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2.
Mol Ther ; 30(5): 1952-1965, 2022 May 04.
Article in English | MEDLINE | ID: covidwho-1783847

ABSTRACT

For coronavirus disease 2019 (COVID-19), effective and well-understood treatment options are still scarce. Since vaccine efficacy is challenged by novel variants, short-lasting immunity, and vaccine hesitancy, understanding and optimizing therapeutic options remains essential. We aimed at better understanding the effects of two standard-of-care drugs, dexamethasone and anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies, on infection and host responses. By using two COVID-19 hamster models, pulmonary immune responses were analyzed to characterize effects of single or combinatorial treatments. Pulmonary viral burden was reduced by anti-SARS-CoV-2 antibody treatment and unaltered or increased by dexamethasone alone. Dexamethasone exhibited strong anti-inflammatory effects and prevented fulminant disease in a severe disease model. Combination therapy showed additive benefits with both anti-viral and anti-inflammatory potency. Bulk and single-cell transcriptomic analyses confirmed dampened inflammatory cell recruitment into lungs upon dexamethasone treatment and identified a specifically responsive subpopulation of neutrophils, thereby indicating a potential mechanism of action. Our analyses confirm the anti-inflammatory properties of dexamethasone and suggest possible mechanisms, validate anti-viral effects of anti-SARS-CoV-2 antibody treatment, and reveal synergistic effects of a combination therapy, thus informing more effective COVID-19 therapies.


Subject(s)
COVID-19 , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antibodies, Viral , Antiviral Agents , COVID-19/drug therapy , Cricetinae , Dexamethasone/pharmacology , SARS-CoV-2 , Transcriptome
4.
Am J Physiol Lung Cell Mol Physiol ; 322(1): L176-L177, 2022 01 01.
Article in English | MEDLINE | ID: covidwho-1723939

Subject(s)
Hemoglobins , Oxygen
5.
Am J Physiol Lung Cell Mol Physiol ; 321(3): L638-L639, 2021 09 01.
Article in English | MEDLINE | ID: covidwho-1611089

Subject(s)
Nitric Oxide
6.
Blood Adv ; 6(3): 1074-1087, 2022 02 08.
Article in English | MEDLINE | ID: covidwho-1551193

ABSTRACT

The high incidence of thrombotic events suggests a possible role of the contact system pathway in COVID-19 pathology. In this study, we determined the altered levels of factor XII (FXII) and its activation products in critically ill patients with COVID-19 in comparison with patients with severe acute respiratory distress syndrome related to the influenza virus (acute respiratory distress syndrome [ARDS]-influenza). Compatible with those data, we found rapid consumption of FXII in COVID-19 but not in ARDS-influenza plasma. Interestingly, the lag phase in fibrin formation, triggered by the FXII activator kaolin, was not prolonged in COVID-19, as opposed to that in ARDS-influenza. Confocal and electron microscopy showed that increased FXII activation rate, in conjunction with elevated fibrinogen levels, triggered formation of fibrinolysis-resistant, compact clots with thin fibers and small pores in COVID-19. Accordingly, clot lysis was markedly impaired in COVID-19 as opposed to that in ARDS-influenza. Dysregulated fibrinolytic system, as evidenced by elevated levels of thrombin-activatable fibrinolysis inhibitor, tissue-plasminogen activator, and plasminogen activator inhibitor-1 in COVID-19 potentiated this effect. Analysis of lung tissue sections revealed widespread extra- and intravascular compact fibrin deposits in patients with COVID-19. A compact fibrin network structure and dysregulated fibrinolysis may collectively contribute to a high incidence of thrombotic events in COVID-19.


Subject(s)
COVID-19 , Thrombosis , Fibrin , Fibrinolysis , Humans , SARS-CoV-2 , Thrombosis/etiology
7.
iScience ; 24(9): 103030, 2021 Sep 24.
Article in English | MEDLINE | ID: covidwho-1370553

ABSTRACT

Understanding host cell heterogeneity is critical for unraveling disease mechanism. Utilizing large-scale single-cell transcriptomics, we analyzed multiple tissue specimens from patients with life-threatening COVID-19 pneumonia, compared with healthy controls. We identified a subtype of monocyte-derived alveolar macrophages (MoAMs) where genes associated with severe COVID-19 comorbidities are significantly upregulated in bronchoalveolar lavage fluid of critical cases. FCGR3B consistently demarcated MoAM subset in different samples from severe COVID-19 cohorts and in CCL3L1-upregulated cells from nasopharyngeal swabs. In silico findings were validated by upregulation of FCGR3B in nasopharyngeal swabs of severe ICU COVID-19 cases, particularly in older patients and those with comorbidities. Additional lines of evidence from transcriptomic data and in vivo of severe COVID-19 cases suggest that FCGR3B may identify a specific subtype of MoAM in patients with severe COVID-19 that may present a novel biomarker for screening and prognosis, as well as a potential therapeutic target.

