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1.
Clin Sci (Lond) ; 136(10): 747-769, 2022 May 27.
Article in English | MEDLINE | ID: covidwho-1873565

ABSTRACT

Pneumonia and its sequelae, acute lung injury, present unique challenges for pulmonary and critical care healthcare professionals, and these challenges have recently garnered global attention due to the ongoing Sars-CoV-2 pandemic. One limitation to translational investigation of acute lung injury, including its most severe manifestation (acute respiratory distress syndrome, ARDS) has been heterogeneity resulting from the clinical and physiologic diagnosis that represents a wide variety of etiologies. Recent efforts have improved our understanding and approach to heterogeneity by defining sub-phenotypes of ARDS although significant gaps in knowledge remain. Improving our mechanistic understanding of acute lung injury and its most common cause, infectious pneumonia, can advance our approach to precision targeted clinical interventions. Here, we review the pathogenesis of pneumonia and acute lung injury, including how respiratory infections and lung injury disrupt lung homoeostasis, and provide an overview of respiratory microbial pathogenesis, the lung microbiome, and interventions that have been demonstrated to improve outcomes-or not-in human clinical trials.


Subject(s)
Acute Lung Injury , COVID-19 , Pneumonia , Respiratory Distress Syndrome , Acute Lung Injury/etiology , Acute Lung Injury/pathology , Humans , Respiratory Distress Syndrome/etiology , SARS-CoV-2
2.
Front Immunol ; 13: 871828, 2022.
Article in English | MEDLINE | ID: covidwho-1855360

ABSTRACT

Background and Objectives: The novel coronavirus disease 2019 (COVID-19) has been a pandemic health issue in 30 January 2020. The mortality rate is as high as 50% in critically ill patients. Stem cell therapy is effective for those who are refractory to standard treatments. However, the immune responses that underlie stem cell therapy have not been well reported, particularly, in patients associated with moderate to severe acute respiratory distress syndrome (ARDS). Methods: On Days 0 and 4, an intravenous infusion of 2 × 107 placenta-derived mesenchymal stem cells (pcMSCs) (MatriPlax) were administered to five severe COVID-19 patients refractory to current standard therapies. Peripheral blood inflammatory markers and immune profiles were determined by multi-parameter flow cytometry and studied at Days 0, 4, and 8. Clinical outcomes were also observed. Results: None of the pc-MSC treated patients experienced 28-day mortality compared with the control group and showed a significant improvement in the PaO2/FiO2 ratio, Murray's lung injury scores, reduction in serum ferritin, lactate dehydrogenase (LDH), and C-reactive protein (CRP) levels. The cytokine profiles also showed a reduction in IL-1ß, IFN-γ, IL-2, and IL-6, and an increase in IL-13 and IL-5 type 2 cytokines within 7 days of therapy. Lymphopenia was also significantly improved after 7 days of treatment. Immune cell profiles showed an increase in the proportions of CD4+ T cells (namely, CD4+ naïve T cells and CD4+ memory T cell subtypes), Treg cells, CD19+ B cells (namely, CD19+ naïve B cells, CD27+ switched B cell subtypes) and dendritic cells, and a significant decrease in the proportion of CD14+ monocytes (namely, CD16- classical and CD16+ non-classical subtypes), and plasma/plasmablast cells. No adverse effects were seen at the serial follow-up visits for 2 months after initial therapy. Conclusion: pc-MSCs therapy suppressed hyper-inflammatory states of the innate immune response to COVID-19 infection by increasing Treg cells, decreasing monocytes and plasma/plasmablast cells, and promoting CD4+ T cells and CD19+ B cells toward adaptive immune responses in severely critically ill COVID-19 patients with moderate to severe ARDS, especially those who were refractory to current standard care and immunosuppressive therapies.


