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1.
J Allergy Clin Immunol ; 147(1): 81-91, 2021 01.
Article in English | MEDLINE | ID: covidwho-2095538

ABSTRACT

BACKGROUND: Severe immunopathology may drive the deleterious manifestations that are observed in the advanced stages of coronavirus disease 2019 (COVID-19) but are poorly understood. OBJECTIVE: Our aim was to phenotype leukocyte subpopulations and the cytokine milieu in the lungs and blood of critically ill patients with COVID-19 acute respiratory distress syndrome (ARDS). METHODS: We consecutively included patients less than 72 hours after intubation following informed consent from their next of kin. Bronchoalveolar lavage fluid was evaluated by microscopy; bronchoalveolar lavage fluid and blood were assessed by 10-color flow cytometry and a multiplex cytokine panel. RESULTS: Four mechanically ventilated patients (aged 40-75 years) with moderate-to-severe COVID-19 ARDS were included. Immature neutrophils dominated in both blood and lungs, whereas CD4 and CD8 T-cell lymphopenia was observed in the 2 compartments. However, regulatory T cells and TH17 cells were found in higher fractions in the lung. Lung CD4 and CD8 T cells and macrophages expressed an even higher upregulation of activation markers than in blood. A wide range of cytokines were expressed at high levels both in the blood and in the lungs, most notably, IL-1RA, IL-6, IL-8, IP-10, and monocyte chemoattactant protein-1, consistent with hyperinflammation. CONCLUSION: COVID-19 ARDS exhibits a distinct immunologic profile in the lungs, with a depleted and exhausted CD4 and CD8 T-cell population that resides within a heavily hyperinflammatory milieu.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Lung/immunology , Lymphopenia/immunology , Respiratory Distress Syndrome/immunology , SARS-CoV-2/immunology , Th17 Cells/immunology , Adult , Aged , CD8-Positive T-Lymphocytes/pathology , COVID-19/pathology , Cross-Sectional Studies , Cytokines/immunology , Female , Humans , Immunophenotyping , Lung/pathology , Lymphopenia/pathology , Male , Middle Aged , Respiratory Distress Syndrome/pathology , Th17 Cells/pathology
2.
Int J Mol Sci ; 23(3)2022 Feb 08.
Article in English | MEDLINE | ID: covidwho-1674674

ABSTRACT

Preventing the cytokine storm observed in COVID-19 is a crucial goal for reducing the occurrence of severe acute respiratory failure and improving outcomes. Here, we identify Aldo-Keto Reductase 1B10 (AKR1B10) as a key enzyme involved in the expression of pro-inflammatory cytokines. The analysis of transcriptomic data from lung samples of patients who died from COVID-19 demonstrates an increased expression of the gene encoding AKR1B10. Measurements of the AKR1B10 protein in sera from hospitalised COVID-19 patients suggests a significant link between AKR1B10 levels and the severity of the disease. In macrophages and lung cells, the over-expression of AKR1B10 induces the expression of the pro-inflammatory cytokines Interleukin-6 (IL-6), Interleukin-1ß (IL-1ß) and Tumor Necrosis Factor a (TNFα), supporting the biological plausibility of an AKR1B10 involvement in the COVID-19-related cytokine storm. When macrophages were stressed by lipopolysaccharides (LPS) exposure and treated by Zopolrestat, an AKR1B10 inhibitor, the LPS-induced production of IL-6, IL-1ß, and TNFα is significantly reduced, reinforcing the hypothesis that the pro-inflammatory expression of cytokines is AKR1B10-dependant. Finally, we also show that AKR1B10 can be secreted and transferred via extracellular vesicles between different cell types, suggesting that this protein may also contribute to the multi-organ systemic impact of COVID-19. These experiments highlight a relationship between AKR1B10 production and severe forms of COVID-19. Our data indicate that AKR1B10 participates in the activation of cytokines production and suggest that modulation of AKR1B10 activity might be an actionable pharmacological target in COVID-19 management.