8.
Cells ; 10(7)2021 07 01.
Article in English | MEDLINE | ID: covidwho-1323124

ABSTRACT

Activation of Transient Receptor Potential (TRP) channels can disrupt endothelial barrier function, as their mediated Ca2+ influx activates the CaM (calmodulin)/MLCK (myosin light chain kinase)-signaling pathway, and thereby rearranges the cytoskeleton, increases endothelial permeability and thus can facilitate activation of inflammatory cells and formation of pulmonary edema. Interestingly, TRP channel subunits can build heterotetramers, whereas heteromeric TRPC1/4, TRPC3/6 and TRPV1/4 are expressed in the lung endothelium and could be targeted as a protective strategy to reduce endothelial permeability in pulmonary inflammation. An update on TRP heteromers and their role in lung inflammation will be provided with this review.


Subject(s)
Pneumonia/metabolism , Protein Multimerization , Transient Receptor Potential Channels/metabolism , Animals , Endothelial Cells/metabolism , Endothelial Cells/pathology , Humans , Ion Channel Gating , Models, Biological , Pneumonia/pathology , Pneumonia/physiopathology
9.
Int J Mol Sci ; 22(8)2021 Apr 08.
Article in English | MEDLINE | ID: covidwho-1299441

ABSTRACT

Pneumonia due to respiratory infection with most prominently bacteria, but also viruses, fungi, or parasites is the leading cause of death worldwide among all infectious disease in both adults and infants. The introduction of modern antibiotic treatment regimens and vaccine strategies has helped to lower the burden of bacterial pneumonia, yet due to the unavailability or refusal of vaccines and antimicrobials in parts of the global population, the rise of multidrug resistant pathogens, and high fatality rates even in patients treated with appropriate antibiotics pneumonia remains a global threat. As such, a better understanding of pathogen virulence on the one, and the development of innovative vaccine strategies on the other hand are once again in dire need in the perennial fight of men against microbes. Recent data show that the secretome of bacteria consists not only of soluble mediators of virulence but also to a significant proportion of extracellular vesicles-lipid bilayer-delimited particles that form integral mediators of intercellular communication. Extracellular vesicles are released from cells of all kinds of organisms, including both Gram-negative and Gram-positive bacteria in which case they are commonly termed outer membrane vesicles (OMVs) and membrane vesicles (MVs), respectively. (O)MVs can trigger inflammatory responses to specific pathogens including S. pneumonia, P. aeruginosa, and L. pneumophila and as such, mediate bacterial virulence in pneumonia by challenging the host respiratory epithelium and cellular and humoral immunity. In parallel, however, (O)MVs have recently emerged as auspicious vaccine candidates due to their natural antigenicity and favorable biochemical properties. First studies highlight the efficacy of such vaccines in animal models exposed to (O)MVs from B. pertussis, S. pneumoniae, A. baumannii, and K. pneumoniae. An advanced and balanced recognition of both the detrimental effects of (O)MVs and their immunogenic potential could pave the way to novel treatment strategies in pneumonia and effective preventive approaches.


Subject(s)
Bacteria/metabolism , Bacterial Outer Membrane/metabolism , Extracellular Vesicles/metabolism , Pneumonia, Bacterial/microbiology , Adaptive Immunity , Animals , Antigens, Bacterial/immunology , Bacteria/immunology , Bacterial Outer Membrane/immunology , Bacterial Vaccines/immunology , Host-Pathogen Interactions/immunology , Humans , Pneumonia, Bacterial/immunology , Pneumonia, Bacterial/prevention & control , Respiratory Mucosa/immunology , Respiratory Mucosa/microbiology , Respiratory Tract Infections/immunology , Respiratory Tract Infections/microbiology , Respiratory Tract Infections/prevention & control , Virulence
10.
Am J Physiol Lung Cell Mol Physiol ; 321(1): L287-L289, 2021 07 01.
Article in English | MEDLINE | ID: covidwho-1299248
11.
Sci Rep ; 11(1): 10678, 2021 05 21.
Article in English | MEDLINE | ID: covidwho-1238016