Subject(s)
Acute Lung Injury , COVID-19 , Respiratory Distress Syndrome , Acute Lung Injury/etiology , Acute Lung Injury/therapy , COVID-19/therapy , Critical Illness , Humans , Pandemics , Respiratory Distress Syndrome/therapy
3.
JCI Insight ; 7(5)2022 03 08.
Article in English | MEDLINE | ID: covidwho-1759583

ABSTRACT

Severe acute lung injury has few treatment options and a high mortality rate. Upon injury, neutrophils infiltrate the lungs and form neutrophil extracellular traps (NETs), damaging the lungs and driving an exacerbated immune response. Unfortunately, no drug preventing NET formation has completed clinical development. Here, we report that disulfiram - an FDA-approved drug for alcohol use disorder - dramatically reduced NETs, increased survival, improved blood oxygenation, and reduced lung edema in a transfusion-related acute lung injury (TRALI) mouse model. We then tested whether disulfiram could confer protection in the context of SARS-CoV-2 infection, as NETs are elevated in patients with severe COVID-19. In SARS-CoV-2-infected golden hamsters, disulfiram reduced NETs and perivascular fibrosis in the lungs, and it downregulated innate immune and complement/coagulation pathways, suggesting that it could be beneficial for patients with COVID-19. In conclusion, an existing FDA-approved drug can block NET formation and improve disease course in 2 rodent models of lung injury for which treatment options are limited.


Subject(s)
Acute Lung Injury/drug therapy , COVID-19/complications , Disulfiram/pharmacology , Extracellular Traps/drug effects , Lung/immunology , SARS-CoV-2 , Acetaldehyde Dehydrogenase Inhibitors/pharmacology , Acute Lung Injury/etiology , Animals , COVID-19/virology , Disease Models, Animal , Extracellular Traps/immunology , Rodentia
4.
Clin Exp Pharmacol Physiol ; 49(4): 483-491, 2022 04.
Article in English | MEDLINE | ID: covidwho-1691664

ABSTRACT

Progress in the study of Covid-19 disease in rodents has been hampered by the lack of angiotensin-converting enzyme 2 (ACE2; virus entry route to the target cell) affinities for the virus spike proteins across species. Therefore, we sought to determine whether a modified protocol of lipopolysaccharide (LPS)-induced acute respiratory distress syndrome in rats can mimic both cell signalling pathways as well as severe disease phenotypes of Covid-19 disease. Rats were injected via intratracheal (IT) instillation with either 15 mg/kg of LPS (model group) or saline (control group) before being killed after 3 days. A severe acute respiratory syndrome (SARS)-like effect was observed in the model group as demonstrated by the development of a "cytokine storm" (>2.7 fold increase in blood levels of IL-6, IL-17A, GM-CSF, and TNF-α), high blood ferritin, demonstrable coagulopathy, including elevated D-dimer (approximately 10-fold increase), PAI-1, PT, and APTT (p < 0.0001). In addition, LPS increased the expression of lung angiotensin II type I receptor (AT1R)-JAK-STAT axis (>4 fold increase). Chest imaging revealed bilateral small patchy opacities of the lungs. Severe lung injury was noted by the presence of both, alveolar collapse and haemorrhage, desquamation of epithelial cells in the airway lumen, infiltration of inflammatory cells (CD45+ leukocytes), widespread thickening of the interalveolar septa, and ultrastructural alterations similar to Covid-19. Thus, these findings demonstrate that IT injection of 15 mg/kg LPS into rats, induced an AT1R/JAK/STAT-mediated cytokine storm with resultant pneumonia and coagulopathy that was commensurate with moderate and severe Covid-19 disease noted in humans.


Subject(s)
Acute Lung Injury/etiology , Blood Coagulation Disorders/etiology , COVID-19/pathology , Cytokine Release Syndrome/etiology , Hemorrhage/etiology , Lipopolysaccharides/adverse effects , Lung Diseases/etiology , Receptor, Angiotensin, Type 1/metabolism , STAT Transcription Factors/metabolism , Signal Transduction , Acute Lung Injury/pathology , Animals , Blood Coagulation Disorders/pathology , COVID-19/etiology , Cytokine Release Syndrome/pathology , Disease Models, Animal , Hemorrhage/pathology , Janus Kinases , Lung Diseases/pathology , Male , Rats , Rats, Wistar
5.
Int J Mol Sci ; 22(23)2021 Nov 29.
Article in English | MEDLINE | ID: covidwho-1561718