Subject(s)
Aldo-Keto Reductases/physiology , COVID-19/genetics , Cytokine Release Syndrome/genetics , Respiratory Distress Syndrome/genetics , Aldo-Keto Reductases/antagonists & inhibitors , Aldo-Keto Reductases/genetics , Animals , COVID-19/complications , COVID-19/metabolism , COVID-19/pathology , Case-Control Studies , Cells, Cultured , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Cytokines/metabolism , Enzyme Inhibitors/pharmacology , Humans , Macrophages/drug effects , Macrophages/metabolism , Mice , Patient Acuity , RAW 264.7 Cells , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , SARS-CoV-2/physiology , Transcriptome
3.
Cell Rep Med ; 3(2): 100522, 2022 02 15.
Article in English | MEDLINE | ID: covidwho-1650891

ABSTRACT

The molecular mechanisms underlying the clinical manifestations of coronavirus disease 2019 (COVID-19), and what distinguishes them from common seasonal influenza virus and other lung injury states such as acute respiratory distress syndrome, remain poorly understood. To address these challenges, we combine transcriptional profiling of 646 clinical nasopharyngeal swabs and 39 patient autopsy tissues to define body-wide transcriptome changes in response to COVID-19. We then match these data with spatial protein and expression profiling across 357 tissue sections from 16 representative patient lung samples and identify tissue-compartment-specific damage wrought by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, evident as a function of varying viral loads during the clinical course of infection and tissue-type-specific expression states. Overall, our findings reveal a systemic disruption of canonical cellular and transcriptional pathways across all tissues, which can inform subsequent studies to combat the mortality of COVID-19 and to better understand the molecular dynamics of lethal SARS-CoV-2 and other respiratory infections.


Subject(s)
COVID-19/genetics , COVID-19/pathology , Lung/pathology , SARS-CoV-2 , Transcriptome/genetics , Adult , Aged , Aged, 80 and over , COVID-19/metabolism , COVID-19/virology , Case-Control Studies , Cohort Studies , Female , Gene Expression Regulation , Humans , Influenza, Human/genetics , Influenza, Human/pathology , Influenza, Human/virology , Lung/metabolism , Male , Middle Aged , Orthomyxoviridae , RNA-Seq/methods , Respiratory Distress Syndrome/genetics , Respiratory Distress Syndrome/microbiology , Respiratory Distress Syndrome/pathology , Viral Load
4.
Cells ; 11(2)2022 01 06.
Article in English | MEDLINE | ID: covidwho-1613628

ABSTRACT

Inflammatory lung injury is characterized by lung endothelial cell (LEC) death, alveolar epithelial cell (AEC) death, LEC-LEC junction weakening, and leukocyte infiltration, which together disrupt nutrient and oxygen transport. Subsequently, lung vascular repair is characterized by LEC and AEC regeneration and LEC-LEC junction re-annealing, which restores nutrient and oxygen delivery to the injured tissue. Pulmonary hypoxia is a characteristic feature of several inflammatory lung conditions, including acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and severe coronavirus disease 2019 (COVID-19). The vascular response to hypoxia is controlled primarily by the hypoxia-inducible transcription factors (HIFs) 1 and 2. These transcription factors control the expression of a wide variety of target genes, which in turn mediate key pathophysiological processes including cell survival, differentiation, migration, and proliferation. HIF signaling in pulmonary cell types such as LECs and AECs, as well as infiltrating leukocytes, tightly regulates inflammatory lung injury and repair, in a manner that is dependent upon HIF isoform, cell type, and injury stimulus. The aim of this review is to describe the HIF-dependent regulation of inflammatory lung injury and vascular repair. The review will also discuss potential areas for future study and highlight putative targets for inflammatory lung conditions such as ALI/ARDS and severe COVID-19. In the development of HIF-targeted therapies to reduce inflammatory lung injury and/or enhance pulmonary vascular repair, it will be vital to consider HIF isoform- and cell-specificity, off-target side-effects, and the timing and delivery strategy of the therapeutic intervention.