ABSTRACT

With an urgent need for bedside imaging of coronavirus disease 2019 (COVID-19), this study's main goal was to assess inter- and intraobserver agreement in lung ultrasound (LUS) of COVID-19 patients. In this single-center study we prospectively acquired and evaluated 100 recorded ten-second cine-loops in confirmed COVID-19 intensive care unit (ICU) patients. All loops were rated by ten observers with different subspeciality backgrounds for four times by each observer (400 loops overall) in a random sequence using a web-based rating tool. We analyzed inter- and intraobserver variability for specific pathologies and a semiquantitative LUS score. Interobserver agreement for both, identification of specific pathologies and assignment of LUS scores was fair to moderate (e.g., LUS score 1 Fleiss' κ = 0.27; subpleural consolidations Fleiss' κ = 0.59). Intraobserver agreement was mostly moderate to substantial with generally higher agreement for more distinct findings (e.g., lowest LUS score 0 vs. highest LUS score 3 (median Fleiss' κ = 0.71 vs. 0.79) or air bronchograms (median Fleiss' κ = 0.72)). Intraobserver consistency was relatively low for intermediate LUS scores (e.g. LUS Score 1 median Fleiss' κ = 0.52). We therefore conclude that more distinct LUS findings (e.g., air bronchograms, subpleural consolidations) may be more suitable for disease monitoring, especially with more than one investigator and that training material used for LUS in point-of-care ultrasound (POCUS) should pay refined attention to areas such as B-line quantification and differentiation of intermediate LUS scores.


Subject(s)
COVID-19/diagnostic imaging , Lung/diagnostic imaging , Point-of-Care Systems , SARS-CoV-2 , COVID-19/therapy , Female , Humans , Male , Middle Aged , Monitoring, Physiologic , Observer Variation , Prospective Studies , Ultrasonography
12.
Am J Physiol Lung Cell Mol Physiol ; 321(2): L349-L357, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1225725

ABSTRACT

COVID-19 hinders oxygen transport to the consuming tissues by at least two mechanisms: In the injured lung, saturation of hemoglobin is compromised, and in the tissues, an associated anemia reduces the volume of delivered oxygen. For the first problem, increased hemoglobin oxygen affinity [left shift of the oxygen dissociation curve (ODC)] is of advantage, for the second, however, the contrary is the case. Indeed a right shift of the ODC has been found in former studies for anemia caused by reduced cell production or hemolysis. This resulted from increased 2,3-bisphosphoglycerate (2,3-BPG) concentration. In three investigations in COVID-19, however, no change of hemoglobin affinity was detected in spite of probably high [2,3-BPG]. The most plausible cause for this finding is formation of methemoglobin (MetHb), which increases the oxygen affinity and thus apparently compensates for the 2,3-BPG effect. However, this "useful effect" is cancelled by the concomitant reduction of functional hemoglobin. In the largest study on COVID-19, even a clear left shift of the ODC was detected when calculated from measurements in fresh blood rather than after equilibration with gases outside the body. This additional "in vivo" left shift possibly results from various factors, e.g., concentration changes of Cl-, 2,3-BPG, ATP, lactate, nitrocompounds, glutathione, glutamate, because of time delay between blood sampling and end of equilibration, or enlarged distribution space including interstitial fluid and is useful for O2 uptake in the lungs. Under discussion for therapy are the affinity-increasing 5-hydroxymethyl-2-furfural (5-HMF), erythropoiesis-stimulating substances like erythropoietin, and methylene blue against MetHb formation.


Subject(s)
COVID-19/blood , Hemoglobins/analysis , Oxygen/blood , SARS-CoV-2/isolation & purification , Biological Transport , COVID-19/epidemiology , COVID-19/virology , Humans
13.
Eur Respir J ; 57(1)2021 01.
Article in English | MEDLINE | ID: covidwho-1041881

ABSTRACT

Epidemiological data from the SARS-CoV-2 outbreak suggest sex differences in mortality and vulnerability; however, sex-dependent incidence of acute respiratory distress syndrome (ARDS) remains controversial and the sex-dependent mechanisms of endothelial barrier regulation are unknown. In premenopausal women, increased signalling of angiotensin (Ang)(1-7) via the Mas receptor has been linked to lower cardiovascular risk. Since stimulation of the Ang(1-7)/Mas axis protects the endothelial barrier in acute lung injury (ALI), we hypothesised that increased Ang(1-7)/Mas signalling may protect females over males in ALI/ARDS.Clinical data were collected from Charité inpatients (Berlin) and sex differences in ALI were assessed in wild-type (WT) and Mas-receptor deficient (Mas-/- ) mice. Endothelial permeability was assessed as weight change in isolated lungs and as transendothelial electrical resistance (TEER) in vitroIn 734 090 Charité inpatients (2005-2016), ARDS had a higher incidence in men as compared to women. In murine ALI, male WT mice had more lung oedema, protein leaks and histological evidence of injury than female WT mice. Lung weight change in response to platelet-activating factor (PAF) was more pronounced in male WT and female Mas-/- mice than in female WT mice, whereas Mas-receptor expression was higher in female WT lungs. Ovariectomy attenuated protection in female WT mice and reduced Mas-receptor expression. Oestrogen increased Mas-receptor expression and attenuated endothelial leakage in response to thrombin in vitro This effect was alleviated by Mas-receptor blockade.Improved lung endothelial barrier function protects female mice from ALI-induced lung oedema. This effect is partially mediated via enhanced Ang(1-7)/Mas signalling as a result of oestrogen-dependent Mas expression.