ABSTRACT

S100A9, a pro-inflammatory alarmin, is up-regulated in inflamed tissues. However, the role of S100A9 in regulating neutrophil activation, inflammation and lung damage in sepsis is not known. Herein, we hypothesized that blocking S100A9 function may attenuate neutrophil recruitment in septic lung injury. Male C57BL/6 mice were pretreated with the S100A9 inhibitor ABR-238901 (10 mg/kg), prior to cercal ligation and puncture (CLP). Bronchoalveolar lavage fluid (BALF) and lung tissue were harvested for analysis of neutrophil infiltration as well as edema and CXC chemokine production. Blood was collected for analysis of membrane-activated complex-1 (Mac-1) expression on neutrophils as well as CXC chemokines and IL-6 in plasma. Induction of CLP markedly increased plasma levels of S100A9. ABR-238901 decreased CLP-induced neutrophil infiltration and edema formation in the lung. In addition, inhibition of S100A9 decreased the CLP-induced up-regulation of Mac-1 on neutrophils. Administration of ABR-238901 also inhibited the CLP-induced increase of CXCL-1, CXCL-2 and IL-6 in plasma and lungs. Our results suggest that S100A9 promotes neutrophil activation and pulmonary accumulation in sepsis. Targeting S100A9 function decreased formation of CXC chemokines in circulation and lungs and attenuated sepsis-induced lung damage. These novel findings suggest that S100A9 plays an important pro-inflammatory role in sepsis and could be a useful target to protect against the excessive inflammation and lung damage associated with the disease.


Subject(s)
Acute Lung Injury/prevention & control , Calgranulin B/metabolism , Neutrophil Infiltration/drug effects , Sepsis/complications , Acute Lung Injury/etiology , Acute Lung Injury/metabolism , Animals , Chemokines, CXC/metabolism , Drug Evaluation, Preclinical , Interleukin-6/metabolism , Lung/metabolism , Male , Mice, Inbred C57BL , Sepsis/immunology , Sepsis/metabolism
6.
Mod Pathol ; 35(Suppl 1): 1-7, 2022 01.
Article in English | MEDLINE | ID: covidwho-1402049

ABSTRACT

Recent world events have refocused attention on the pathology associated with clinical acute respiratory distress syndrome (ARDS). The vast majority of cases of clinical ARDS will have diffuse alveolar damage (DAD) histologically, but other histologies may occur less frequently. The aim of this paper is to provide a review of the pathology of DAD and acute fibrinous and organizing pneumonia and provide insights into the pathologic features associated with the E-cigarette/vaping-associated lung-injury outbreak and the ongoing SARS-CoV-2 pandemic.


Subject(s)
Acute Lung Injury/etiology , COVID-19/complications , Respiratory Distress Syndrome/etiology , Vaping/adverse effects , Cannabis , Electronic Nicotine Delivery Systems , Humans , Lung/pathology
7.
Am J Physiol Lung Cell Mol Physiol ; 321(2): L477-L484, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1376529

ABSTRACT

Acute lung injury (ALI) leading to acute respiratory distress syndrome is the major cause of COVID-19 lethality. Cell entry of SARS-CoV-2 occurs via the interaction between its surface spike protein (SP) and angiotensin-converting enzyme-2 (ACE2). It is unknown if the viral spike protein alone is capable of altering lung vascular permeability in the lungs or producing lung injury in vivo. To that end, we intratracheally instilled the S1 subunit of SARS-CoV-2 spike protein (S1SP) in K18-hACE2 transgenic mice that overexpress human ACE2 and examined signs of COVID-19-associated lung injury 72 h later. Controls included K18-hACE2 mice that received saline or the intact SP and wild-type (WT) mice that received S1SP. K18-hACE2 mice instilled with S1SP exhibited a decline in body weight, dramatically increased white blood cells and protein concentrations in bronchoalveolar lavage fluid (BALF), upregulation of multiple inflammatory cytokines in BALF and serum, histological evidence of lung injury, and activation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways in the lung. K18-hACE2 mice that received either saline or SP exhibited little or no evidence of lung injury. WT mice that received S1SP exhibited a milder form of COVID-19 symptoms, compared with the K18-hACE2 mice. Furthermore, S1SP, but not SP, decreased cultured human pulmonary microvascular transendothelial resistance (TER) and barrier function. This is the first demonstration of a COVID-19-like response by an essential virus-encoded protein by SARS-CoV-2 in vivo. This model of COVID-19-induced ALI may assist in the investigation of new therapeutic approaches for the management of COVID-19 and other coronaviruses.


