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1.
Trials ; 22(1): 643, 2021 Sep 20.
Article in English | MEDLINE | ID: covidwho-1435265

ABSTRACT

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a complex clinical diagnosis with various possible etiologies. One common feature, however, is pulmonary permeability edema, which leads to an increased alveolar diffusion pathway and, subsequently, impaired oxygenation and decarboxylation. A novel inhaled peptide agent (AP301, solnatide) was shown to markedly reduce pulmonary edema in animal models of ARDS and to be safe to administer to healthy humans in a Phase I clinical trial. Here, we present the protocol for a Phase IIB clinical trial investigating the safety and possible future efficacy endpoints in ARDS patients. METHODS: This is a randomized, placebo-controlled, double-blind intervention study. Patients with moderate to severe ARDS in need of mechanical ventilation will be randomized to parallel groups receiving escalating doses of solnatide or placebo, respectively. Before advancing to a higher dose, a data safety monitoring board will investigate the data from previous patients for any indication of patient safety violations. The intervention (application of the investigational drug) takes places twice daily over the course of 7 days, ensued by a follow-up period of another 21 days. DISCUSSION: The patients to be included in this trial will be severely sick and in need of mechanical ventilation. The amount of data to be collected upon screening and during the course of the intervention phase is substantial and the potential timeframe for inclusion of any given patient is short. However, when prepared properly, adherence to this protocol will make for the acquisition of reliable data. Particular diligence needs to be exercised with respect to informed consent, because eligible patients will most likely be comatose and/or deeply sedated at the time of inclusion. TRIAL REGISTRATION: This trial was prospectively registered with the EU Clinical trials register (clinicaltrialsregister.eu). EudraCT Number: 2017-003855-47 .


Subject(s)
COVID-19 , Pulmonary Edema , Respiratory Distress Syndrome , Double-Blind Method , Edema , Humans , Peptides, Cyclic , Permeability , Pulmonary Edema/diagnosis , Pulmonary Edema/drug therapy , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/drug therapy , SARS-CoV-2 , Treatment Outcome
2.
ACS Nano ; 14(6): 7651-7658, 2020 06 23.
Article in English | MEDLINE | ID: covidwho-1387149

ABSTRACT

Layered systems of commonly available fabric materials can be used by the public and healthcare providers in face masks to reduce the risk of inhaling viruses with protection that is about equivalent to or better than the filtration and adsorption offered by 5-layer N95 respirators. Over 70 different common fabric combinations and masks were evaluated under steady-state, forced convection air flux with pulsed aerosols that simulate forceful respiration. The aerosols contain fluorescent virus-like nanoparticles to track transmission through materials that greatly assist the accuracy of detection, thus avoiding artifacts including pore flooding and the loss of aerosol due to evaporation and droplet breakup. Effective materials comprise both absorbent, hydrophilic layers and barrier, hydrophobic layers. Although the hydrophobic layers can adhere virus-like nanoparticles, they may also repel droplets from adjacent absorbent layers and prevent wicking transport across the fabric system. Effective designs are noted with absorbent layers comprising terry cloth towel, quilting cotton, and flannel. Effective designs are noted with barrier layers comprising nonwoven polypropylene, polyester, and polyaramid.


Subject(s)
Betacoronavirus , Coronavirus Infections/prevention & control , Masks , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Textiles , Aerosols , Air Microbiology , Betacoronavirus/ultrastructure , COVID-19 , Coronavirus Infections/transmission , Filtration , Humans , In Vitro Techniques , Masks/supply & distribution , Nanoparticles/ultrastructure , Particle Size , Permeability , Pneumonia, Viral/transmission , SARS-CoV-2 , Water
4.
J Clin Invest ; 131(14)2021 07 15.
Article in English | MEDLINE | ID: covidwho-1311202