Subject(s)
Acute Lung Injury/genetics , Angiotensin I/metabolism , COVID-19/epidemiology , Capillary Permeability/genetics , Endothelium, Vascular/metabolism , Estrogens/metabolism , Lung/metabolism , Peptide Fragments/metabolism , Proto-Oncogene Proteins/genetics , Receptors, G-Protein-Coupled/genetics , Respiratory Distress Syndrome/epidemiology , Acute Lung Injury/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Angiotensin I/pharmacology , Angiotensin-Converting Enzyme 2 , Animals , Capillary Permeability/drug effects , Child , Electric Impedance , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Estradiol/pharmacology , Female , Humans , In Vitro Techniques , Lung/drug effects , Male , Mice , Mice, Knockout , Middle Aged , Ovariectomy , Peptide Fragments/pharmacology , Platelet Activating Factor/pharmacology , Proto-Oncogene Proteins/metabolism , Receptors, G-Protein-Coupled/metabolism , SARS-CoV-2 , Sex Distribution , Sex Factors , Up-Regulation , Young Adult
14.
Am J Physiol Lung Cell Mol Physiol ; 320(3): L430-L435, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-1024271

ABSTRACT

The tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a virus responsible for the ongoing coronavirus disease 2019 (COVID-19) pandemic, toward the host cells is determined, at least in part, by the expression and distribution of its cell surface receptor, angiotensin-converting enzyme 2 (ACE2). The virus further exploits the host cellular machinery to gain access into the cells; its spike protein is cleaved by a host cell surface transmembrane serine protease 2 (TMPRSS2) shortly after binding ACE2, followed by its proteolytic activation at a furin cleavage site. The virus primarily targets the epithelium of the respiratory tract, which is covered by a tightly regulated airway surface liquid (ASL) layer that serves as a primary defense mechanism against respiratory pathogens. The volume and viscosity of this fluid layer is regulated and maintained by a coordinated function of different transport pathways in the respiratory epithelium. We argue that SARS-CoV-2 may potentially alter evolutionary conserved second-messenger signaling cascades via activation of G protein-coupled receptors (GPCRs) or by directly modulating G protein signaling. Such signaling may in turn adversely modulate transepithelial transport processes, especially those involving cystic fibrosis transmembrane conductance regulator (CFTR) and epithelial Na+ channel (ENaC), thereby shifting the delicate balance between anion secretion and sodium absorption, which controls homeostasis of this fluid layer. As a result, activation of the secretory pathways including CFTR-mediated Cl- transport may overwhelm the absorptive pathways, such as ENaC-dependent Na+ uptake, and initiate a pathophysiological cascade leading to lung edema, one of the most serious and potentially deadly clinical manifestations of COVID-19.


Subject(s)
COVID-19/pathology , Lung/physiopathology , Receptors, G-Protein-Coupled/metabolism , SARS-CoV-2/isolation & purification , Biological Transport , COVID-19/metabolism , COVID-19/virology , Humans , Lung/virology , Signal Transduction
16.
EClinicalMedicine ; 28: 100579, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-845228