Subject(s)
Acute Lung Injury/metabolism , Basic Helix-Loop-Helix Transcription Factors/metabolism , COVID-19/metabolism , Hypoxia-Inducible Factor 1/metabolism , Lung/metabolism , Respiratory Distress Syndrome/metabolism , SARS-CoV-2/metabolism , Signal Transduction , Acute Lung Injury/pathology , COVID-19/pathology , Humans , Lung/pathology , Respiratory Distress Syndrome/pathology
5.
EBioMedicine ; 74: 103695, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1596202

ABSTRACT

BACKGROUND: The heterogeneity in symptomatology and phenotypic profile attributable to COVID-19 is widely unknown. The objective of this manuscript is to conduct a trans-ancestry genome wide association study (GWAS) meta-analysis of COVID-19 severity to improve the understanding of potentially causal targets for SARS-CoV-2. METHODS: This cross-sectional study recruited 646 participants in the UAE that were divided into two phenotypic groups based on the severity of COVID-19 phenotypes, hospitalized (n=482) and non-hospitalized (n=164) participants. Hospitalized participants were COVID-19 patients that developed acute respiratory distress syndrome (ARDS), pneumonia or progression to respiratory failure that required supplemental oxygen therapy or mechanical ventilation support or had severe complications such as septic shock or multi-organ failure. We conducted a trans-ancestry meta-analysis GWAS of European (n=302), American (n=102), South Asian (n=99), and East Asian (n=107) ancestry populations. We also carried out comprehensive post-GWAS analysis, including enrichment of SNP associations in tissues and cell-types, expression quantitative trait loci and differential expression analysis. FINDINGS: Eight genes demonstrated a strong association signal: VWA8 gene in locus 13p14·11 (SNP rs10507497; p=9·54 x10-7), PDE8B gene in locus 5q13·3 (SNP rs7715119; p=2·19 x10-6), CTSC gene in locus 11q14·2 (rs72953026; p=2·38 x10-6), THSD7B gene in locus 2q22·1 (rs7605851; p=3·07x10-6), STK39 gene in locus 2q24·3 (rs7595310; p=4·55 x10-6), FBXO34 gene in locus 14q22·3 (rs10140801; p=8·26 x10-6), RPL6P27 gene in locus 18p11·31 (rs11659676; p=8·88 x10-6), and METTL21C gene in locus 13q33·1 (rs599976; p=8·95 x10-6). The genes are expressed in the lung, associated to tumour progression, emphysema, airway obstruction, and surface tension within the lung, as well as an association to T-cell-mediated inflammation and the production of inflammatory cytokines. INTERPRETATION: We have discovered eight highly plausible genetic association with hospitalized cases in COVID-19. Further studies must be conducted on worldwide population genetics to facilitate the development of population specific therapeutics to mitigate this worldwide challenge. FUNDING: This review was commissioned as part of a project to study the host cell receptors of coronaviruses funded by Khalifa University's CPRA grant (Reference number 2020-004).


Subject(s)
Genetic Predisposition to Disease/genetics , Quantitative Trait Loci/genetics , Quantitative Trait, Heritable , Respiratory Distress Syndrome/genetics , Severity of Illness Index , Adolescent , Adult , Aged , COVID-19/mortality , COVID-19/pathology , Cross-Sectional Studies , Female , Genome-Wide Association Study , Hospitalization/statistics & numerical data , Humans , Inflammation/genetics , Lung/pathology , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Population Groups/genetics , Respiratory Distress Syndrome/pathology , SARS-CoV-2 , T-Lymphocytes/immunology , Treatment Outcome , United Arab Emirates , Young Adult
6.
JCI Insight ; 7(2)2022 01 25.
Article in English | MEDLINE | ID: covidwho-1575230

ABSTRACT

Acute respiratory distress syndrome (ARDS) is a life-threatening syndrome, constituted by respiratory failure and diffuse alveolar damage that results from dysregulated local and systemic immune activation, causing pulmonary vascular, parenchymal, and alveolar damage. SARS-CoV-2 infection has become the dominant cause of ARDS worldwide, and emerging evidence implicates neutrophils and their cytotoxic arsenal of effector functions as central drivers of immune-mediated lung injury in COVID-19 ARDS. However, key outstanding questions are whether COVID-19 drives a unique program of neutrophil activation or effector functions that contribute to the severe pathogenesis of this pandemic illness and whether this unique neutrophil response can be targeted to attenuate disease. Using a combination of high-dimensional single-cell analysis and ex vivo functional assays of neutrophils from patients with COVID-19 ARDS, compared with those with non-COVID ARDS (caused by bacterial pneumonia), we identified a functionally distinct landscape of neutrophil activation in COVID-19 ARDS that was intrinsically programmed during SARS-CoV-2 infection. Furthermore, neutrophils in COVID-19 ARDS were functionally primed to produce high amounts of neutrophil extracellular traps. Surprisingly, this unique pathological program of neutrophil priming escaped conventional therapy with dexamethasone, thereby revealing a promising target for adjunctive immunotherapy in severe COVID-19.