Subject(s)
Acute Lung Injury/pathology , COVID-19/complications , Cell Membrane Permeability , Endothelial Cells/pathology , Lung/pathology , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/metabolism , Acute Lung Injury/etiology , Acute Lung Injury/metabolism , Animals , Disease Models, Animal , Endothelial Cells/metabolism , Endothelial Cells/virology , Humans , Lung/metabolism , Lung/virology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Protein Subunits , Spike Glycoprotein, Coronavirus/genetics , Virus Replication
8.
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
10.
Am J Physiol Lung Cell Mol Physiol ; 321(2): L477-L484, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1280498

ABSTRACT

Acute lung injury (ALI) leading to acute respiratory distress syndrome is the major cause of COVID-19 lethality. Cell entry of SARS-CoV-2 occurs via the interaction between its surface spike protein (SP) and angiotensin-converting enzyme-2 (ACE2). It is unknown if the viral spike protein alone is capable of altering lung vascular permeability in the lungs or producing lung injury in vivo. To that end, we intratracheally instilled the S1 subunit of SARS-CoV-2 spike protein (S1SP) in K18-hACE2 transgenic mice that overexpress human ACE2 and examined signs of COVID-19-associated lung injury 72 h later. Controls included K18-hACE2 mice that received saline or the intact SP and wild-type (WT) mice that received S1SP. K18-hACE2 mice instilled with S1SP exhibited a decline in body weight, dramatically increased white blood cells and protein concentrations in bronchoalveolar lavage fluid (BALF), upregulation of multiple inflammatory cytokines in BALF and serum, histological evidence of lung injury, and activation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways in the lung. K18-hACE2 mice that received either saline or SP exhibited little or no evidence of lung injury. WT mice that received S1SP exhibited a milder form of COVID-19 symptoms, compared with the K18-hACE2 mice. Furthermore, S1SP, but not SP, decreased cultured human pulmonary microvascular transendothelial resistance (TER) and barrier function. This is the first demonstration of a COVID-19-like response by an essential virus-encoded protein by SARS-CoV-2 in vivo. This model of COVID-19-induced ALI may assist in the investigation of new therapeutic approaches for the management of COVID-19 and other coronaviruses.


Subject(s)
Acute Lung Injury/pathology , COVID-19/complications , Cell Membrane Permeability , Endothelial Cells/pathology , Lung/pathology , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/metabolism , Acute Lung Injury/etiology , Acute Lung Injury/metabolism , Animals , Disease Models, Animal , Endothelial Cells/metabolism , Endothelial Cells/virology , Humans , Lung/metabolism , Lung/virology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Protein Subunits , Spike Glycoprotein, Coronavirus/genetics , Virus Replication
12.
Front Immunol ; 12: 669539, 2021.
Article in English | MEDLINE | ID: covidwho-1259346

ABSTRACT

Acute lung injury (ALI) is an intractable disorder associated with macrophages. This bibliometric analysis was applied to identify the characteristics of global scientific output, the hotspots, and frontiers about macrophages in ALI over the past 10 years. We retrieved publications published from 2011 to 2020 and their recorded information from Science Citation Index Expanded (SCI-expanded) of Web of Science Core Collection (WoSCC). Bibliometrix package was used to analyze bibliometric indicators, and the VOSviewer was used to visualize the trend and hotspots of researches on macrophages in ALI. Altogether, 2,632 original articles were reviewed, and the results showed that the annual number of publications (Np) concerning the role of macrophages in ALI kept increasing over the past 10 years. China produced the most papers, the number of citations (Nc) and H-index of the USA ranked first. Shanghai Jiaotong University and INT IMMUNOPHARMACOL were the most prolific affiliation and journal, respectively. Papers published by Matute-Bello G in 2011 had the highest local citation score (LCS). Recently, the keywords "NLRP3" and "extracellular vesicles" appeared most frequently. Besides, researches on COVID-19-induced ALI related to macrophages seemed to be the hotspot recently. This bibliometric study revealed that publications related to macrophages in ALI tend to increase continuously. China was a big producer and the USA was an influential country in this field. Most studies were mainly centered on basic researches in the past decade, and pathways associated with the regulatory role of macrophages in inhibiting and attenuating ALI have become the focus of attention in more recent studies. What is more, our bibliometric analysis showed that macrophages play an important role in COVID-19-induced ALI and may be a target for the treatment of COVID-19.