ABSTRACT

BACKGROUND: In face of the Coronavirus Disease (COVID)-19 pandemic, best practice for mechanical ventilation in COVID-19 associated Acute Respiratory Distress Syndrome (ARDS) is intensely debated. Specifically, the rationale for high positive end-expiratory pressure (PEEP) and prone positioning in early COVID-19 ARDS has been questioned. METHODS: The first 23 consecutive patients with COVID-19 associated respiratory failure transferred to a single ICU were assessed. Eight were excluded: five were not invasively ventilated and three received veno-venous ECMO support. The remaining 15 were assessed over the first 15 days of mechanical ventilation. Best PEEP was defined by maximal oxygenation and was determined by structured decremental PEEP trials comprising the monitoring of oxygenation, airway pressures and trans-pulmonary pressures. In nine patients the impact of prone positioning on oxygenation was investigated. Additionally, the effects of high PEEP and prone positioning on pulmonary opacities in serial chest x-rays were determined by applying a semiquantitative scoring-system. This investigation is part of the prospective observational PA-COVID-19 study. FINDINGS: Patients responded to initiation of invasive high PEEP ventilation with markedly improved oxygenation, which was accompanied by reduced pulmonary opacities within 6 h of mechanical ventilation. Decremental PEEP trials confirmed the need for high PEEP (17.9 (SD ± 3.9) mbar) for optimal oxygenation, while driving pressures remained low. Prone positioning substantially increased oxygenation (p<0.01). INTERPRETATION: In early COVID-19 ARDS, substantial PEEP values were required for optimizing oxygenation. Pulmonary opacities resolved during mechanical ventilation with high PEEP suggesting recruitment of lung volume. FUNDING: German Research Foundation, German Federal Ministry of Education and Research.

17.
Am J Physiol Lung Cell Mol Physiol ; 319(5): L863-L866, 2020 11 01.
Article in English | MEDLINE | ID: covidwho-808658
18.
Cell Syst ; 11(1): 11-24.e4, 2020 07 22.
Article in English | MEDLINE | ID: covidwho-459007

ABSTRACT

The COVID-19 pandemic is an unprecedented global challenge, and point-of-care diagnostic classifiers are urgently required. Here, we present a platform for ultra-high-throughput serum and plasma proteomics that builds on ISO13485 standardization to facilitate simple implementation in regulated clinical laboratories. Our low-cost workflow handles up to 180 samples per day, enables high precision quantification, and reduces batch effects for large-scale and longitudinal studies. We use our platform on samples collected from a cohort of early hospitalized cases of the SARS-CoV-2 pandemic and identify 27 potential biomarkers that are differentially expressed depending on the WHO severity grade of COVID-19. They include complement factors, the coagulation system, inflammation modulators, and pro-inflammatory factors upstream and downstream of interleukin 6. All protocols and software for implementing our approach are freely available. In total, this work supports the development of routine proteomic assays to aid clinical decision making and generate hypotheses about potential COVID-19 therapeutic targets.


Subject(s)
Blood Proteins/metabolism , Coronavirus Infections/blood , Pneumonia, Viral/blood , Proteomics/methods , Adult , Aged , Aged, 80 and over , Betacoronavirus/isolation & purification , Biomarkers/blood , Blood Proteins/analysis , COVID-19 , Coronavirus Infections/classification , Coronavirus Infections/pathology , Coronavirus Infections/virology , Female , Humans , Male , Middle Aged , Pandemics/classification , Pneumonia, Viral/classification , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2 , Young Adult
19.
Am J Physiol Lung Cell Mol Physiol ; 318(6): L1239-L1243, 2020 06 01.
Article in English | MEDLINE | ID: covidwho-246452

ABSTRACT

Lethality of coronavirus disease (COVID-19) during the 2020 pandemic, currently still in the exponentially accelerating phase in most countries, is critically driven by disruption of the alveolo-capillary barrier of the lung, leading to lung edema as a direct consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We argue for inhibition of the transient receptor potential vanilloid 4 (TRPV4) calcium-permeable ion channel as a strategy to address this issue, based on the rationale that TRPV4 inhibition is protective in various preclinical models of lung edema and that TRPV4 hyperactivation potently damages the alveolo-capillary barrier, with lethal outcome. We believe that TRPV4 inhibition has a powerful prospect at protecting this vital barrier in COVID-19 patients, even to rescue a damaged barrier. A clinical trial using a selective TRPV4 inhibitor demonstrated a benign safety profile in healthy volunteers and in patients suffering from cardiogenic lung edema. We argue for expeditious clinical testing of this inhibitor in COVID-19 patients with respiratory malfunction and at risk for lung edema. Perplexingly, among the currently pursued therapeutic strategies against COVID-19, none is designed to directly protect the alveolo-capillary barrier. Successful protection of the alveolo-capillary barrier will not only reduce COVID-19 lethality but will also preempt a distressing healthcare scenario with insufficient capacity to provide ventilator-assisted respiration.


Subject(s)
Betacoronavirus , Coronavirus Infections , Lung/virology , Pandemics , Pneumonia, Viral , Pulmonary Edema/prevention & control , TRPV Cation Channels/antagonists & inhibitors , COVID-19 , Calcium/metabolism , Coronavirus Infections/virology , Humans , Lung/metabolism , Pneumonia, Viral/virology , Pulmonary Edema/virology , Respiration, Artificial , SARS-CoV-2
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