Subject(s)
COVID-19/immunology , Extracellular Traps/immunology , Neutrophil Activation , Neutrophils/immunology , Respiratory Distress Syndrome/immunology , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , COVID-19/pathology , Female , Humans , Male , Middle Aged , Neutrophils/pathology , Pneumonia, Bacterial/immunology , Pneumonia, Bacterial/pathology , Respiratory Distress Syndrome/pathology , Severity of Illness Index
7.
Int J Mol Sci ; 22(23)2021 Nov 27.
Article in English | MEDLINE | ID: covidwho-1560687

ABSTRACT

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe respiratory disorders that are caused by aspiration, sepsis, trauma, and pneumonia. A clinical feature of ALI/ARDS is the acute onset of severe hypoxemia, and the mortality rate, which is estimated at 38-50%, remains high. Although prostaglandins (PGs) are detected in the bronchoalveolar lavage fluid of patients with ALI/ARDS, the role of PGF2α in ALI remains unclear. We aimed to clarify the role of PGF2α/PGF2α receptor (FP) signaling in acid-induced ALI using an FP receptor antagonist, AL8810. Intratracheal injection of hydrochloric acid (HCl) increased neutrophil migration into the lungs, leading to respiratory dysfunction. Pre-administration of AL8810 further increased these features. Moreover, pre-treatment with AL8810 enhanced the HCl-induced expression of pro-inflammatory cytokines and neutrophil migratory factors in the lungs. Administration of HCl decreased the gene expression of lung surfactant proteins, which was further reduced by co-administration of AL8810. Administration of AL8810 also increased lung edema and reduced mRNA expression of epithelial sodium channel in the lungs, indicating that AL8810 reduced fluid clearance. Furthermore, AL8810 also increased lipopolysaccharide-induced expression of adhesion molecules such as intracellular adhesion molecule-1 and E-selectin in human umbilical vein endothelial cells. These results indicate that inhibition of FP receptors by AL8810 exacerbated HCl-induced ALI.


Subject(s)
Acute Lung Injury/metabolism , Lung/drug effects , Pneumonia/metabolism , Receptors, Prostaglandin/antagonists & inhibitors , Respiratory Distress Syndrome/metabolism , Acute Lung Injury/chemically induced , Acute Lung Injury/pathology , Animals , Disease Models, Animal , Female , Hydrochloric Acid/toxicity , Lung/metabolism , Lung/pathology , Mice , Mice, Inbred C57BL , Pneumonia/chemically induced , Pneumonia/immunology , Pneumonia/pathology , Prostaglandins F/metabolism , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/pathology
8.
Viral Immunol ; 34(10): 679-688, 2021 12.
Article in English | MEDLINE | ID: covidwho-1560640

ABSTRACT

The newfound coronavirus disease 2019 (COVID-19), initiated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an international public health concern, threatening the lives of millions of people worldwide. The virus seems to have a propensity to infect older males, especially those with underlying diseases. The cytokine storm following hyperactivated immune responses due to SARS-CoV-2 infection is probably the crucial source of severe pneumonia that leads to acute lung injury, systemic inflammatory response syndrome, or acute respiratory distress syndrome, and finally multiple organ dysfunction syndromes, as well as death in many cases. Several studies revealed that interleukin (IL)-1ß levels were elevated during COVID-19 infection. In addition, the IL-1 cytokine family has a pivotal role in the induction of cytokine storm due to uncontrolled immune responses in COVID-19 infection. This article reviews the role of IL-1 in inflammation and utilization of IL-1 inhibitor agents in controlling the inflammatory outcomes initiated by SARS-CoV-2 infection.