Subject(s)
Acute Lung Injury/immunology , Bibliometrics , Macrophages/immunology , Acute Lung Injury/etiology , Asia , Brazil , COVID-19/complications , COVID-19/immunology , Europe , Humans , North America , Publishing/trends , SARS-CoV-2
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.
J Clin Endocrinol Metab ; 106(6): 1637-1648, 2021 05 13.
Article in English | MEDLINE | ID: covidwho-1099909

ABSTRACT

CONTEXT: Dysnatremia is an independent predictor of mortality in patients with bacterial pneumonia. There is paucity of data about the incidence and prognostic impact of abnormal sodium concentration in patients with coronavirus disease 2019 (COVID-19). OBJECTIVE: This work aimed to examine the association of serum sodium during hospitalization with key clinical outcomes, including mortality, need for advanced respiratory support and acute kidney injury (AKI), and to explore the role of serum sodium as a marker of inflammatory response in COVID-19. METHODS: This retrospective longitudinal cohort study, including all adult patients who presented with COVID-19 to 2 hospitals in London over an 8-week period, evaluated the association of dysnatremia (serum sodium < 135 or > 145 mmol/L, hyponatremia, and hypernatremia, respectively) at several time points with inpatient mortality, need for advanced ventilatory support, and AKI. RESULTS: The study included 488 patients (median age, 68 years). At presentation, 24.6% of patients were hyponatremic, mainly due to hypovolemia, and 5.3% hypernatremic. Hypernatremia 2 days after admission and exposure to hypernatremia at any time point during hospitalization were associated with a 2.34-fold (95% CI, 1.08-5.05; P = .0014) and 3.05-fold (95% CI, 1.69-5.49; P < .0001) increased risk of death, respectively, compared to normonatremia. Hyponatremia at admission was linked with a 2.18-fold increase in the likelihood of needing ventilatory support (95% CI, 1.34-3.45, P = .0011). Hyponatremia was not a risk factor for in-hospital mortality, except for the subgroup of patients with hypovolemic hyponatremia. Sodium values were not associated with the risk for AKI and length of hospital stay. CONCLUSION: Abnormal sodium levels during hospitalization are risk factors for poor prognosis, with hypernatremia and hyponatremia being associated with a greater risk of death and respiratory failure, respectively. Serum sodium values could be used for risk stratification in patients with COVID-19.


Subject(s)
COVID-19/epidemiology , COVID-19/mortality , Sodium/blood , Acute Lung Injury/epidemiology , Acute Lung Injury/etiology , Aged , Aged, 80 and over , COVID-19/blood , Cohort Studies , Female , Hospital Mortality , Humans , Hypernatremia/etiology , Hypernatremia/mortality , Hyponatremia/etiology , Hyponatremia/mortality , Incidence , Length of Stay , London/epidemiology , Longitudinal Studies , Male , Middle Aged , Predictive Value of Tests , Prognosis , Respiration, Artificial , Risk Factors , Systemic Inflammatory Response Syndrome/blood , Systemic Inflammatory Response Syndrome/etiology
15.
Cell Rep Med ; 1(8): 100145, 2020 11 17.
Article in English | MEDLINE | ID: covidwho-1065661

ABSTRACT

A screen by Kost-Alimova et al.1 suggests that the FDA-approved SYK inhibitor fostamatinib inhibits MUC1 in the respiratory tract and has the potential to treat serious outcomes of coronavirus COVID-19, including acute respiratory distress syndrome (ARDS) and acute lung injury (ALI).


Subject(s)
Acute Lung Injury/drug therapy , Aminopyridines/therapeutic use , COVID-19/drug therapy , Drug Repositioning , Morpholines/therapeutic use , Pyrimidines/therapeutic use , SARS-CoV-2/pathogenicity , Acute Lung Injury/etiology , Acute Lung Injury/metabolism , COVID-19/complications , COVID-19/metabolism , Humans , Mucin-1/metabolism , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/metabolism , Syk Kinase/antagonists & inhibitors
16.
Adv Ther ; 38(1): 782-791, 2021 01.
Article in English | MEDLINE | ID: covidwho-1064616

