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1.
Crit Care ; 25(1): 390, 2021 11 15.
Article in English | MEDLINE | ID: covidwho-1518286

ABSTRACT

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by lung inflammation and pulmonary edema. Coronavirus disease 2019 (COVID-19) is associated with ARDS in the more severe cases. This study aimed to compare the specificity of the metabolic alterations induced by COVID-19 or Influenza A pneumonia (IAP) in ARDS. METHODS: Eighteen patients with ARDS due to COVID-19 and twenty patients with ARDS due to IAP, admitted to the intensive care unit. ARDS was defined as in the American-European Consensus Conference. As compared with patients with COVID-19, patients with IAP were younger and received more often noradrenaline to maintain a mean arterial pressure > 65 mm Hg. Serum samples were analyzed by Nuclear Magnetic Resonance Spectroscopy. Multivariate Statistical Analyses were used to identify metabolic differences between groups. Metabolic pathway analysis was performed to identify the most relevant pathways involved in ARDS development. RESULTS: ARDS due to COVID-19 or to IAP induces a different regulation of amino acids metabolism, lipid metabolism, glycolysis, and anaplerotic metabolism. COVID-19 causes a significant energy supply deficit that induces supplementary energy-generating pathways. In contrast, IAP patients suffer more marked inflammatory and oxidative stress responses. The classificatory model discriminated against the cause of pneumonia with a success rate of 100%. CONCLUSIONS: Our findings support the concept that ARDS is associated with a characteristic metabolomic profile that may discriminate patients with ARDS of different etiologies, being a potential biomarker for the diagnosis, prognosis, and management of this condition.


Subject(s)
COVID-19/metabolism , Influenza A Virus, H1N1 Subtype , Influenza, Human/metabolism , Respiratory Distress Syndrome/metabolism , Adult , Aged , COVID-19/complications , Female , Humans , Influenza, Human/complications , Male , Middle Aged , Respiratory Distress Syndrome/virology
2.
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
3.
Am J Respir Crit Care Med ; 204(9): 1024-1034, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1495777

ABSTRACT

Rationale: ACE2 (angiotensin-converting enzyme 2), the entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is expressed in type 2 alveolar epithelial cells (AT2) that may play key roles in postinjury repair. An imbalance between ACE2 and ACE has also been hypothesized to contribute to lung injury. Objectives: To characterize the expression and distribution of ACE2 and ACE and to compare AT2 with endothelial cell expression in coronavirus disease (COVID-19)-related or -unrelated acute respiratory distress syndrome (ARDS) and controls. Methods: Lung tissue stainings (using multiplex immunofluorescence) and serum concentrations of ACEs were determined retrospectively in two different cohorts of patients. AT2 and endothelial cells were stained in lung tissue for ProSPC (pro-surfactant protein C) and CD31, respectively. Measurements and Main Results: Pulmonary ACE2 expression was increased in patients with COVID-19-related and -unrelated ARDS (0.06% of tissue area and 0.12% vs. 0.006% for control subjects; P = 0.013 and P < 0.0001, respectively). ACE2 was upregulated in endothelial cells (0.32% and 0.53% vs. 0.01%; P = 0.009 and P < 0.0001) but not in AT2 cells (0.13% and 0.08% vs. 0.03%; P = 0.94 and P = 0.44). Pulmonary expression of ACE was decreased in both COVID-19-related and -unrelated ARDS (P = 0.057 and P = 0.032). Similar increases in ACE2 and decreases in ACE were observed in sera of COVID-19 (P = 0.0054 and P < 0.0001) and non-COVID-19 ARDS (P < 0.0001 and P = 0.016). In addition, AT2 cells were decreased in patients with COVID-19-related ARDS compared with COVID-19-unrelated ARDS (1.395% vs. 2.94%, P = 0.0033). Conclusions: ACE2 is upregulated in lung tissue and serum of both COVID-19-related and -unrelated ARDS, whereas a loss of AT2 cells is selectively observed in COVID-19-related ARDS.


Subject(s)
Alveolar Epithelial Cells/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Peptidyl-Dipeptidase A/metabolism , Respiratory Distress Syndrome/metabolism , Adult , Aged , Biomarkers/metabolism , COVID-19/diagnosis , COVID-19/physiopathology , Case-Control Studies , Female , Humans , Immunohistochemistry , Logistic Models , Male , Middle Aged , Proportional Hazards Models , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/virology , Retrospective Studies , Severity of Illness Index , Up-Regulation
5.
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
6.
FASEB J ; 35(9): e21798, 2021 09.
Article in English | MEDLINE | ID: covidwho-1334263