Subject(s)
COVID-19/drug therapy , COVID-19/immunology , Cytokine Release Syndrome/drug therapy , Interleukin-1/immunology , Acute Lung Injury/drug therapy , Acute Lung Injury/immunology , Acute Lung Injury/pathology , COVID-19/mortality , COVID-19/pathology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Humans , Interleukin-1/antagonists & inhibitors , Multiple Organ Failure/drug therapy , Multiple Organ Failure/immunology , Multiple Organ Failure/pathology , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/pathology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity
9.
Cell ; 184(26): 6243-6261.e27, 2021 12 22.
Article in English | MEDLINE | ID: covidwho-1536467

ABSTRACT

COVID-19-induced "acute respiratory distress syndrome" (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyze pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single-cell genomics, immunohistology, and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.


Subject(s)
COVID-19/pathology , COVID-19/virology , Idiopathic Pulmonary Fibrosis/pathology , Idiopathic Pulmonary Fibrosis/virology , Macrophages/pathology , Macrophages/virology , SARS-CoV-2/physiology , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , COVID-19/diagnostic imaging , Cell Communication , Cohort Studies , Fibroblasts/pathology , Gene Expression Regulation , Humans , Idiopathic Pulmonary Fibrosis/diagnostic imaging , Idiopathic Pulmonary Fibrosis/genetics , Mesenchymal Stem Cells/pathology , Phenotype , Proteome/metabolism , Receptors, Cell Surface/metabolism , Respiratory Distress Syndrome/diagnostic imaging , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , Tomography, X-Ray Computed , Transcription, Genetic
10.
Int J Mol Sci ; 22(22)2021 Nov 17.
Article in English | MEDLINE | ID: covidwho-1524026

ABSTRACT

The rapid mutation of the SARS-CoV-2 virus is now a major concern with no effective drugs and treatments. The severity of the disease is linked to the induction of a cytokine storm that promotes extensive inflammation in the lung, leading to many acute lung injuries, pulmonary edema, and eventually death. Mesenchymal stem cells (MSCs) might prove to be a treatment option as they have immunomodulation and regenerative properties. Clinical trials utilizing MSCs in treating acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) have provided a basis in treating post-COVID-19 patients. In this review, we discussed the effects of MSCs as an immunomodulator to reduce the severity and death in patients with COVID-19, including the usage of MSCs as an alternative regenerative therapy in post-COVID-19 patients. This review also includes the current clinical trials in utilizing MSCs and their potential future utilization for long-COVID treatments.


Subject(s)
COVID-19/complications , Immunomodulation/physiology , Mesenchymal Stem Cell Transplantation , Regeneration/physiology , COVID-19/pathology , COVID-19/therapy , COVID-19/virology , Humans , Lung/pathology , Lung/physiology , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/therapy , SARS-CoV-2/isolation & purification
11.
Nat Immunol ; 23(1): 62-74, 2022 01.
Article in English | MEDLINE | ID: covidwho-1514418

ABSTRACT

The molecular mechanisms governing orderly shutdown and retraction of CD4+ type 1 helper T (TH1) cell responses remain poorly understood. Here we show that complement triggers contraction of TH1 responses by inducing intrinsic expression of the vitamin D (VitD) receptor and the VitD-activating enzyme CYP27B1, permitting T cells to both activate and respond to VitD. VitD then initiated the transition from pro-inflammatory interferon-γ+ TH1 cells to suppressive interleukin-10+ cells. This process was primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating super-enhancers and recruiting several transcription factors, notably c-JUN, STAT3 and BACH2, which together with VitD receptor shaped the transcriptional response to VitD. Accordingly, VitD did not induce interleukin-10 expression in cells with dysfunctional BACH2 or STAT3. Bronchoalveolar lavage fluid CD4+ T cells of patients with COVID-19 were TH1-skewed and showed de-repression of genes downregulated by VitD, from either lack of substrate (VitD deficiency) and/or abnormal regulation of this system.