ABSTRACT

INTRODUCTION: The COVID-19 global pandemic caused by the novel coronavirus, SARS-CoV-2, and the consequent morbidity and mortality attributable to progressive hypoxemia and subsequent respiratory failure threaten to overrun hospital critical care units globally. New agents that address the hyperinflammatory "cytokine storm" and hypercoagulable pathology seen in these patients may be a promising approach to treat patients, minimize hospital stays, and ensure hospital wards and critical care units are able to operate effectively. Dociparstat sodium (DSTAT) is a glycosaminoglycan derivative of heparin with robust anti-inflammatory properties, with the potential to address underlying causes of coagulation disorders with substantially reduced risk of bleeding compared to commercially available heparin. METHODS: This study is a randomized, double-blind, placebo-controlled, phase 2/3 trial to determine the safety and efficacy of DSTAT added to standard of care in hospitalized adults with COVID-19 who require supplemental oxygen. Phase 2 will enroll 12 participants in each of two dose-escalating cohorts to confirm the safety of DSTAT in this population. Following review of the data, an additional 50 participants will be enrolled. Contingent upon positive results, phase 3 will enroll approximately 450 participants randomized to DSTAT or placebo. The primary endpoint is the proportion of participants who survive and do not require mechanical ventilation through day 28. DISCUSSION: Advances in standard of care, recent emergency use authorizations, and positive data with dexamethasone have likely contributed to an increasing proportion of patients who are surviving without the need for mechanical ventilation. Therefore, examining the time to improvement in the NIAID score will be essential to provide a measure of drug effect on recovery. Analysis of additional endpoints, including supportive biomarkers (e.g., IL-6, HMGB1, soluble-RAGE, D-dimer), will be performed to further define the effect of DSTAT in patients with COVID-19 infection. TRIAL REGISTRATION: ClinicalTrials.gov identifier; NCT04389840, Registered 13 May 2020.


Subject(s)
Acute Lung Injury/drug therapy , Anti-Inflammatory Agents/therapeutic use , COVID-19/complications , COVID-19/drug therapy , Heparin/therapeutic use , Respiratory Insufficiency/drug therapy , Acute Lung Injury/etiology , Adult , Aged , Aged, 80 and over , Double-Blind Method , Female , Humans , Male , Middle Aged , Respiratory Insufficiency/etiology , SARS-CoV-2/drug effects , Treatment Outcome
17.
Int J Infect Dis ; 102: 196-202, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1059376

ABSTRACT

A novel coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) has been confirmed as having the capacity to transmit from humans to humans, causing acute respiratory distress syndrome (ARDS) and acute lung injury. Angiotensin converting enzyme-2 (ACE2) is known to be expressed on type II pneumocytes. As a counter-regulatory arm of the renin-angiotensin system (RAS), ACE2 plays critical roles in the pathogenesis of ARDS and acute lung injury. The affinity of the spike protein receptor binding domain (RBD) of SARS-CoV-2 for human ACE2 (hACE2) largely determines the degree of clinical symptoms after infection by SARS-CoV-2. Previous studies have shown that regulating the ACE2/RAS system is effective in the treatment of severe acute respiratory syndrome coronavirus (SARS-CoV)-induced ARDS and acute lung injury. Since ACE2 is the host cell receptor for both SARS-CoV-2 and SARS-CoV, regulating the ACE2/RAS system may alleviate ARDS and acute lung injury caused by SARS-CoV-2 as well as SARS-CoV. Vitamin D was found to affect ACE2, the target of SARS-CoV-2; therefore, we propose that vitamin D might alleviate ARDS and acute lung injury induced by SARS-CoV-2 by modulating ACE2.


Subject(s)
Acute Lung Injury/etiology , COVID-19/complications , SARS-CoV-2 , Vitamin D/therapeutic use , Acute Lung Injury/drug therapy , Angiotensin-Converting Enzyme 2/physiology , Humans , Renin-Angiotensin System/physiology , Respiratory Distress Syndrome/etiology
18.
Pediatrics ; 147(1)2021 01.
Article in English | MEDLINE | ID: covidwho-1059364

ABSTRACT

A 16-year-old white boy with a history of chronic lung disease of prematurity, cough-variant asthma, and incidental lung nodules presented to the emergency center in spring 2020 with acute onset dry cough, shortness of breath, and fever. An initial history, gathered from his mother because of the patient's respiratory distress, revealed no recent travel. However, his mother is a health care worker at a hospital, and sick contacts included ongoing contact with a friend with cold-like symptoms. He had a variety of animals at home, including a dog, cats, fish, rodents, and reptiles. He had a history of vaping tobacco products >6 months ago. Fever and respiratory symptoms were associated with fatigue, chest tightness, abdominal pain, and myalgias. On examination, he was ill appearing and had tachycardia, tachypnea, borderline hypoxia with an oxygen saturation of 91% on room air, diminished breath sounds at the lung bases, and unremarkable abdominal examination results. A chest radiograph was consistent with the lung examination, revealing bilateral lower lobe hazy infiltrates. He showed initial improvement for 48 hours with antibiotics, intravenous fluid resuscitation, oxygen via nasal cannula, albuterol, and prednisone. Subsequently, he worsened with persistent high fever, increasing respiratory distress with pulmonary findings, and severe persistent epigastric pain, which added a layer of diagnostic complexity. As this patient's clinical course evolved and further history became available, pulmonary medicine and infectious diseases services were consulted to guide diagnostic evaluation and treatment of this patient early in the era of coronavirus disease 2019.