ABSTRACT

BACKGROUNDWeeks after SARS-CoV-2 infection or exposure, some children develop a severe, life-threatening illness called multisystem inflammatory syndrome in children (MIS-C). Gastrointestinal (GI) symptoms are common in patients with MIS-C, and a severe hyperinflammatory response ensues with potential for cardiac complications. The cause of MIS-C has not been identified to date.METHODSHere, we analyzed biospecimens from 100 children: 19 with MIS-C, 26 with acute COVID-19, and 55 controls. Stools were assessed for SARS-CoV-2 by reverse transcription PCR (RT-PCR), and plasma was examined for markers of breakdown of mucosal barrier integrity, including zonulin. Ultrasensitive antigen detection was used to probe for SARS-CoV-2 antigenemia in plasma, and immune responses were characterized. As a proof of concept, we treated a patient with MIS-C with larazotide, a zonulin antagonist, and monitored the effect on antigenemia and the patient's clinical response.RESULTSWe showed that in children with MIS-C, a prolonged presence of SARS-CoV-2 in the GI tract led to the release of zonulin, a biomarker of intestinal permeability, with subsequent trafficking of SARS-CoV-2 antigens into the bloodstream, leading to hyperinflammation. The patient with MIS-C treated with larazotide had a coinciding decrease in plasma SARS-CoV-2 spike antigen levels and inflammatory markers and a resultant clinical improvement above that achieved with currently available treatments.CONCLUSIONThese mechanistic data on MIS-C pathogenesis provide insight into targets for diagnosing, treating, and preventing MIS-C, which are urgently needed for this increasingly common severe COVID-19-related disease in children.


Subject(s)
COVID-19/etiology , COVID-19/physiopathology , Haptoglobins/physiology , Intestinal Mucosa/physiopathology , Protein Precursors/physiology , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/etiology , Systemic Inflammatory Response Syndrome/physiopathology , Adolescent , Antigens, Viral/blood , Biomarkers/blood , COVID-19/virology , Case-Control Studies , Child , Child, Preschool , Female , Haptoglobins/antagonists & inhibitors , Humans , Infant , Infant, Newborn , Intestinal Mucosa/drug effects , Intestinal Mucosa/virology , Male , Oligopeptides/pharmacology , Permeability/drug effects , Proof of Concept Study , Protein Precursors/antagonists & inhibitors , Protein Precursors/blood , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/blood , Spike Glycoprotein, Coronavirus/immunology , Systemic Inflammatory Response Syndrome/virology , Young Adult
5.
J Chem Phys ; 154(24): 245101, 2021 Jun 28.
Article in English | MEDLINE | ID: covidwho-1293030

ABSTRACT

Ethanol is highly effective against various enveloped viruses and can disable the virus by disintegrating the protective envelope surrounding it. The interactions between the coronavirus envelope (E) protein and its membrane environment play key roles in the stability and function of the viral envelope. By using molecular dynamics simulation, we explore the underlying mechanism of ethanol-induced disruption of a model coronavirus membrane and, in detail, interactions of the E-protein and lipids. We model the membrane bilayer as N-palmitoyl-sphingomyelin and 1-palmitoyl-2-oleoylphosphatidylcholine lipids and the coronavirus E-protein. The study reveals that ethanol causes an increase in the lateral area of the bilayer along with thinning of the bilayer membrane and orientational disordering of lipid tails. Ethanol resides at the head-tail region of the membrane and enhances bilayer permeability. We found an envelope-protein-mediated increase in the ordering of lipid tails. Our simulations also provide important insights into the orientation of the envelope protein in a model membrane environment. At ∼25 mol. % of ethanol in the surrounding ethanol-water phase, we observe disintegration of the lipid bilayer and dislocation of the E-protein from the membrane environment.


Subject(s)
Cell Membrane/drug effects , Cell Membrane/metabolism , Coronavirus/metabolism , Disinfectants/pharmacology , Ethanol/pharmacology , Viral Envelope Proteins/metabolism , Coronavirus/physiology , Lipid Bilayers/metabolism , Molecular Conformation , Molecular Dynamics Simulation , Permeability
6.
Front Immunol ; 12: 686240, 2021.
Article in English | MEDLINE | ID: covidwho-1285294

