates the potent inflammatory agent bradykinin, and SARS-CoV-2 infection could interfere with the catalytic activity of ACE2, leading to the accumulation of bradykinin. Methods: In this case control study, we tested two pharmacological inhibitors of the kinin–kallikrein system that are currently approved for the treatment of hereditary angioedema, icatibant, and inhibitor of C1 esterase/kallikrein, in a group of 30 patients with severe COVID-19. Results: Neither icatibant nor inhibitor of C1 esterase/kallikrein resulted in changes in time to clinical improvement. However, both compounds were safe and promoted the significant improvement of lung computed tomography scores and increased blood eosinophils, which are indicators of disease recovery. Conclusions: In this small cohort, we found evidence for safety and a beneficial role of pharmacological inhibition of the kinin–kallikrein system in two markers that indicate improved disease recovery.

scholarly journals A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension

2018 ◽  
Vol 51 (6) ◽  
pp. 1702638 ◽  
Author(s):  
Anna R. Hemnes ◽  
Anandharajan Rathinasabapathy ◽  
Eric A. Austin ◽  
Evan L. Brittain ◽  
Erica J. Carrier ◽  
...  
Keyword(s):  
Pilot Study ◽  
Pulmonary Arterial Hypertension ◽  
Angiotensin Converting Enzyme ◽  
Arterial Hypertension ◽  
Pulmonary Arteries ◽  
Converting Enzyme ◽  
Open Label ◽  
Angiotensin Converting Enzyme 2 ◽  
Markers Of Inflammation ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a deadly disease with no cure. Alternate conversion of angiotensin II (AngII) to angiotensin-(1–7) (Ang-(1–7)) by angiotensin-converting enzyme 2 (ACE2) resulting in Mas receptor (Mas1) activation improves rodent models of PAH. Effects of recombinant human (rh) ACE2 in human PAH are unknown. Our objective was to determine the effects of rhACE2 in PAH.We defined the molecular effects of Mas1 activation using porcine pulmonary arteries, measured AngII/Ang-(1–7) levels in human PAH and conducted a phase IIa, open-label pilot study of a single infusion of rhACE2 (GSK2586881, 0.2 or 0.4 mg·kg−1 intravenously).Superoxide dismutase 2 (SOD2) and inflammatory gene expression were identified as markers of Mas1 activation. After confirming reduced plasma ACE2 activity in human PAH, five patients were enrolled in the trial. GSK2586881 was well tolerated with significant improvement in cardiac output and pulmonary vascular resistance. GSK2586881 infusion was associated with reduced plasma markers of inflammation within 2–4 h and increased SOD2 plasma protein at 2 weeks.PAH is characterised by reduced ACE2 activity. Augmentation of ACE2 in a pilot study was well tolerated, associated with improved pulmonary haemodynamics and reduced markers of oxidant and inflammatory mediators. Targeting this pathway may be beneficial in human PAH.

scholarly journals Single-agent belantamab mafodotin for relapsed/refractory multiple myeloma: analysis of the lyophilised presentation cohort from the pivotal DREAMM-2 study

2020 ◽  
Vol 10 (10) ◽  
Author(s):  
Paul G. Richardson ◽  
Hans C. Lee ◽  
Al-Ola Abdallah ◽  
Adam D. Cohen ◽  
Prashant Kapoor ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Single Agent ◽  
Pathological Finding ◽  
Progression Free Survival ◽  
Antibody Drug Conjugate ◽  
Open Label ◽  
Blurred Vision ◽  
Refractory Multiple Myeloma ◽  
Open Label Phase ◽  
Duration Of Response