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic threatens human species with mortality rate of roughly 2%. We can hardly predict the time of herd immunity against and end of COVID-19 with or without success of vaccine. One way to overcome the situation is to define what delineates disease severity and serves as a molecular target. The most successful analogy is found in BCR-ABL in chronic myeloid leukemia, which is the golden biomarker, and simultaneously, the most effective molecular target. We hypothesize that S100 calcium-binding protein A8 (S100A8) is one such molecule. The underlying evidence includes accumulating clinical information that S100A8 is upregulated in severe forms of COVID-19, pathological similarities of the affected lungs between COVID-19 and S100A8-induced acute respiratory distress syndrome (ARDS) model, homeostatic inflammation theory in which S100A8 is an endogenous ligand for endotoxin sensor Toll-like receptor 4/Myeloid differentiation protein-2 (TLR4/MD-2) and mediates hyper-inflammation even after elimination of endotoxin-producing extrinsic pathogens, analogous findings between COVID-19-associated ARDS and pre-metastatic lungs such as S100A8 upregulation, pulmonary recruitment of myeloid cells, increased vascular permeability, and activation coagulation cascade. A successful treatment in an animal COVID-19 model is given with a reagent capable of abrogating interaction between S100A8/S100A9 and TLR4. In this paper, we try to verify our hypothesis that S100A8 governs COVID-19-associated ARDS.


Subject(s)
COVID-19/complications , Calgranulin A/physiology , Cytokine Release Syndrome/etiology , Inflammation/etiology , Pandemics , Respiratory Distress Syndrome/etiology , SARS-CoV-2/genetics , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/physiology , Animals , Antiviral Agents/pharmacology , COVID-19/genetics , COVID-19/pathology , Calgranulin A/blood , Calgranulin A/genetics , Chemokine CXCL11/blood , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/pathology , Disaccharides/pharmacology , Disaccharides/therapeutic use , Disease Models, Animal , Drug Discovery , Epithelial Cells/metabolism , Epithelial Cells/virology , Humans , Inflammation/genetics , Inflammation/pathology , Lung/metabolism , Lung/pathology , Lung/virology , Lung Neoplasms/drug therapy , Lung Neoplasms/secondary , Lymphocyte Antigen 96/physiology , Macaca mulatta , Mice , Mice, Transgenic , Models, Biological , Mutation , Respiratory Distress Syndrome/genetics , Respiratory Distress Syndrome/metabolism , Species Specificity , Sugar Phosphates/pharmacology , Sugar Phosphates/therapeutic use , Toll-Like Receptor 4/physiology , Up-Regulation , Virus Internalization
7.
Angiogenesis ; 24(4): 755-788, 2021 11.
Article in English | MEDLINE | ID: covidwho-1286153

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is presenting as a systemic disease associated with vascular inflammation and endothelial injury. Severe forms of SARS-CoV-2 infection induce acute respiratory distress syndrome (ARDS) and there is still an ongoing debate on whether COVID-19 ARDS and its perfusion defect differs from ARDS induced by other causes. Beside pro-inflammatory cytokines (such as interleukin-1 ß [IL-1ß] or IL-6), several main pathological phenomena have been seen because of endothelial cell (EC) dysfunction: hypercoagulation reflected by fibrin degradation products called D-dimers, micro- and macrothrombosis and pathological angiogenesis. Direct endothelial infection by SARS-CoV-2 is not likely to occur and ACE-2 expression by EC is a matter of debate. Indeed, endothelial damage reported in severely ill patients with COVID-19 could be more likely secondary to infection of neighboring cells and/or a consequence of inflammation. Endotheliopathy could give rise to hypercoagulation by alteration in the levels of different factors such as von Willebrand factor. Other than thrombotic events, pathological angiogenesis is among the recent findings. Overexpression of different proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2) or placental growth factors (PlGF) have been found in plasma or lung biopsies of COVID-19 patients. Finally, SARS-CoV-2 infection induces an emergency myelopoiesis associated to deregulated immunity and mobilization of endothelial progenitor cells, leading to features of acquired hematological malignancies or cardiovascular disease, which are discussed in this review. Altogether, this review will try to elucidate the pathophysiology of thrombotic complications, pathological angiogenesis and EC dysfunction, allowing better insight in new targets and antithrombotic protocols to better address vascular system dysfunction. Since treating SARS-CoV-2 infection and its potential long-term effects involves targeting the vascular compartment and/or mobilization of immature immune cells, we propose to define COVID-19 and its complications as a systemic vascular acquired hemopathy.