Subject(s)
Interferon-gamma/immunology , Interleukin-10/immunology , SARS-CoV-2/immunology , Th1 Cells/immunology , Vitamin D/metabolism , 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/metabolism , Basic-Leucine Zipper Transcription Factors/metabolism , Bronchoalveolar Lavage Fluid/cytology , COVID-19/immunology , COVID-19/pathology , Complement C3a/immunology , Complement C3b/immunology , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , Lymphocyte Activation/immunology , Receptors, Calcitriol/metabolism , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , STAT3 Transcription Factor/metabolism , Signal Transduction/immunology , Transcription, Genetic/genetics
12.
Cells ; 10(11)2021 11 07.
Article in English | MEDLINE | ID: covidwho-1512135

ABSTRACT

The bronchial vascular endothelial network plays important roles in pulmonary pathology during respiratory viral infections, including respiratory syncytial virus (RSV), influenza A(H1N1) and importantly SARS-Cov-2. All of these infections can be severe and even lethal in patients with underlying risk factors.A major obstacle in disease prevention is the lack of appropriate efficacious vaccine(s) due to continuous changes in the encoding capacity of the viral genome, exuberant responsiveness of the host immune system and lack of effective antiviral drugs. Current management of these severe respiratory viral infections is limited to supportive clinical care. The primary cause of morbidity and mortality is respiratory failure, partially due to endothelial pulmonary complications, including edema. The latter is induced by the loss of alveolar epithelium integrity and by pathological changes in the endothelial vascular network that regulates blood flow, blood fluidity, exchange of fluids, electrolytes, various macromolecules and responses to signals triggered by oxygenation, and controls trafficking of leukocyte immune cells. This overview outlines the latest understanding of the implications of pulmonary vascular endothelium involvement in respiratory distress syndrome secondary to viral infections. In addition, the roles of infection-induced cytokines, growth factors, and epigenetic reprogramming in endothelial permeability, as well as emerging treatment options to decrease disease burden, are discussed.


Subject(s)
Endothelial Cells/pathology , Oxidative Stress , Respiratory Distress Syndrome/pathology , Virus Diseases/pathology , Epigenesis, Genetic , Humans , Influenza A Virus, H1N1 Subtype/physiology , Pulmonary Edema/genetics , Pulmonary Edema/pathology , Pulmonary Edema/virology , Respiratory Distress Syndrome/genetics , Respiratory Distress Syndrome/virology , Respiratory Syncytial Viruses/pathogenicity , SARS-CoV-2/pathogenicity , Virus Diseases/genetics , Virus Diseases/virology
13.
Clin Appl Thromb Hemost ; 27: 10760296211051764, 2021.
Article in English | MEDLINE | ID: covidwho-1511654

ABSTRACT

The precise mechanisms of pathology in severe COVID-19 remains elusive. Current evidence suggests that inflammatory mediators are responsible for the manifestation of clinical symptoms that precedes a fatal response to infection. This review examines the nature of platelet activating factor and emphasizes the similarities between the physiological effects of platelet activating factor and the clinical complications of severe COVID-19.


Subject(s)
COVID-19/metabolism , Platelet Activating Factor/metabolism , Animals , COVID-19/complications , COVID-19/mortality , COVID-19/pathology , Humans , Inflammation/complications , Inflammation/metabolism , Inflammation/mortality , Inflammation/pathology , Multiple Organ Failure/complications , Multiple Organ Failure/metabolism , Multiple Organ Failure/mortality , Multiple Organ Failure/pathology , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/mortality , Respiratory Distress Syndrome/pathology , SARS-CoV-2/physiology , Severity of Illness Index , Thrombosis/complications , Thrombosis/metabolism , Thrombosis/mortality , Thrombosis/pathology
15.
Front Immunol ; 12: 742941, 2021.
Article in English | MEDLINE | ID: covidwho-1477827

ABSTRACT

The coronavirus disease-19 (COVID-19) elicited by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused devastating health, economic and social impact worldwide. Its clinical spectrum ranges from asymptomatic to respiratory failure and multi-organ failure or death. The pathogenesis of SARS-CoV-2 infection is attributed to a complex interplay between virus and host immune response. It involves activation of multiple inflammatory pathways leading to hyperinflammation and cytokine storm, resulting in tissue damage, acute respiratory distress syndrome (ARDS) and multi-organ failure. Accumulating evidence has raised concern over the long-term health effects of COVID-19. Importantly, the neuroinvasive potential of SARS-CoV-2 may have devastating consequences in the brain. This review provides a conceptual framework on how the virus tricks the host immune system to induce infection and cause severe disease. We also explore the key differences between mild and severe COVID-19 and its short- and long-term effects, particularly on the human brain.