Abstract DREAMM-2 (NCT03525678) is an ongoing global, open-label, phase 2 study of single-agent belantamab mafodotin (belamaf; GSK2857916), a B-cell maturation antigen-targeting antibody-drug conjugate, in a frozen-liquid presentation in patients with relapsed/refractory multiple myeloma (RRMM). Alongside the main study, following identical inclusion/exclusion criteria, a separate patient cohort was enrolled to receive belamaf in a lyophilised presentation (3.4 mg/kg, every 3 weeks) until disease progression/unacceptable toxicity. Primary outcome was independent review committee-assessed overall response rate (ORR). Twenty-five patients were enrolled; 24 received ≥1 dose of belamaf. As of 31 January 2020, ORR was 52% (95% CI: 31.3–72.2); 24% of patients achieved very good partial response. Median duration of response was 9.0 months (2.8–not reached [NR]); median progression-free survival was 5.7 months (2.2–9.7); median overall survival was not reached (8.7 months–NR). Most common grade 3/4 adverse events were keratopathy (microcyst-like corneal epithelial changes, a pathological finding seen on eye examination [75%]), thrombocytopenia (21%), anaemia (17%), hypercalcaemia and hypophosphatemia (both 13%), neutropenia and blurred vision (both 8%). Pharmacokinetics supported comparability of frozen-liquid and lyophilised presentations. Single-agent belamaf in a lyophilised presentation (intended for future use) showed a deep and durable clinical response and acceptable safety profile in patients with heavily pre-treated RRMM.

scholarly journals SARS-CoV-2 receptor is co-expressed with elements of the kinin–kallikrein, renin–angiotensin and coagulation systems in alveolar cells

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Davi Sidarta-Oliveira ◽  
Carlos Poblete Jara ◽  
Adriano J. Ferruzzi ◽  
Munir S. Skaf ◽  
William H. Velander ◽  
...  
Keyword(s):  
Meta Analysis ◽  
Renin Angiotensin System ◽  
Cell Entry ◽  
Coagulation System ◽  
Alveolar Cells ◽  
Healthy Human ◽  
Angiotensin Converting Enzyme 2 ◽  
Renin Angiotensin ◽  
Cardiovascular Failure ◽  
Lethal Triad

Abstract SARS-CoV-2, the pathogenic agent of COVID-19, employs angiotensin converting enzyme-2 (ACE2) as its cell entry receptor. Clinical data reveal that in severe COVID-19, SARS-CoV-2 infects the lung, leading to a frequently lethal triad of respiratory insufficiency, acute cardiovascular failure, and coagulopathy. Physiologically, ACE2 plays a role in the regulation of three systems that could potentially be involved in the pathogenesis of severe COVID-19: the kinin–kallikrein system, resulting in acute lung inflammatory edema; the renin–angiotensin system, promoting cardiovascular instability; and the coagulation system, leading to thromboembolism. Here we assembled a healthy human lung cell atlas meta-analysis with ~ 130,000 public single-cell transcriptomes and show that key elements of the bradykinin, angiotensin and coagulation systems are co-expressed with ACE2 in alveolar cells and associated with their differentiation dynamics, which could explain how changes in ACE2 promoted by SARS-CoV-2 cell entry result in the development of the three most severe clinical components of COVID-19.

Abstract MP62: Sars-cov-2 Spike Protein Regulation Of Angiotensin Converting Enzyme 2 And Tissue Renin-angiotensin Systems: Influence Of Biologic Sex

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Lisa A Cassis ◽  
Christopher M Waters ◽  
Robin C Shoemaker ◽  
Jamie Sturgill ◽  
Yasir AlSiraj ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Mrna Abundance ◽  
Protein Regulation ◽  
Converting Enzyme ◽  
Alveolar Cells ◽  
Male And Female ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Renin Angiotensin ◽  
Female Mice

Angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 receptor and an enzyme of the renin-angiotensin system (RAS), is on the X chromosome and stimulated by estrogen. Male sex is a risk factor for SARS-CoV-2 severity. Previous investigators demonstrated that the SARs-CoV-2 Spike (S) protein decreases tissue ACE2 by protein internalization or shedding. This study defined sex differences in tissue ACE2 expression and their impact on SARS-CoV-2 S protein regulation of ACE2 activity and AngII levels. Male and female intact or gonadectomized (GDX) low density lipoprotein receptor deficient ( Ldlr -/- ) mice, and Four Core Genotype (FCG) male (XY or XX) or female (XX or XY) mice were fed a Western diet for 4 months. In lung, ACE2 mRNA abundance was similar in male and female mice and reduced by GDX (Male XY intact: 1.04 ± 0.15; Female XX intact: 1.13 ± 0.13; Male XY GDX: 0.11 ± 0.03; Female XX GDX: 0.18 ± 0.04 ΔΔCt; P<0.05). Lungs from XX mice had higher ACE2 mRNA abundance than XY mice regardless of gonadal sex (P<0.05), and GDX reduced ACE2 mRNA abundance in lungs of XX, but not XY females (XX Female GDX: 0.18 ± 0.04; XY Female GDX: 0.38 ± 0.09; P<0.05). In adipose, XX females had higher ACE2 mRNA abundance than XY males (XX female: 5.4 ± 0.7; XY male: 1.0 ± 0.1; P<0.05), regardless of gonadal sex (XY females: 3.3 ± 0.7; XX males: 1.5 ± 0.3; P<0.05). Male XY and female XX Ldlr -/- mice were administered vehicle or SARS-CoV-2 S protein (2 nmol/kg, ip, 3 doses) with tissue harvest six hours later. In lung, AngII levels were increased by S protein in male, but not female mice (Male, vehicle: 12.3 ± 2.3; Male, S protein: 33.6 ± 7.1; Female, vehicle: 16.1 ± 2.0; Female, S protein: 20.2 ± 1.3 pg/μg protein; P<0.05). In adipose, ACE2 activity was reduced by S protein in male, but not female mice (Male, vehicle: 63.6 ± 13.9; Male, S protein: 26.1 ± 1.9; Female, vehicle: 32.5 ± 1.9; Female, S protein: 25.1 ± 1.3 RFU/hr/mg tissue; P<0.05). SARS-CoV-2 S protein (35 nM) decreased ACE2 activity in type II lung alveolar cells (Vehicle: 2.0 x 10 4 ; S protein: 1.2 x 10 4 RFU/10 6 cells) and 3T3-L1 adipocytes (Vehicle: 2.1 x 10 4 ± 0.3 x 10 4 ; S protein: 1.1 x 10 4 ± 0.8 x 10 3 RFU/10 5 cells; P<0.05). Biologic sex regulation of ACE2 may protect females from SARS-CoV-2 S protein-mediated ACE2 reductions and activation of the local RAS.

scholarly journals Elovanoids downregulate canonical SARS-CoV-2 cell-entry mediators and enhance protective signaling in human alveolar cells

2020 ◽  
Author(s):  
Jorgelina Calandria ◽  
Surjyadipta Bhattacharjee ◽  
Marie-Audrey I. Kautzmann ◽  
Aram Asatryan ◽  
William C. Gordon ◽  
...  
Keyword(s):  
Cell Entry ◽  
Lung Damage ◽  
Chain Polyunsaturated Fatty Acid ◽  
Therapeutic Approaches ◽  
Cell Binding ◽  
Alveolar Cells ◽  
Virus Binding ◽  
Angiotensin Converting Enzyme 2 ◽  
Protective Proteins ◽  
Protective Signaling

Abstract The pro-homeostatic lipid mediators elovanoids (ELVs) attenuate cell binding and entrance of the SARS-CoV-2 receptor-binding domain (RBD) in human primary alveoli cells in culture. We uncovered that very-long-chain polyunsaturated fatty acid precursors (VLC-PUFA,n-3) activate ELV biosynthesis in lung cells. Both ELVs and their precursors reduce the binding to RBD. ELVs downregulate angiotensin-converting enzyme 2 (ACE2) and enhance the expression of a set of protective proteins hindering cell surface virus binding and upregulating defensive proteins against lung damage. These findings open avenues for potential preventive and disease-modifiable therapeutic approaches for COVID-19.

scholarly journals Pathogenesis of COVID-19: ACE2, Cytokine Storm and Extrapulmonary Manifestations