Subject(s)
COVID-19/metabolism , Myelopoiesis , Neovascularization, Pathologic/metabolism , Respiratory Distress Syndrome/metabolism , SARS-CoV-2/metabolism , Thrombosis/metabolism , COVID-19/pathology , COVID-19/therapy , Endothelial Cells/metabolism , Endothelial Cells/pathology , Endothelial Cells/virology , Fibrin Fibrinogen Degradation Products/metabolism , Fibroblast Growth Factor 2/metabolism , Humans , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Membrane Proteins/metabolism , Neovascularization, Pathologic/pathology , Neovascularization, Pathologic/therapy , Neovascularization, Pathologic/virology , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/therapy , Respiratory Distress Syndrome/virology , Thrombosis/pathology , Thrombosis/therapy , Thrombosis/virology , Vascular Endothelial Growth Factor A/metabolism , von Willebrand Factor/metabolism
8.
Am J Physiol Lung Cell Mol Physiol ; 321(2): L358-L376, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1280497

ABSTRACT

Capillary endothelial cells possess a specialized metabolism necessary to adapt to the unique alveolar-capillary environment. Here, we highlight how endothelial metabolism preserves the integrity of the pulmonary circulation by controlling vascular permeability, defending against oxidative stress, facilitating rapid migration and angiogenesis in response to injury, and regulating the epigenetic landscape of endothelial cells. Recent reports on single-cell RNA-sequencing reveal subpopulations of pulmonary capillary endothelial cells with distinctive reparative capacities, which potentially offer new insight into their metabolic signature. Lastly, we discuss broad implications of pulmonary vascular metabolism on acute respiratory distress syndrome, touching on emerging findings of endotheliitis in coronavirus disease 2019 (COVID-19) lungs.


Subject(s)
COVID-19/complications , Endothelium, Vascular/metabolism , Neovascularization, Pathologic/pathology , Pulmonary Circulation , Respiratory Distress Syndrome/epidemiology , SARS-CoV-2/isolation & purification , COVID-19/transmission , COVID-19/virology , Endothelium, Vascular/pathology , Endothelium, Vascular/virology , Humans , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/virology , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology
9.
Genes Immun ; 22(3): 141-160, 2021 07.
Article in English | MEDLINE | ID: covidwho-1275909

ABSTRACT

When surveying the current literature on COVID-19, the "cytokine storm" is considered to be pathogenetically involved in its severe outcomes such as acute respiratory distress syndrome, systemic inflammatory response syndrome, and eventually multiple organ failure. In this review, the similar role of DAMPs is addressed, that is, of those molecules, which operate upstream of the inflammatory pathway by activating those cells, which ultimately release the cytokines. Given the still limited reports on their role in COVID-19, the emerging topic is extended to respiratory viral infections with focus on influenza. At first, a brief introduction is given on the function of various classes of activating DAMPs and counterbalancing suppressing DAMPs (SAMPs) in initiating controlled inflammation-promoting and inflammation-resolving defense responses upon infectious and sterile insults. It is stressed that the excessive emission of DAMPs upon severe injury uncovers their fateful property in triggering dysregulated life-threatening hyperinflammatory responses. Such a scenario may happen when the viral load is too high, for example, in the respiratory tract, "forcing" many virus-infected host cells to decide to commit "suicidal" regulated cell death (e.g., necroptosis, pyroptosis) associated with release of large amounts of DAMPs: an important topic of this review. Ironically, although the aim of this "suicidal" cell death is to save and restore organismal homeostasis, the intrinsic release of excessive amounts of DAMPs leads to those dysregulated hyperinflammatory responses-as typically involved in the pathogenesis of acute respiratory distress syndrome and systemic inflammatory response syndrome in respiratory viral infections. Consequently, as briefly outlined in this review, these molecules can be considered valuable diagnostic and prognostic biomarkers to monitor and evaluate the course of the viral disorder, in particular, to grasp the eventual transition precociously from a controlled defense response as observed in mild/moderate cases to a dysregulated life-threatening hyperinflammatory response as seen, for example, in severe/fatal COVID-19. Moreover, the pathogenetic involvement of these molecules qualifies them as relevant future therapeutic targets to prevent severe/ fatal outcomes. Finally, a theory is presented proposing that the superimposition of coronavirus-induced DAMPs with non-virus-induced DAMPs from other origins such as air pollution or high age may contribute to severe and fatal courses of coronavirus pneumonia.


Subject(s)
Alarmins/immunology , COVID-19/immunology , Cytokine Release Syndrome/immunology , Respiratory Distress Syndrome/immunology , SARS-CoV-2/immunology , Virus Diseases/immunology , Alarmins/metabolism , COVID-19/metabolism , COVID-19/virology , Cytokine Release Syndrome/metabolism , Cytokines/immunology , Cytokines/metabolism , Humans , Inflammation/immunology , Inflammation/metabolism , Models, Immunological , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/metabolism , SARS-CoV-2/physiology , Virus Diseases/complications , Virus Diseases/metabolism
10.
Am J Respir Cell Mol Biol ; 64(6): 677-686, 2021 06.
Article in English | MEDLINE | ID: covidwho-1259048