ABSTRACT

A disruption of the crosstalk between the gut and the lung has been implicated as a driver of severity during respiratory-related diseases. Lung injury causes systemic inflammation, which disrupts gut barrier integrity, increasing the permeability to gut microbes and their products. This exacerbates inflammation, resulting in positive feedback. We aimed to test whether severe Coronavirus disease 2019 (COVID-19) is associated with markers of disrupted gut permeability. We applied a multi-omic systems biology approach to analyze plasma samples from COVID-19 patients with varying disease severity and SARS-CoV-2 negative controls. We investigated the potential links between plasma markers of gut barrier integrity, microbial translocation, systemic inflammation, metabolome, lipidome, and glycome, and COVID-19 severity. We found that severe COVID-19 is associated with high levels of markers of tight junction permeability and translocation of bacterial and fungal products into the blood. These markers of disrupted intestinal barrier integrity and microbial translocation correlate strongly with higher levels of markers of systemic inflammation and immune activation, lower levels of markers of intestinal function, disrupted plasma metabolome and glycome, and higher mortality rate. Our study highlights an underappreciated factor with significant clinical implications, disruption in gut functions, as a potential force that may contribute to COVID-19 severity.


Subject(s)
COVID-19/immunology , Gastrointestinal Microbiome/immunology , Inflammation/immunology , Intestines/physiology , SARS-CoV-2/physiology , Female , Glycomics , Haptoglobins/metabolism , Humans , Lipidomics , Male , Metabolomics , Middle Aged , Permeability , Protein Precursors/metabolism , Tight Junctions/metabolism
7.
PLoS One ; 16(6): e0253347, 2021.
Article in English | MEDLINE | ID: covidwho-1280628

ABSTRACT

The unprecedented global COVID-19 pandemic has prompted a desperate international effort to accelerate the development of anti-viral candidates. For unknown reasons, COVID-19 infections are associated with adverse cardiovascular complications, implicating that vascular endothelial cells are essential in viral propagation. The etiological pathogen, SARS-CoV-2, has a higher reproductive number and infection rate than its predecessors, indicating it possesses novel characteristics that infers enhanced transmissibility. A unique K403R spike protein substitution encodes an Arg-Gly-Asp (RGD) motif, introducing a potential role for RGD-binding host integrins. Integrin αVß3 is widely expressed across the host, particularly in the endothelium, which acts as the final barrier before microbial entry into the bloodstream. This mutagenesis creates an additional binding site, which may be sufficient to increase SARS-CoV-2 pathogenicity. Here, we investigate how SARS-CoV-2 passes from the epithelium to endothelium, the effects of αVß3 antagonist, Cilengitide, on viral adhesion, vasculature permeability and leakage, and also report on a simulated interaction between the viral and host protein in-silico.


Subject(s)
Endothelium, Vascular/virology , Integrin alphaVbeta3/metabolism , SARS-CoV-2/pathogenicity , Snake Venoms/pharmacology , Antigens, CD/metabolism , Binding Sites , COVID-19/metabolism , COVID-19/physiopathology , Caco-2 Cells , Cadherins/metabolism , Computer Simulation , Endothelium, Vascular/cytology , Endothelium, Vascular/physiopathology , Host-Pathogen Interactions/drug effects , Humans , Integrin alphaVbeta3/chemistry , Models, Molecular , Mutation , Permeability , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization
8.
Drug Dev Res ; 82(7): 873-879, 2021 11.
Article in English | MEDLINE | ID: covidwho-1263077

ABSTRACT

COVID-19 manifests as a mild disease in most people but can progress to severe disease in nearly 20% of individuals. Disease progression is likely driven by a cytokine storm, either directly stimulated by SARS-CoV-2 or by increased systemic inflammation in which the gut might play an integral role. SARS-CoV-2 replication in the gut may cause increased intestinal permeability, alterations to the fecal microbiome, and increased inflammatory cytokines. Each effect may lead to increased systemic inflammation and the transport of cytokines and inflammatory antigens from the gut to the lung. Few interventions are being studied to treat people with mild disease and prevent the cytokine storm. Serumderived bovine immunoglobulin/protein isolate (SBI) may prevent progression by (1) binding and neutralizing inflammatory antigens, (2) decreasing gut permeability, (3) interfering with ACE2 binding by viral proteins, and (4) improving the fecal microbiome. SBI is therefore a promising intervention to prevent disease progression in COVID-19 patients.