Subject(s)
Adaptive Immunity/immunology , COVID-19/pathology , Cytokine Release Syndrome/pathology , Immunity, Innate/immunology , SARS-CoV-2/immunology , COVID-19/complications , COVID-19/immunology , Cytokine Release Syndrome/immunology , Cytokines/blood , Humans , Multiple Organ Failure/pathology , Respiratory Distress Syndrome/pathology , Sex Factors
16.
Front Immunol ; 12: 687397, 2021.
Article in English | MEDLINE | ID: covidwho-1477818

ABSTRACT

Severe COVID-19 is characterized by acute respiratory distress syndrome (ARDS)-like hyperinflammation and endothelial dysfunction, that can lead to respiratory and multi organ failure and death. Interstitial lung diseases (ILD) and pulmonary fibrosis confer an increased risk for severe disease, while a subset of COVID-19-related ARDS surviving patients will develop a fibroproliferative response that can persist post hospitalization. Autotaxin (ATX) is a secreted lysophospholipase D, largely responsible for the extracellular production of lysophosphatidic acid (LPA), a pleiotropic signaling lysophospholipid with multiple effects in pulmonary and immune cells. In this review, we discuss the similarities of COVID-19, ARDS and ILDs, and suggest ATX as a possible pathologic link and a potential common therapeutic target.


Subject(s)
COVID-19/pathology , Phosphoric Diester Hydrolases/metabolism , Pulmonary Fibrosis/pathology , Respiratory Distress Syndrome/pathology , Anti-Inflammatory Agents/therapeutic use , COVID-19/blood , Dexamethasone/therapeutic use , Humans , Lung/pathology , Lysophospholipids/metabolism , Phosphoric Diester Hydrolases/blood , Pulmonary Fibrosis/blood , Respiratory Distress Syndrome/blood , SARS-CoV-2 , Signal Transduction/immunology
17.
PLoS One ; 16(10): e0254985, 2021.
Article in English | MEDLINE | ID: covidwho-1448572

ABSTRACT

BACKGROUND: The goal of this study was to determine if IL-22:Fc would Acute Respiratory Distress Syndrome (ARDS). SUMMARY BACKGROUND DATA: No therapies exist for ARDS and treatment is purely supportive. Interleukin-22 (IL-22) plays an integral component in recovery of the lung from infection. IL-22:Fc is a recombinant protein with a human FC immunoglobulin that increases the half-life of IL-22. STUDY DESIGN: ARDS was induced in C57BL/6 mice with intra-tracheal lipopolysaccharide (LPS) at a dose of 33.3 or 100 ug. In the low-dose LPS group (LDG), IL-22:FC was administered via tail vein injection at 30 minutes (n = 9) and compared to sham (n = 9). In the high-dose LPS group (HDG), IL-22:FC was administered (n = 11) then compared to sham (n = 8). Euthanasia occurred after bronchioalveolar lavage (BAL) on post-injury day 4. RESULTS: In the LDG, IL-22:FC resulted in decreased protein leak (0.15 vs. 0.25 ug/uL, p = 0.02). BAL protein in animals receiving IL-22:Fc in the HDG was not different. For the HDG, animals receiving IL-22:Fc had lower BAL cell counts (539,636 vs 3,147,556 cells/uL, p = 0.02). For the HDG, IL-6 (110.6 vs. 527.1 pg/mL, p = 0.04), TNF-α (5.87 vs. 25.41 pg/mL, p = 0.04), and G-CSF (95.14 vs. 659.6, p = 0.01) levels were lower in the BAL fluid of IL-22:Fc treated animals compared to sham. CONCLUSIONS: IL-22:Fc decreases lung inflammation and lung capillary leak in ARDS. IL-22:Fc may be a novel therapy for ARDS.