ABSTRACT

There is an urgent need for new drugs for patients with acute respiratory distress syndrome (ARDS), including those with coronavirus disease (COVID-19). ARDS in influenza-infected mice is associated with reduced concentrations of liponucleotides (essential precursors for de novo phospholipid synthesis) in alveolar type II (ATII) epithelial cells. Because surfactant phospholipid synthesis is a primary function of ATII cells, we hypothesized that disrupting this process could contribute significantly to the pathogenesis of influenza-induced ARDS. The goal of this study was to determine whether parenteral liponucleotide supplementation can attenuate ARDS. C57BL/6 mice inoculated intranasally with 10,000 plaque-forming units/mouse of H1N1 influenza A/WSN/33 virus were treated with CDP (cytidine 5'-diphospho)-choline (100 µg/mouse i.p.) ± CDP -diacylglycerol 16:0/16:0 (10 µg/mouse i.p.) once daily from 1 to 5 days after inoculation (to model postexposure influenza prophylaxis) or as a single dose on Day 5 (to model treatment of patients with ongoing influenza-induced ARDS). Daily postexposure prophylaxis with CDP-choline attenuated influenza-induced hypoxemia, pulmonary edema, alterations in lung mechanics, impairment of alveolar fluid clearance, and pulmonary inflammation without altering viral replication. These effects were not recapitulated by the daily administration of CTP (cytidine triphosphate) and/or choline. Daily coadministration of CDP-diacylglycerol significantly enhanced the beneficial effects of CDP-choline and also modified the ATII cell lipidome, reversing the infection-induced decrease in phosphatidylcholine and increasing concentrations of most other lipid classes in ATII cells. Single-dose treatment with both liponucleotides at 5 days after inoculation also attenuated hypoxemia, altered lung mechanics, and inflammation. Overall, our data show that liponucleotides act rapidly to reduce disease severity in mice with severe influenza-induced ARDS.


Subject(s)
Alveolar Epithelial Cells/metabolism , Cytidine Diphosphate Choline/pharmacology , Cytidine Diphosphate Diglycerides/pharmacology , Influenza A Virus, H1N1 Subtype/metabolism , Orthomyxoviridae Infections/drug therapy , Respiratory Distress Syndrome/prevention & control , Alveolar Epithelial Cells/pathology , Alveolar Epithelial Cells/virology , Animals , COVID-19/drug therapy , COVID-19/pathology , Mice , Orthomyxoviridae Infections/complications , Orthomyxoviridae Infections/metabolism , Orthomyxoviridae Infections/pathology , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/pathology , SARS-CoV-2/metabolism
11.
Crit Care ; 25(1): 186, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1255959

ABSTRACT

BACKGROUND: In acute respiratory distress syndrome (ARDS), extravascular lung water index (EVLWi) and pulmonary vascular permeability index (PVPI) measured by transpulmonary thermodilution reflect the degree of lung injury. Whether EVLWi and PVPI are different between non-COVID-19 ARDS and the ARDS due to COVID-19 has never been reported. We aimed at comparing EVLWi, PVPI, respiratory mechanics and hemodynamics in patients with COVID-19 ARDS vs. ARDS of other origin. METHODS: Between March and October 2020, in an observational study conducted in intensive care units from three university hospitals, 60 patients with COVID-19-related ARDS monitored by transpulmonary thermodilution were compared to the 60 consecutive non-COVID-19 ARDS admitted immediately before the COVID-19 outbreak between December 2018 and February 2020. RESULTS: Driving pressure was similar between patients with COVID-19 and non-COVID-19 ARDS, at baseline as well as during the study period. Compared to patients without COVID-19, those with COVID-19 exhibited higher EVLWi, both at the baseline (17 (14-21) vs. 15 (11-19) mL/kg, respectively, p = 0.03) and at the time of its maximal value (24 (18-27) vs. 21 (15-24) mL/kg, respectively, p = 0.01). Similar results were observed for PVPI. In COVID-19 patients, the worst ratio between arterial oxygen partial pressure over oxygen inspired fraction was lower (81 (70-109) vs. 100 (80-124) mmHg, respectively, p = 0.02) and prone positioning and extracorporeal membrane oxygenation (ECMO) were more frequently used than in patients without COVID-19. COVID-19 patients had lower maximal lactate level and maximal norepinephrine dose than patients without COVID-19. Day-60 mortality was similar between groups (57% vs. 65%, respectively, p = 0.45). The maximal value of EVLWi and PVPI remained independently associated with outcome in the whole cohort. CONCLUSION: Compared to ARDS patients without COVID-19, patients with COVID-19 had similar lung mechanics, but higher EVLWi and PVPI values from the beginning of the disease. This was associated with worse oxygenation and with more requirement of prone positioning and ECMO. This is compatible with the specific lung inflammation and severe diffuse alveolar damage related to COVID-19. By contrast, patients with COVID-19 had fewer hemodynamic derangement. Eventually, mortality was similar between groups. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: ClinicalTrials.gov (NCT04337983). Registered 30 March 2020-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04337983 .


