SARS-CoV-2 Spike Protein Suppresses ACE2 and Type I Interferon Expression in Primary Cells From Macaque Lung Bronchoalveolar Lavage

SARS-CoV-2 virus causes upper and lower respiratory diseases including pneumonia, and in some cases, leads to lethal pulmonary failure. Angiotensin converting enzyme-2 (ACE2), the receptor for cellular entry of SARS-CoV-2 virus, has been shown to protect against severe acute lung failure. Here, we provide evidence that SARS-CoV-2 spike protein S1 reduced the mRNA expression of ACE2 and type I interferons in primary cells of lung bronchoalveolar lavage (BAL) from naïve rhesus macaques. The expression levels of ACE2 and type I interferons were also found to be correlated with each other, consistent with the recent finding that ACE2 is an interferon-inducible gene. Furthermore, induction of ACE2 and type I interferons by poly I:C, an interferon inducer, was suppressed by S1 protein in primary cells of BAL. These observations suggest that the downregulation of ACE2 and type I interferons induced by S1 protein may directly contribute to SARS-CoV-2-associated lung diseases.

Respiratory physiology of COVID-19 and Influenza associated Acute Respiratory Distress Syndrome

Background: There is ongoing debate whether lung physiology of COVID-19 associated acute respiratory distress syndrome (ARDS) differs from ARDS of other origin.Objective: The aim of this study was to analyze and compare how critically ill patients with COVID-19 and Influenza A or B were ventilated in our tertiary care center with or without extracorporeal membrane oxygenation (ECMO). We ask if acute lung failure due to COVID-19 requires different intensive care management compared to conventional ARDS. Methods: 25 patients with COVID-19 associated ARDS were matched to a cohort of 25 Influenza patients treated in our center from 2011 to 2021. Subgroup analysis addressed whether patients on ECMO received different mechanical ventilation than patients without extracorporeal support.Results: Compared to Influenza-associated ARDS, COVID-19 patients had higher ventilatory system compliance (40.7 ml/mbar [31.8 – 46.7 ml/mbar] vs. 31.4 ml/mbar [13.7 – 42.8 ml/mbar], p = 0.198), higher ventilatory ratio (1.57 [1.31 – 1.84] vs. 0.91 [0.44 – 1.38], p = 0.006) and higher minute ventilation at the time of intubation (mean minute ventilation 10.7 l/min [7.2 – 12.2 l/min] for COVID-19 vs. 6.0 l/min [2.5 – 10.1 l/min] for Influenza, p = 0.013). There were no measurable differences in P/F ratio, positive end-expiratory pressure (PEEP) and driving pressures (ΔP). Respiratory system compliance deteriorated considerably in COVID-19 patients on ECMO during 2 weeks of mechanical ventilation (Crs, mean decrease over 2 weeks -23.87 ml/mbar ± 32.94 ml/mbar, p = 0.037), but not in ventilated Influenza patients on ECMO and less so in ventilated COVID-19 patients without ECMO. For COVID-19 patients, low driving pressures on ECMO were strongly correlated to a decline in compliance after 2 weeks (Pearson’s R 0.80, p = 0.058). Overall mortality was insignificantly lower for COVID-19 patients compared to Influenza patients (40% vs. 48%, p = 0.31). Outcome was insignificantly worse for patients requiring veno-venous ECMO in both groups (50% mortality for COVID-19 on ECMO vs. 27% without ECMO, p = 0.30 / 56% vs 34% mortality for Influenza A/B with and without ECMO, p = 0.31)Conclusion: The pathophysiology of early COVID-19-associated ARDS differs from Influenza-associated acute lung failure by sustained respiratory mechanics during the early phase of ventilation. We question whether intubated COVID-19 patients on ECMO benefit from extremely low driving pressures, as this appears to accelerate derecruitment and consecutive loss of ventilatory system compliance.

The Roles of Membrane Technology in Artificial Organs: Current Challenges and Perspectives

The recent outbreak of the COVID-19 pandemic in 2020 reasserted the necessity of artificial lung membrane technology to treat patients with acute lung failure. In addition, the aging world population inevitably leads to higher demand for better artificial organ (AO) devices. Membrane technology is the central component in many of the AO devices including lung, kidney, liver and pancreas. Although AO technology has improved significantly in the past few decades, the quality of life of organ failure patients is still poor and the technology must be improved further. Most of the current AO literature focuses on the treatment and the clinical use of AO, while the research on the membrane development aspect of AO is relatively scarce. One of the speculated reasons is the wide interdisciplinary spectrum of AO technology, ranging from biotechnology to polymer chemistry and process engineering. In this review, in order to facilitate the membrane aspects of the AO research, the roles of membrane technology in the AO devices, along with the current challenges, are summarized. This review shows that there is a clear need for better membranes in terms of biocompatibility, permselectivity, module design, and process configuration.

A potential hypothesis for 2019-nCoV infection therapy through delivery of recombinant ACE2 by red blood cell-hitchhiking

A novel infectious disease, caused by 2019 Novel Coronavirus (2019-nCoV) is responsible for the recent outbreak of severe respiratory disease. The 2019-nCoV spread rapidly and reaching epidemic proportions in many countries of the world. ACE2 was identified as a key receptor for 2019-nCoV infections. Excessive form of soluble ACE2 rescues cellular ACE2 activity which has a protective role in acute lung failure and neutralizes the virus. The short half-life of ACE2 is a major limitation to its practical application. Nanoparticle-based drug delivery systems are one of the most widely investigated approaches for developing novel therapies for a variety of diseases. Nevertheless, nanoparticles suffer from the rapid removal from the bloodstream by the reticuloendothelial system (RES). A noncovalent attachment of nanoparticles to RBCs increases their half-life in blood and allows transient accumulation in the lungs, while decreases their uptake by the liver and spleen. Connecting the recombinant ACE2 into the surface of nanoparticles that were attached to RBCs can be a potential therapeutic approach for 2019-nCoV infection through increasing their lung targeting to naturalize the virus and also acting as a bioreactor in the blood circulation to decrease serum level of Angiotensin II and protects lungs from injury/ARDS.