Subject(s)
COVID-19/drug therapy , Immunization, Passive/methods , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/complications , Cattle , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/prevention & control , Gastrointestinal Microbiome , Gastrointestinal Tract/pathology , Humans , Permeability
9.
Clin Transl Gastroenterol ; 12(6): e00367, 2021 06 04.
Article in English | MEDLINE | ID: covidwho-1259761

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 infection has been associated with both endotoxemia and thrombosis of small and large vessels, but the relationship between these 2 phenomena has not been pursued. Oliva et al. in this issue of Clinical and Translational Gastroenterology demonstrate an association between the 2 findings and suggest that increased intestinal permeability is a possible mechanism to explain the endotoxemia. Although the evidence to support this hypothesis is only suggestive, the role of the small intestine in the illness produced by the virus needs to be further explored.


Subject(s)
COVID-19 , Endotoxemia , Intestine, Small , SARS-CoV-2 , Thrombosis , COVID-19/blood , COVID-19/complications , COVID-19/physiopathology , Correlation of Data , Endotoxemia/diagnosis , Endotoxemia/metabolism , Endotoxemia/virology , Humans , Intestine, Small/metabolism , Intestine, Small/virology , Permeability , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Thrombosis/blood , Thrombosis/diagnosis , Thrombosis/etiology
10.
Clin Transl Gastroenterol ; 12(6): e00348, 2021 06 04.
Article in English | MEDLINE | ID: covidwho-1259760

ABSTRACT

INTRODUCTION: Patients with community-acquired pneumonia display enhanced levels of lipopolysaccharides (LPS) compared with controls, suggesting that low-grade endotoxemia may be implicated in vascular disturbances. It is unknown whether this occurs in patients with coronavirus 2019 (COVID-19) and its impact on thrombotic complications. METHODS: We measured serum levels of zonulin, a marker of gut permeability, LPS, and D-dimer in 81 patients with COVID-19 and 81 healthy subjects; the occurrence of thrombotic events in COVID-19 during the intrahospital stay was registered. RESULTS: Serum LPS and zonulin were higher in patients with COVID-19 than in control subjects and, in COVID-19, significantly correlated (R = 0.513; P < 0.001). Among the 81 patients with COVID-19, 11 (14%) experienced thrombotic events in the arterial (n = 5) and venous circulation (n = 6) during a median follow-up of 18 days (interquartile range 11-27 days). A logistic regression analysis showed that LPS (P = 0.024) and D-dimer (P = 0.041) independently predicted thrombotic events. DISCUSSION: The study reports that low-grade endotoxemia is detectable in patients with COVID-19 and is associated with thrombotic events. The coexistence of low-grade endotoxemia with enhanced levels of zonulin may suggest enhanced gut permeability as an underlying mechanism.


Subject(s)
COVID-19 , Endotoxemia , Haptoglobins/metabolism , Intestinal Mucosa , Protein Precursors/metabolism , SARS-CoV-2 , Thrombosis , Biomarkers/blood , COVID-19/blood , COVID-19/complications , COVID-19/physiopathology , Correlation of Data , Endotoxemia/diagnosis , Endotoxemia/metabolism , Endotoxemia/virology , Female , Fibrin Fibrinogen Degradation Products/analysis , Humans , Intestinal Mucosa/metabolism , Intestinal Mucosa/virology , Lipopolysaccharides/analysis , Male , Middle Aged , Permeability , Pneumonia, Viral/diagnosis , Pneumonia, Viral/etiology , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Thrombosis/blood , Thrombosis/diagnosis , Thrombosis/etiology
11.
Am J Chin Med ; 48(6): 1315-1330, 2020.
Article in English | MEDLINE | ID: covidwho-1243726