Subject(s)
COVID-19/metabolism , Capillary Permeability , Extravascular Lung Water/metabolism , Respiratory Distress Syndrome/metabolism , Severity of Illness Index , COVID-19/complications , Hemodynamics , Humans , Lung/blood supply , Male , Middle Aged , Monitoring, Physiologic/methods , Prognosis , Pulmonary Edema/metabolism , Thermodilution
12.
J Leukoc Biol ; 110(1): 27-38, 2021 07.
Article in English | MEDLINE | ID: covidwho-1222640

ABSTRACT

Acute respiratory distress syndrome (ARDS) is a devastating and life-threatening syndrome that results in high morbidity and mortality. Current pharmacologic treatments and mechanical ventilation have limited value in targeting the underlying pathophysiology of ARDS. Mesenchymal stromal cells (MSCs) have shown potent therapeutic advantages in experimental and clinical trials through direct cell-to-cell interaction and paracrine signaling. However, safety concerns and the indeterminate effects of MSCs have resulted in the investigation of MSC-derived extracellular vesicles (MSC-EVs) due to their low immunogenicity and tumorigenicity. Over the past decades, soluble proteins, microRNAs, and organelles packaged in EVs have been identified as efficacious molecules to orchestrate nearby immune responses, which attenuate acute lung injury by facilitating pulmonary epithelium repair, reducing acute inflammation, and restoring pulmonary vascular leakage. Even though MSC-EVs possess similar bio-functional effects to their parental cells, there remains existing barriers to employing this alternative from bench to bedside. Here, we summarize the current established research in respect of molecular mechanisms of MSC-EV effects in ARDS and highlight the future challenges of MSC-EVs for clinical application.


Subject(s)
Extracellular Vesicles/metabolism , Mesenchymal Stem Cells/metabolism , Respiratory Distress Syndrome/metabolism , Animals , Clinical Trials as Topic , Humans , Mitochondria/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism
13.
Transl Res ; 233: 104-116, 2021 07.
Article in English | MEDLINE | ID: covidwho-1051128

ABSTRACT

The p53/p21 pathway is activated in response to cell stress. However, its role in acute lung injury has not been elucidated. Acute lung injury is associated with disruption of the alveolo-capillary barrier leading to acute respiratory distress syndrome (ARDS). Mechanical ventilation may be necessary to support gas exchange in patients with ARDS, however, high positive airway pressures can cause regional overdistension of alveolar units and aggravate lung injury. Here, we report that acute lung injury and alveolar overstretching activate the p53/p21 pathway to maintain homeostasis and avoid massive cell apoptosis. A systematic pooling of transcriptomic data from animal models of lung injury demonstrates the enrichment of specific p53- and p21-dependent gene signatures and a validated senescence profile. In a clinically relevant, murine model of acid aspiration and mechanical ventilation, we observed changes in the nuclear envelope and the underlying chromatin, DNA damage and activation of the Tp53/p21 pathway. Absence of Cdkn1a decreased the senescent response, but worsened lung injury due to increased cell apoptosis. Conversely, treatment with lopinavir and/or ritonavir led to Cdkn1a overexpression and ameliorated cell apoptosis and lung injury. The activation of these mechanisms was associated with early markers of senescence, including expression of senescence-related genes and increases in senescence-associated heterochromatin foci in alveolar cells. Autopsy samples from lungs of patients with ARDS revealed increased senescence-associated heterochromatin foci. Collectively, these results suggest that acute lung injury activates p53/p21 as an antiapoptotic mechanism to ameliorate damage, but with the side effect of induction of senescence.


Subject(s)
Acute Lung Injury/metabolism , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Acids/administration & dosage , Acids/toxicity , Acute Lung Injury/etiology , Acute Lung Injury/pathology , Animals , Apoptosis , Cellular Senescence , Cyclin-Dependent Kinase Inhibitor p21/deficiency , Cyclin-Dependent Kinase Inhibitor p21/genetics , DNA Damage , Disease Models, Animal , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Respiration, Artificial/adverse effects , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/pathology , Signal Transduction , Stress, Mechanical , Tumor Suppressor Protein p53/deficiency , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism
14.
Eur J Gastroenterol Hepatol ; 33(5): 695-700, 2021 05 01.
Article in English | MEDLINE | ID: covidwho-1159966