Novel Coronavirus Disease 2019 (COVID-19) Current Update; Perspective on Epidemiology, Diagnosis, Drug Targets and Vaccines

Background:: A novel coronavirus disease, 2019-nCoV (COVID-19), reported first in Wuhan, the capital of Hubei, China in late December 2019 and subsequently reached pandemic level affecting around 213 countries. As of 24th May 2020, the total number of positive cases confirmed is 5,446,514 and 344,754 death reports worldwide. COVID-19 infection causes pneumonia-like severe respiratory infection and acute lung failure. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense single-stranded RNA beta coronavirus that is a confirmed causative agent of COVID-19. SARS-CoV-2 may use angiotensin-converting enzyme 2 (ACE2), unlike the receptor utilized by SARS-CoV (emerged in 2002) to infect humans. People with a history of hypertension, chronic obstructive pulmonary disease, diabetes, cardiovascular disease are more susceptible to SARS-CoV-2. Objective:: The purpose behind this review is to help the society to distinguish and deal with SARS-CoV-2, and make available a reference for forthcoming studies. Methods:: Recently, a diagnostic primer sets on the SARS-CoV-2 genome have been identified. The receptor-binding domain of SARS-COV-2 highlighted the mode by which beta-CoV recognizes ACE2. Various diagnostic tools are available to differentiate and identify SARS-CoV-2 infection as RT-PCR, antigen detection assay, and antibody detection assay. Different strategies have been employed to control the SARS-CoV-2, considering various drug targets like the main protease (3CLPro), papain-like protease (PLpro), helicase (NSP13), RNA dependent RNA polymerase (RdRp), and viral envelope (E) protein. Conclusion:: In the present review, we have updated details of transmission, pathogenesis, genome structure, diagnostic criteria, clinical characteristics, therapeutics, and vaccine development of the SARS-CoV-2 infection, which may be significant in the control and response to the COVID-19 outbreak.

Molecular Features of Non-Selective Small Molecule Antagonists of the Bradykinin Receptors

Angiotensin converting enzyme 2 (ACE2) downregulation is a key negative factor for the severity of lung edema and acute lung failure observed in patients infected with SARS-CoV-2. ACE2 downregulation affects the levels of diverse peptide mediators of the renin-agiotensin-aldestosterone and kallikrein-kinin systems, compromising vascular hemostasis. Increasing evidence suggests that the inflammatory response observed in covid-19 patients is initiated by the action of kinins on the bradykinin receptors. Accordingly, the use of bradykinin antagonists should be considered as a strategy for therapeutic intervention against covid-19 illness progression. Presently, icatibant is the only bradykinin antagonist drug approved. In the present report, we investigated the molecular features characterizing non-selective antagonists targeting the bradykinin receptors and carried out a in silico screening of approved drugs, aimed at the identification of compounds with a non-selective bradykinin antagonist profile that can be evaluated for drug repurposing. The study permitted to identify eight compounds as prospective non-selective antagonists of the bradykinin receptors, including raloxifene; sildenafil; cefepime; cefpirome; imatinib; ponatinib; abemaciclib and entrectinib.

COVID-19: is it just a lung disease? A case-based review

Due to its extreme virulence, COVID-19 virus has rapidly spread, developing a severe pandemic. SARS-COV-2 mostly affected the respiratory tract, causing a severe acute lung failure. Although the infection of airways, COVID-19 can be associated with chronic and systemic damages still not so much known. The purpose of this research is to collect recent evidence in literature about systemic diseases caused by COVID-19. The format of the present article has features of a systematic case-based review (level of evidence), and it is structured as a case series report (patients of our COVID-19 Medicine Ward have been selected as cases). Data for this review have been selected systematically, taking evidence only from indexed journals and databases: PubMed, Scopus, MEDLINE, and Cochrane systems. Papers chosen included systematic reviews, case series, clinical cases, meta-analysis studies, and RCTs. We start collecting studies since 2003. The main keywords used were “COVID-19” “OR” “SARS” “OR” “SARS – COV 2” “AND” “systemic disease” / “nephropathy” / “cardiac pathology” / “central nervous system.” Clinical cases belong to our COVID-19 Medicine Ward. One of the most severe COVID-19 clinical presentations includes cardiovascular problems, like myocarditis, pericarditis, and acute hearth failure. Cytokine release syndrome caused by COVID-19 develops severe acute kidney failure. It is still unknown the way coronavirus damages the liver, brain, and reproductive system. Considering the majority of the new studies about this pathology, it issues that COVID-19 is considered to be a multi-organ disease.

A Case of Acute Lung Failure: Administration of Exogenous Surfactant As A Successful Treatment

We are describing a case of acute lung injury associated with uraemia and haemorrhagic shock. The treatment has consisted of the administration of repeated and equal doses of exogenous surfactant for 72 hours, starting within 48 hours from the beginning of the symptoms. A rapid improvement in the lung function has been detected, with consequent weaning from mechanical ventilation. The CT scan has confirmed the enhancement of atelectasis and hypoventilation. This case highlights the pivotal role of the administration of exogenous surfactant in selected cases of acute lung injury. If an anti-inflammatory effect is needed, we suppose that a repeated treatment with fractional dose is more effective.