ABSTRACT

Critical care medicine is a medical specialty engaging the diagnosis and treatment of critically ill patients who have or are likely to have life-threatening organ failure. Sepsis, a life-threatening condition that arises when the body responds to infection, is currently the major cause of death in intensive care units (ICU). Although progress has been made in understanding the pathophysiology of sepsis, many drawbacks in sepsis treatment remains unresolved. For example, antimicrobial resistance, controversial of glucocorticoids use, prolonged duration of ICU care and the subsequent high cost of the treatment. Recent years have witnessed a growing trend of applying traditional Chinese medicine (TCM) in sepsis management. The TCM application emphasizes use of herbal formulation to balance immune responses to infection, which include clearing heat and toxin, promoting blood circulation and removing its stasis, enhancing gastrointestinal function, and strengthening body resistance. In this paper, we will provide an overview of the current status of Chinese herbal formulations, single herbs, and isolated compounds, as an add-on therapy to the standard Western treatment in the sepsis management. With the current trajectory of worldwide pandemic eruption of newly identified Coronavirus Disease-2019 (COVID-19), the adjuvant TCM therapy can be used in the ICU to treat critically ill patients infected with the novel coronavirus.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Coronavirus Infections/drug therapy , Drugs, Chinese Herbal/therapeutic use , Immunologic Factors/therapeutic use , Medicine, Chinese Traditional , Pneumonia, Viral/drug therapy , Sepsis/drug therapy , Artemisinins/therapeutic use , Astragalus propinquus , Berberine/therapeutic use , Betacoronavirus , COVID-19 , Critical Illness , Emodin/therapeutic use , Humans , Intensive Care Units , Intestinal Mucosa , Microcirculation , Pandemics , Permeability , Rheum , SARS-CoV-2 , Salvia miltiorrhiza
12.
Altern Lab Anim ; 48(5-6): 252-267, 2020.
Article in English | MEDLINE | ID: covidwho-1054770

ABSTRACT

The incidence of inflammatory lung diseases such as acute respiratory distress syndrome (ARDS) remains an important problem, particularly in the present time with the Covid-19 pandemic. However, an adequate in vitro test system to monitor the barrier function of the alveolar epithelium during inflammation and for assessing anti-inflammatory drugs is urgently needed. Therefore, we treated human Alveolar Epithelial Lentivirus-immortalised cells (hAELVi cells) with the pro-inflammatory cytokines TNF-α (25 ng/ml) and IFN-γ (30 ng/ml), in the presence or absence of hydrocortisone (HC). While TNF-α and IFN-γ are known to reduce epithelial barrier properties, HC could be expected to protect the barrier function and result in an anti-inflammatory effect. We investigated the impact of anti-inflammatory/inflammatory treatment on transepithelial electrical resistance (TEER) and the apparent permeability coefficient (Papp) of the low permeability marker sodium fluorescein (NaFlu). After incubating hAELVi cells for 48 hours with a combination of TNF-α and IFN-γ, there was a significant decrease in TEER and a significant increase in the Papp. The presence of HC maintained the TEER values and barrier properties, so that no significant Papp change was observed. By using hAELVi cells to study anti-inflammatory drugs in vitro, the need for animal experiments could be reduced and pulmonary drug development accelerated.


Subject(s)
Inflammation , Alveolar Epithelial Cells , COVID-19 , Humans , Permeability , SARS-CoV-2
13.
J Phys Chem Lett ; 12(5): 1384-1389, 2021 Feb 11.
Article in English | MEDLINE | ID: covidwho-1052086

ABSTRACT

One of the key parameters required to identify effective drugs is membrane permeability, as a compound intended for an intracellular target with poor permeability will have low efficacy. In this paper, we leverage a computational approach recently developed by our group to study the interactions between nanoparticles and mammalian membranes to study the time of entry of a variety of drugs into the viral envelope of coronavirus as well as cellular organelles. Using a combination of all-atoms molecular dynamics simulations and statistical analysis, we consider both drug characteristics and membrane properties to determine the behavior of 79 drugs and their interactions with the viral envelope, composed of the membrane and spike protein, as well as five other membranes that correspond to various mammalian compartments (lysosome, plasma, Golgi, mitochondrial, and endoplasmic reticulum membranes). The results highlight important trends that can be exploited for drug design, from the relatively high permeability of the viral envelope and the effect of transmembrane proteins, to the differences in permeability between organelles. When compared with bioavailability data present in the literature, the model results suggest a negative correlation between time of permeation and bioavailability of promising drugs. The method is general and flexible and can be employed for a variety of molecules, from small drugs to small nanoparticles, as well to a variety of biological membranes. Overall, the results indicate that this model can contribute to the identification of successful drugs as it predicts the ability of compounds to reach both intended and unintended intracellular targets.