ABSTRACT

BACKGROUND: The data on clinical course and outcome of acute pancreatitis among patients with coronavirus disease 2019 (COVID-19) are sparse. In this study, we analyzed the clinical profiles of patients with COVID 19 and acute pancreatitis. METHODS: This retrospective study was conducted on Research Patient Data Registry data which was pooled from five Mass General Brigham Healthcare Network hospitals. We extracted data on demographics, symptoms, ICU transfer, mechanical ventilation, laboratories' profiles, imaging findings, and patient outcomes. RESULT: Of 985 screened adult patients, 17 were eligible for the study, 9 (52.9%) were admitted primarily for respiratory failure and developed acute pancreatitis after a median of 22.5 days (13-76 days) from the onset of COVID-19 symptoms. On contrary, eight patients presented with typical symptoms and were diagnosed with acute pancreatitis, the majority with mild severity (62.5%) on admission. Patients who were admitted primarily with severe COVID-19 illness were younger (median age 57 vs. 63 years), females (55.6 vs. 25%), of Hispanic ethnicity (55.6 vs. 25%), and obese (88.9 vs. 37.5%). The median peak lipase, C reactive protein, ferritin, lactate dehydrogenase, D-dimer were higher among patients who developed acute pancreatitis later during hospitalization. Patients who developed acute pancreatitis later also experienced higher episodes of necrotizing pancreatitis (11.1% vs. 0), thromboembolic complications (55.6 vs. 12.5%), and higher mortality (37.5 vs. 12.5%). CONCLUSION: Acute pancreatitis is not common among patients with COVID-19. Patients with COVID-19 who had acute pancreatitis on admission had more benign course and overall better outcome as compared to the patients who developed acute pancreatitis during hospitalization.


Subject(s)
COVID-19/physiopathology , Hospital Mortality , Pancreatitis/physiopathology , Respiratory Distress Syndrome/physiopathology , Adult , African Americans , Age Distribution , Aged , C-Reactive Protein/metabolism , COVID-19/complications , COVID-19/metabolism , Female , Ferritins/metabolism , Fibrin Fibrinogen Degradation Products/metabolism , Humans , L-Lactate Dehydrogenase/metabolism , Length of Stay , Lipase/metabolism , Male , Middle Aged , Pancreatitis/complications , Pancreatitis/epidemiology , Pancreatitis/metabolism , Pancreatitis, Acute Necrotizing/epidemiology , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/metabolism , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , Sex Distribution , Thromboembolism/epidemiology
15.
Trends Microbiol ; 29(11): 967-969, 2021 11.
Article in English | MEDLINE | ID: covidwho-1157751

ABSTRACT

Severe coronavirus disease 2019 (COVID-19) infection leads to multifactorial acute respiratory distress syndrome (ARDS), with little therapeutic success. The pathophysiology associated with ARDS or post-ARDS is not yet well understood. We hypothesize that amyloid formation occurring due to protein homeostasis disruption can be one of the complications associated with COVID-19-induced-ARDS.


Subject(s)
Amyloid/metabolism , COVID-19/complications , COVID-19/virology , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/metabolism , SARS-CoV-2 , Amyloidosis/etiology , Amyloidosis/metabolism , Amyloidosis/pathology , Animals , Disease Management , Disease Susceptibility , Humans , Respiratory Distress Syndrome/diagnosis
16.
Nanomedicine ; 34: 102388, 2021 06.
Article in English | MEDLINE | ID: covidwho-1142161

ABSTRACT

Acute respiratory distress syndrome (ARDS) is a devastating pulmonary disease with significant in-hospital mortality and is the leading cause of death in COVID-19 patients. Excessive leukocyte recruitment, unregulated inflammation, and resultant fibrosis contribute to poor ARDS outcomes. Nanoparticle technology with cerium oxide nanoparticles (CNP) offers a mechanism by which unstable therapeutics such as the anti-inflammatory microRNA-146a can be locally delivered to the injured lung without systemic uptake. In this study, we evaluated the potential of the radical scavenging CNP conjugated to microRNA-146a (termed CNP-miR146a) in preventing acute lung injury (ALI) following exposure to bleomycin. We have found that intratracheal delivery of CNP-miR146a increases pulmonary levels of miR146a without systemic increases, and prevents ALI by altering leukocyte recruitment, reducing inflammation and oxidative stress, and decreasing collagen deposition, ultimately improving pulmonary biomechanics.