Subject(s)
Immunoglobulin Fc Fragments/pharmacology , Interleukins/pharmacology , Lung Injury/drug therapy , Pneumonia/drug therapy , Respiratory Distress Syndrome/drug therapy , Animals , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/cytology , Female , Lipopolysaccharides/toxicity , Lung Injury/pathology , Lymphocyte Count , Lymphocytes/immunology , Macrophages/immunology , Male , Mice , Mice, Inbred C57BL , Neutrophils/immunology , Pneumonia/pathology , Receptors, Interleukin/metabolism , Recombinant Proteins/pharmacology , Respiratory Distress Syndrome/pathology , Respiratory Mucosa/pathology
18.
Respiration ; 101(2): 155-165, 2022.
Article in English | MEDLINE | ID: covidwho-1410800

ABSTRACT

BACKGROUND: Findings from autopsies have provided evidence on systemic microvascular damage as one of the underlying mechanisms of Coronavirus disease 2019 (CO-VID-19). The aim of this study was to correlate autopsy-based cause of death in SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive patients with chest imaging and severity grade of pulmonary and systemic morphological vascular pathology. METHODS: Fifteen SARS-CoV-2 positive autopsies with clinically distinct presentations (age 22-89 years) were retrospectively analyzed with focus on vascular, thromboembolic, and ischemic changes in pulmonary and in extrapulmonary sites. Eight patients died due to COVID-19 associated respiratory failure with diffuse alveolar damage in various stages and/or multi-organ failure, whereas other reasons such as cardiac decompensation, complication of malignant tumors, or septic shock were the cause of death in 7 further patients. The severity of gross and histopathological changes was semi-quantitatively scored as 0 (absent), 1 (mild), and 3 (severe). Severity scores between the 2 groups were correlated with selected clinical parameters, initial chest imaging, autopsy-based cause of death, and compared using Pearson χ2 and Mann-Whitney U tests. RESULTS: Severe pulmonary endotheliitis (p = 0.031, p = 0.029) and multi-organ involvement (p = 0.026, p = 0.006) correlated significantly with COVID-19 associated death. Pulmonary microthrombi showed limited statistical correlation, while tissue necrosis, gross pulmonary embolism, and bacterial superinfection did not differentiate the 2 study groups. Chest imaging at hospital admission did not differ either. CONCLUSIONS: Extensive pulmonary endotheliitis and multi-organ involvement are characteristic autopsy features in fatal CO-VID-19 associated deaths. Thromboembolic and ischemic events and bacterial superinfections occur frequently in SARS-CoV-2 infection independently of outcome.


Subject(s)
COVID-19/mortality , COVID-19/pathology , Endothelium, Vascular/pathology , Multiple Organ Failure/virology , Respiratory Distress Syndrome/virology , Vasculitis/virology , Adult , Aged , Aged, 80 and over , Autopsy , COVID-19/complications , Cause of Death , Cohort Studies , Female , Humans , Male , Middle Aged , Multiple Organ Failure/mortality , Multiple Organ Failure/pathology , Pulmonary Alveoli/pathology , Respiratory Distress Syndrome/mortality , Respiratory Distress Syndrome/pathology , Vasculitis/mortality , Vasculitis/pathology , Young Adult
20.
Pharmacol Res ; 163: 105224, 2021 01.
Article in English | MEDLINE | ID: covidwho-1364404

ABSTRACT

Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS) as common life-threatening lung diseases with high mortality rates are mostly associated with acute and severe inflammation in lungs. With increasing in-depth studies of ALI/ARDS, significant breakthroughs have been made, however, there are still no effective pharmacological therapies for treatment of ALI/ARDS. Especially, the novel coronavirus pneumonia (COVID-19) is ravaging the globe, and causes severe respiratory distress syndrome. Therefore, developing new drugs for therapy of ALI/ARDS is in great demand, which might also be helpful for treatment of COVID-19. Natural compounds have always inspired drug development, and numerous natural products have shown potential therapeutic effects on ALI/ARDS. Therefore, this review focuses on the potential therapeutic effects of natural compounds on ALI and the underlying mechanisms. Overall, the review discusses 159 compounds and summarizes more than 400 references to present the protective effects of natural compounds against ALI and the underlying mechanism.


Subject(s)
Acute Lung Injury/drug therapy , Lung/drug effects , Phytochemicals/pharmacology , Respiratory Distress Syndrome/drug therapy , Acute Lung Injury/etiology , Acute Lung Injury/metabolism , Acute Lung Injury/pathology , Animals , Humans , Lung/metabolism , Lung/pathology , Phytochemicals/isolation & purification , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/pathology , Signal Transduction
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