Subject(s)
Antiviral Agents/metabolism , COVID-19/drug therapy , SARS-CoV-2/drug effects , Binding Sites , Humans , Hydrophobic and Hydrophilic Interactions , Kinetics , Lipid Bilayers/chemistry , Membrane Glycoproteins/chemistry , Models, Biological , Molecular Dynamics Simulation , Nanoparticles/chemistry , Particle Size , Permeability , Protein Binding , Solubility , Spike Glycoprotein, Coronavirus/metabolism , Viral Envelope/drug effects
14.
PLoS One ; 16(1): e0244626, 2021.
Article in English | MEDLINE | ID: covidwho-1028715

ABSTRACT

BACKGROUND: Face coverings constitute an important strategy for containing pandemics, such as COVID-19. Infection from airborne respiratory viruses including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) can occur in at least three modes; tiny and/or dried aerosols (typically < 1.0 µm) generated through multiple mechanisms including talking, breathing, singing, large droplets (> 0.5 µm) generated during coughing and sneezing, and macro drops transmitted via fomites. While there is a growing number of studies looking at the performance of household materials against some of these situations, to date, there has not been any systematic characterization of household materials against all three modes. METHODS: A three-step methodology was developed and used to characterize the performance of 21 different household materials with various material compositions (e.g. cotton, polyester, polypropylene, cellulose and blends) using submicron sodium chloride aerosols, water droplets, and mucous mimicking macro droplets over an aerosol-droplet size range of ~ 20 nm to 0.6 cm. RESULTS: Except for one thousand-thread-count cotton, most single-layered materials had filtration efficiencies < 20% for sub-micron solid aerosols. However, several of these materials stopped > 80% of larger droplets, even at sneeze-velocities of up to 1700 cm/s. Three or four layers of the same material, or combination materials, would be required to stop macro droplets from permeating out or into the face covering. Such materials can also be boiled for reuse. CONCLUSION: Four layers of loosely knit or woven fabrics independent of the composition (e.g. cotton, polyester, nylon or blends) are likely to be effective source controls. One layer of tightly woven fabrics combined with multiple layers of loosely knit or woven fabrics in addition to being source controls can have sub-micron filtration efficiencies > 40% and may offer some protection to the wearer. However, the pressure drop across such fabrics can be high (> 100 Pa).


Subject(s)
Face , Masks , Textiles , Materials Testing , Permeability
15.
Cell Mol Life Sci ; 77(22): 4725-4727, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-749426

ABSTRACT

P53 is a tumor suppressor protein, associated with strong anti-inflammatory activities. Recent evidence suggest that this transcription factor counteracts lung inflammatory diseases, including the lethal acute respiratory distress syndrome. Herein we provide a brief discussion on the relevant topic.


Subject(s)
Respiratory Distress Syndrome/metabolism , Tumor Suppressor Protein p53/metabolism , Cytokines/metabolism , Endothelium/metabolism , Humans , Inflammation/metabolism , Lung/metabolism , Permeability
16.
PLoS One ; 15(12): e0242536, 2020.
Article in English | MEDLINE | ID: covidwho-965821

ABSTRACT

Retinoic acid (RA) has been shown to improve epithelial and endothelial barrier function and development and even suppress damage inflicted by inflammation on these barriers through regulating immune cell activity. This paper thus sought to determine whether RA could improve baseline barrier function and attenuate TNF-α-induced barrier leak in the human bronchial epithelial cell culture model, 16HBE14o- (16HBE). We show for the first time that RA increases baseline barrier function of these cell layers indicated by an 89% increase in transepithelial electrical resistance (TER) and 22% decrease in 14C-mannitol flux. A simultaneous, RA-induced 70% increase in claudin-4 attests to RA affecting the tight junctional (TJ) complex itself. RA was also effective in alleviating TNF-α-induced 16HBE barrier leak, attenuating 60% of the TNF-α-induced leak to 14C-mannitol and 80% of the leak to 14C-inulin. Interleukin-6-induced barrier leak was also reduced by RA. Treatment of 16HBE cell layers with TNF-α resulted in dramatic decrease in immunostaining for occludin and claudin-4, as well as a downward "band-shift" in occludin Western immunoblots. The presence of RA partially reversed TNF-α's effects on these select TJ proteins. Lastly, RA completely abrogated the TNF-α-induced increase in ERK-1,2 phosphorylation without significantly decreasing the TNF-driven increase in total ERK-1,2. This study suggests RA could be effective as a prophylactic agent in minimizing airway barrier leak and as a therapeutic in preventing leak triggered by inflammatory cascades. Given the growing literature suggesting a "cytokine storm" may be related to COVID-19 morbidity, RA may be a useful adjuvant for use with anti-viral therapies.