Subject(s)
Bleomycin/adverse effects , Cerium , Drug Delivery Systems , MicroRNAs , Respiratory Distress Syndrome/drug therapy , Animals , Bleomycin/pharmacology , COVID-19/drug therapy , COVID-19/genetics , COVID-19/metabolism , Cerium/chemistry , Cerium/pharmacology , Disease Models, Animal , Male , Mice , MicroRNAs/chemistry , MicroRNAs/pharmacology , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/genetics , Respiratory Distress Syndrome/metabolism , SARS-CoV-2/metabolism
17.
Pharmacol Res ; 167: 105548, 2021 05.
Article in English | MEDLINE | ID: covidwho-1135540

ABSTRACT

Acute Respiratory Distress Syndrome (ARDS) is triggered by a variety of agents, including Staphylococcal Enterotoxin B (SEB). Interestingly, a significant proportion of patients with COVID-19, also develop ARDS. In the absence of effective treatments, ARDS results in almost 40% mortality. Previous studies from our laboratory demonstrated that resveratrol (RES), a stilbenoid, with potent anti-inflammatory properties can attenuate SEB-induced ARDS. In the current study, we investigated the role of RES-induced alterations in the gut and lung microbiota in the regulation of ARDS. Our studies revealed that SEB administration induced inflammatory cytokines, ARDS, and 100% mortality in C3H/HeJ mice. Additionally, SEB caused a significant increase in pathogenic Proteobacteria phylum and Propionibacterium acnes species in the lungs. In contrast, RES treatment attenuated SEB-mediated ARDS and mortality in mice, and significantly increased probiotic Actinobacteria phylum, Tenericutes phylum, and Lactobacillus reuteri species in both the colon and lungs. Colonic Microbiota Transplantation (CMT) from SEB-injected mice that were treated with RES as well as the transfer of L. reuteri into recipient mice inhibited the production of SEB-mediated induction of pro-inflammatory cytokines such as IFN-γ and IL-17 but increased that of anti-inflammatory IL-10. Additionally, such CMT and L. reuteri recipient mice exposed to SEB, showed a decrease in lung-infiltrating mononuclear cells, cytotoxic CD8+ T cells, NKT cells, Th1 cells, and Th17 cells, but an increase in the population of regulatory T cells (Tregs) and Th3 cells, and increase in the survival of mice from SEB-mediated ARDS. Together, the current study demonstrates that ARDS induced by SEB triggers dysbiosis in the lungs and gut and that attenuation of ARDS by RES may be mediated, at least in part, by alterations in microbiota in the lungs and the gut, especially through the induction of beneficial bacteria such as L. reuteri.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Colon/drug effects , Enterotoxins , Fecal Microbiota Transplantation , Gastrointestinal Microbiome/drug effects , Lung/drug effects , Respiratory Distress Syndrome/prevention & control , Resveratrol/pharmacology , Superantigens , Animals , Cell Line , Colon/immunology , Colon/metabolism , Colon/microbiology , Cytokines/metabolism , Disease Models, Animal , Dysbiosis , Female , Inflammation Mediators/metabolism , Lactobacillus reuteri/drug effects , Lactobacillus reuteri/growth & development , Lung/immunology , Lung/metabolism , Lung/microbiology , Mice, Inbred C3H , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/microbiology
18.
Biomolecules ; 11(3)2021 03 06.
Article in English | MEDLINE | ID: covidwho-1134010

ABSTRACT

Many individuals infected with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) develop no or only mild symptoms, but some can go on onto develop a spectrum of pathologies including pneumonia, acute respiratory distress syndrome, respiratory failure, systemic inflammation, and multiorgan failure. Many pathogens, viral and non-viral, can elicit these pathologies, which justifies reconsidering whether the target of therapeutic approaches to fight pathogen infections should be (a) the pathogen itself, (b) the pathologies elicited by the pathogen interaction with the human host, or (c) a combination of both. While little is known about the immunopathology of SARS-CoV-2, it is well-established that the above-mentioned pathologies are associated with hyper-inflammation, tissue damage, and the perturbation of target organ metabolism. Mounting evidence has shown that these processes are regulated by endoproteinases (particularly, matrix metalloproteinases (MMPs)). Here, we review what is known about the roles played by MMPs in the development of COVID-19 and postulate a mechanism by which MMPs could influence energy metabolism in target organs, such as the lung. Finally, we discuss the suitability of MMPs as therapeutic targets to increase the metabolic tolerance of the host to damage inflicted by the pathogen infection, with a focus on SARS-CoV-2.


Subject(s)
COVID-19/metabolism , Lung/physiopathology , Matrix Metalloproteinases/metabolism , Protein Kinases/metabolism , Respiratory Distress Syndrome/metabolism , COVID-19/enzymology , COVID-19/physiopathology , COVID-19/virology , Comorbidity , Cytokines/metabolism , Humans , Inflammation/drug therapy , Inflammation/enzymology , Inflammation/metabolism , Inflammation/pathology , Lung/enzymology , Lung/metabolism , Lung/virology , Matrix Metalloproteinase Inhibitors/pharmacology , Respiratory Distress Syndrome/enzymology , Respiratory Distress Syndrome/physiopathology , Respiratory Distress Syndrome/virology , SARS-CoV-2/pathogenicity , Signal Transduction/drug effects , Signal Transduction/genetics
19.
Front Immunol ; 12: 627579, 2021.
Article in English | MEDLINE | ID: covidwho-1127985