2021 ◽  
Vol 2 (4) ◽  
pp. 9
Author(s):  
Muhammad Naeem ◽  
Abdul Muhaymin Muhaymin ◽  
Hyder Wajid Abbasi ◽  
Naeem Ullah ◽  
Adnan Haider ◽  
...  
Keyword(s):  
Immune Responses ◽  
Viral Entry ◽  
Distress Syndrome ◽  
Clinical Manifestations ◽  
First Century ◽  
Infected Person ◽  
Alveolar Cells ◽  
Angiotensin Converting Enzyme 2 ◽  
Global Pandemic ◽  
Taste And Smell

The coronavirus disease 19 (COVID-19) is a global pandemic of the twenty-first century and currently fourthwave is creating fear and panic worldwide. It is caused by severe acute respiratory syndrome coronavirus 2(SARS-COV-2), a highly contagious viral infection of humans. The COVID-19 can be spread mainly throughrespiratory droplet particles and in contact with a COVID-19 infected person. Clinical manifestation of COVID-19patients includes cough, fever, diarrhea, loss of taste and smell. In critical cases of COVID-19, the developmentof pneumonia and dyspnea leads to acute respiratory distress syndrome that may cause the death of thepatient. It is well established that Angiotensin-Converting Enzyme 2 (ACE2) receptors on alveolar cells act as anentry gate for the SARS-COV-2. However, ACE2 is also highly expressed in multiple extrapulmonary vital organssuch as the gastrointestinal system, cardiovascular system, kidney, etc. Therefore, the direct viral entry in theseorgans can be a likely pathway of injury. In addition, decoupling of immune responses leads to the cytokinesstorm, which might contribute to the injury of extrapulmonary organs. In this review, we report the multipleorgan pathogenesis and clinical manifestations of COVID-19 patients, which could aid clinicians and researchersin prioritizing therapeutics remedies and developing research for all vital body systems involved.

Modeling the Interaction of SARS-CoV-2 Binding to the ACE2 Receptor by Molecular Theory of Solvation

2021 ◽  
Author(s):  
Alexander E Kobryn ◽  
Yutaka Maruyama ◽  
Carlos A. Velázquez-Martínez ◽  
Norio Yoshida ◽  
Sergey Gusarov
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Molecular Theory ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Pharmacological Inhibition ◽  
A Cell

The angiotensin-converting enzyme 2 (ACE2) protein is a cell gate receptor for the SARS-CoV-2 virus, responsible for the development of symptoms associated with the Covid-19 disease. Pharmacological inhibition of the...

scholarly journals Neutrophils to Lymphocytes Ratio and the Prognosisof the COVID-19 Patients

2021 ◽  
Vol 3 (2) ◽  
pp. 86-96
Author(s):  
Mahsa Taghavi-Farahabadi ◽  
◽  
Mohammad Mahmoudi ◽  
Seyed Mahmoud Hashemi ◽  
Saeed Namaki ◽  
...  
Keyword(s):  
Immune Responses ◽  
Acute Inflammation ◽  
Innate Immune ◽  
Lung Cells ◽  
Converting Enzyme ◽  
Innate Immune Responses ◽  
Alveolar Cells ◽  
Angiotensin Converting Enzyme 2 ◽  
Multiple Factors ◽  
Global Concern

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a new pandemic virus, a global concern, and has threatened human health. This virus binds to the Angiotensin-Converting Enzyme 2 (ACE2) that is expressed on different cells, especially on the alveolar cells. So the virus can enter the lung cells and causes respiratory syndromes. In Coronavirus Disease 2019 (COVID-19) that is caused by SARS-CoV-2, respiratory failure, and acute inflammation is the main cause of death. According to several reports, multiple factors, such as Neutrophils to Lymphocytes Ratio (NLR) have prognostic potentials in COVID-19. This study aims to review this parameter to have a better prediction about the condition of the patients and their treatments. According to this review, the NLR ratio that is related to the innate immune responses and inflammation can be helpful in the discrimination of severe from non-severe cases of COVID-19 patients.

Sign in / Sign up

Export Citation Format

Share Document