Subject(s)
Bronchi/drug effects , Respiratory Mucosa/drug effects , Tretinoin/pharmacology , Tumor Necrosis Factor-alpha/metabolism , Anti-Inflammatory Agents/pharmacology , Bronchi/cytology , Bronchi/metabolism , Cell Line , Humans , Inflammation/drug therapy , Inflammation/metabolism , Permeability/drug effects , Respiratory Mucosa/cytology , Respiratory Mucosa/metabolism , Tight Junctions/drug effects , Tight Junctions/metabolism
17.
J Phys Chem B ; 124(46): 10374-10385, 2020 11 19.
Article in English | MEDLINE | ID: covidwho-919399

ABSTRACT

Atomistic molecular dynamics simulations have been carried out with a view to investigating the stability of the SARS-CoV-2 exterior membrane with respect to two common disinfectants, namely, aqueous solutions of ethanol and n-propanol. We used dipalmitoylphosphatidylcholine (DPPC) as a model membrane material and did simulations on both gel and liquid crystalline phases of membrane surrounded by aqueous solutions of varying alcohol concentrations (up to 17.5 mol %). While a moderate effect of alcohol on the gel phase of membrane is observed, its liquid crystalline phase is shown to be influenced dramatically by either alcohol. Our results show that aqueous solutions of only 5 and 10 mol % alcohol already have significant weakening effects on the membrane. The effects of n-propanol are always stronger than those of ethanol. The membrane changes its structure, when exposed to disinfectant solutions; uptake of alcohol causes it to swell laterally but to shrink vertically. At the same time, the orientational order of lipid tails decreases significantly. Metadynamics and grand-canonical ensemble simulations were done to calculate the free-energy profiles for permeation of alcohol and alcohol/water solubility in the DPPC. We found that the free-energy barrier to permeation of the DPPC liquid crystalline phase by all permeants is significantly lowered by alcohol uptake. At a disinfectant concentration of 10 mol %, it becomes insignificant enough to allow almost free passage of the disinfectant to the inside of the virus to cause damage there. It should be noted that the disinfectant also causes the barrier for water permeation to drop. Furthermore, the shrinking of the membrane thickness shortens the gap needed to be crossed by penetrants from outside the virus into its core. The lateral swelling also increases the average distance between head groups, which is a secondary barrier to membrane penetration, and hence further increases the penetration by disinfectants. At alcohol concentrations in the disinfectant solution above 15 mol %, we reliably observe disintegration of the DPPC membrane in its liquid crystalline phase.


Subject(s)
1-Propanol/chemistry , Disinfectants/chemistry , Ethanol/chemistry , Lipid Bilayers/chemistry , Membrane Fluidity/drug effects , Permeability/drug effects , 1,2-Dipalmitoylphosphatidylcholine/chemistry , Molecular Dynamics Simulation , SARS-CoV-2/chemistry , Viral Envelope/drug effects
18.
Med Hypotheses ; 145: 110307, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-850291

ABSTRACT

Severe acute respiratory syndrome corona virus 2(SARS-CoV-2), the cause of coronavirus disease- 2019 (COVID-19) after emerging in china in late 2019 is spreading rapidly across the world. The most common cause of death in patient with COVID-19 is the rapid progression of acute respiratory distress syndrome (ARDS) shortly after the beginning of dyspnea and hypoxemia. Patients with severe COVID-19 may also develop acute cardiac, kidney and liver injury that are associated with poor prognosis and can lead to high mortality rate. Numerous randomized trials are ongoing to find an effective, safe and widely available treatment. Remdisivir is the only FDA -approved antiviral agent for treatment of severe COVID-19. Glucocorticoids (GCs) have been used for treatment of cytokine storm syndrome and respiratory failure in hospitalized patient with severe covid-19. One of the therapeutic effects of GCs is stability of vascular endothelial barrier and decreasing tissue edema. In our opinion, the decreasing vascular permeability effect of glucocorticoids in the injured myocardium might has an important additional factor in reducing mortality in severe, hospitalized COVID-19 patients.