ABSTRACT

An important manifestation of severe COVID-19 is the ARDS-like lung injury that is associated with vascular endothelialitis, thrombosis, and angiogenesis. The intravascular innate immune system (IIIS), including the complement, contact, coagulation, and fibrinolysis systems, which is crucial for recognizing and eliminating microorganisms and debris in the body, is likely to be involved in the pathogenesis of COVID-19 ARDS. Biomarkers for IIIS activation were studied in the first 66 patients with COVID-19 admitted to the ICU in Uppsala University Hospital, both cross-sectionally on day 1 and in 19 patients longitudinally for up to a month, in a prospective study. IIIS analyses were compared with biochemical parameters and clinical outcome and survival. Blood cascade systems activation leading to an overreactive conjunct thromboinflammation was demonstrated, reflected in consumption of individual cascade system components, e.g., FXII, prekallikrein, and high molecular weight kininogen and in increased levels of activation products, e.g., C4d, C3a, C3d,g, sC5b-9, TAT, and D-dimer. Strong associations were found between the blood cascade systems and organ damage, illness severity scores, and survival. We show that critically ill COVID-19 patients display a conjunct activation of the IIIS that is linked to organ damage of the lung, heart, kidneys, and death. We present evidence that the complement and in particular the kallikrein/kinin system is strongly activated and that both systems are prognostic markers of the outcome of the patients suggesting their role in driving the inflammation. Already licensed kallikrein/kinin inhibitors are potential drugs for treatment of critically ill patients with COVID-19.


Subject(s)
COVID-19/immunology , COVID-19/metabolism , Inflammation/immunology , Kallikrein-Kinin System/immunology , Thrombosis/immunology , Adult , Aged , Aged, 80 and over , Biomarkers/metabolism , Blood Coagulation , COVID-19/pathology , COVID-19/virology , Critical Illness , Female , Fibrinolysis/immunology , Humans , Immunity, Innate , Inflammation/metabolism , Inflammation/pathology , Inflammation/virology , Male , Middle Aged , Prospective Studies , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , SARS-CoV-2/isolation & purification , Severity of Illness Index , Young Adult
20.
Int J Mol Sci ; 22(4)2021 Feb 20.
Article in English | MEDLINE | ID: covidwho-1090323

ABSTRACT

Severe COVID-19 is characterized by a "cytokine storm", the mechanism of which is not yet understood. I propose that cytokine storms result from synergistic interactions among Toll-like receptors (TLR) and nucleotide-binding oligomerization domain-like receptors (NLR) due to combined infections of SARS-CoV-2 with other microbes, mainly bacterial and fungal. This proposition is based on eight linked types of evidence and their logical connections. (1) Severe cases of COVID-19 differ from healthy controls and mild COVID-19 patients in exhibiting increased TLR4, TLR7, TLR9 and NLRP3 activity. (2) SARS-CoV-2 and related coronaviruses activate TLR3, TLR7, RIG1 and NLRP3. (3) SARS-CoV-2 cannot, therefore, account for the innate receptor activation pattern (IRAP) found in severe COVID-19 patients. (4) Severe COVID-19 also differs from its mild form in being characterized by bacterial and fungal infections. (5) Respiratory bacterial and fungal infections activate TLR2, TLR4, TLR9 and NLRP3. (6) A combination of SARS-CoV-2 with bacterial/fungal coinfections accounts for the IRAP found in severe COVID-19 and why it differs from mild cases. (7) Notably, TLR7 (viral) and TLR4 (bacterial/fungal) synergize, TLR9 and TLR4 (both bacterial/fungal) synergize and TLR2 and TLR4 (both bacterial/fungal) synergize with NLRP3 (viral and bacterial). (8) Thus, a SARS-CoV-2-bacterium/fungus coinfection produces synergistic innate activation, resulting in the hyperinflammation characteristic of a cytokine storm. Unique clinical, experimental and therapeutic predictions (such as why melatonin is effective in treating COVID-19) are discussed, and broader implications are outlined for understanding why other syndromes such as acute lung injury, acute respiratory distress syndrome and sepsis display varied cytokine storm symptoms.


Subject(s)
Acute Lung Injury/immunology , COVID-19/immunology , Cytokine Release Syndrome/immunology , NLR Proteins/immunology , Respiratory Distress Syndrome/immunology , Sepsis/immunology , Toll-Like Receptors/immunology , Acute Lung Injury/drug therapy , Acute Lung Injury/metabolism , Animals , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/metabolism , Humans , Inflammation/drug therapy , Inflammation/immunology , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/metabolism , SARS-CoV-2/immunology , Sepsis/drug therapy , Sepsis/metabolism , Toll-Like Receptors/metabolism
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