Subject(s)
COVID-19/complications , COVID-19/drug therapy , Dexamethasone/therapeutic use , Edema/complications , Myocardium/pathology , Antiviral Agents/therapeutic use , Capillary Permeability , China/epidemiology , Edema/diagnosis , Fibrosis , Glucocorticoids/therapeutic use , Hospitalization , Humans , Inflammation , Permeability
19.
Dig Liver Dis ; 52(12): 1383-1389, 2020 12.
Article in English | MEDLINE | ID: covidwho-834313

ABSTRACT

The microbiota-gut-liver-lung axis plays a bidirectional role in the pathophysiology of a number of infectious diseases. During the course of severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and 2 (SARS-CoV-2) infection, this pathway is unbalanced due to intestinal involvement and systemic inflammatory response. Moreover, there is convincing preliminary evidence linking microbiota-gut-liver axis perturbations, proinflammatory status, and endothelial damage in noncommunicable preventable diseases with coronavirus disease 2019 (Covid-19) severity. Intestinal damage due to SARS-CoV-2 infection, systemic inflammation-induced dysfunction, and IL-6-mediated diffuse vascular damage may increase intestinal permeability and precipitate bacterial translocation. The systemic release of damage- and pathogen-associated molecular patterns (e.g. lipopolysaccharides) and consequent immune-activation may in turn auto-fuel vicious cycles of systemic inflammation and tissue damage. Thus, intestinal bacterial translocation may play an additive/synergistic role in the cytokine release syndrome in Covid-19. This review provides evidence on gut-liver axis involvement in Covid-19 as well as insights into the hypothesis that intestinal endotheliitis and permeability changes with bacterial translocation are key pathophysiologic events modulating systemic inflammatory response. Moreover, it presents an overview of readily applicable measures for the modulation of the gut-liver axis and microbiota in clinical practice.


Subject(s)
Bacterial Translocation/immunology , COVID-19/immunology , Cytokine Release Syndrome/immunology , Gastrointestinal Microbiome/immunology , Intestinal Mucosa/metabolism , Lipopolysaccharides/metabolism , Liver/metabolism , Permeability , Alarmins/immunology , Alarmins/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Cytokine Release Syndrome/metabolism , Disease Progression , Humans , Immunity/immunology , Inflammation , Interleukin-6/immunology , Lipopolysaccharides/immunology , Liver/immunology , Lung/immunology , Lung/metabolism , Microbiota/immunology , Pathogen-Associated Molecular Pattern Molecules/immunology , Pathogen-Associated Molecular Pattern Molecules/metabolism , SARS-CoV-2/metabolism , Serine Endopeptidases/metabolism
20.
Nano Lett ; 20(10): 7642-7647, 2020 10 14.
Article in English | MEDLINE | ID: covidwho-801587

ABSTRACT

Shortages in the availability of personal protective face masks during the COVID-19 pandemic required many to fabricate masks and filter inserts from available materials. While the base filtration efficiency of a material is of primary importance when a perfect seal is possible, ideal fit is not likely to be achieved by the average person preparing to enter a public space or even a healthcare worker without fit-testing before each shift. Our findings suggest that parameters including permeability and pliability can play a strong role in the filtration efficiency of a mask fabricated with various filter media, and that the filtration efficiency of loosely fitting masks/respirators against ultrafine particulates can drop by more than 60% when worn compared to the ideal filtration efficiency of the base material. Further, a test method using SARS-CoV-2 virion-sized silica nanoaerosols is demonstrated to assess the filtration efficiency against nanoparticulates that follow air currents associated with mask leakage.


Subject(s)
Betacoronavirus , Coronavirus Infections/prevention & control , Filtration/instrumentation , Masks , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Respiratory Protective Devices , Textiles , Aerosols , Air Microbiology , Betacoronavirus/ultrastructure , COVID-19 , Coronavirus Infections/transmission , Coronavirus Infections/virology , Cotton Fiber , Filtration/statistics & numerical data , Humans , Inhalation Exposure , Nanoparticles , Particle Size , Permeability , Pneumonia, Viral/transmission , Pneumonia, Viral/virology , SARS-CoV-2 , Silicon Dioxide
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