Subject(s)
Acute Lung Injury/diagnostic imaging , COVID-19 , Cough/diagnostic imaging , Fever/diagnostic imaging , Vaping/adverse effects , Acute Lung Injury/etiology , Adolescent , COVID-19/diagnostic imaging , COVID-19/genetics , Cough/etiology , Diagnosis, Differential , Fever/etiology , Humans , Male , Real-Time Polymerase Chain Reaction/methods , Vaping/pathology
19.
Front Immunol ; 11: 604944, 2020.
Article in English | MEDLINE | ID: covidwho-1058416

ABSTRACT

Hypoxia and inflammation often coincide in pathogenic conditions such as acute respiratory distress syndrome (ARDS) and chronic lung diseases, which are significant contributors to morbidity and mortality for the general population. For example, the recent global outbreak of Coronavirus disease 2019 (COVID-19) has placed viral infection-induced ARDS under the spotlight. Moreover, chronic lung disease ranks the third leading cause of death in the United States. Hypoxia signaling plays a diverse role in both acute and chronic lung inflammation, which could partially be explained by the divergent function of downstream target pathways such as adenosine signaling. Particularly, hypoxia signaling activates adenosine signaling to inhibit the inflammatory response in ARDS, while in chronic lung diseases, it promotes inflammation and tissue injury. In this review, we discuss the role of adenosine at the interphase of hypoxia and inflammation in ARDS and chronic lung diseases, as well as the current strategy for therapeutic targeting of the adenosine signaling pathway.


Subject(s)
Adenosine/metabolism , Hypoxia/metabolism , Inflammation/metabolism , Acute Lung Injury/etiology , Acute Lung Injury/metabolism , Acute Lung Injury/pathology , Acute Lung Injury/therapy , Disease Management , Disease Susceptibility , Humans , Hypoxia-Inducible Factor 1/metabolism , Inflammation/etiology , Molecular Targeted Therapy , Receptors, Purinergic P1/metabolism , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/therapy , Signal Transduction
20.
Radiat Res ; 195(1): 1-24, 2021 01 01.
Article in English | MEDLINE | ID: covidwho-1021760

ABSTRACT

As the multi-systemic components of COVID-19 emerge, parallel etiologies can be drawn between SARS-CoV-2 infection and radiation injuries. While some SARS-CoV-2-infected individuals present as asymptomatic, others exhibit mild symptoms that may include fever, cough, chills, and unusual symptoms like loss of taste and smell and reddening in the extremities (e.g., "COVID toes," suggestive of microvessel damage). Still others alarm healthcare providers with extreme and rapid onset of high-risk indicators of mortality that include acute respiratory distress syndrome (ARDS), multi-organ hypercoagulation, hypoxia and cardiovascular damage. Researchers are quickly refocusing their science to address this enigmatic virus that seems to unveil itself in new ways without discrimination. As investigators begin to identify early markers of disease, identification of common threads with other pathologies may provide some clues. Interestingly, years of research in the field of radiation biology documents the complex multiorgan nature of another disease state that occurs after exposure to high doses of radiation: the acute radiation syndrome (ARS). Inflammation is a key common player in COVID-19 and ARS, and drives the multi-system damage that dramatically alters biological homeostasis. Both conditions initiate a cytokine storm, with similar pro-inflammatory molecules increased and other anti-inflammatory molecules decreased. These changes manifest in a variety of ways, with a demonstrably higher health impact in patients having underlying medical conditions. The potentially dramatic human impact of ARS has guided the science that has identified many biomarkers of radiation exposure, established medical management strategies for ARS, and led to the development of medical countermeasures for use in the event of a radiation public health emergency. These efforts can now be leveraged to help elucidate mechanisms of action of COVID-19 injuries. Furthermore, this intersection between COVID-19 and ARS may point to approaches that could accelerate the discovery of treatments for both.


Subject(s)
COVID-19/physiopathology , Pandemics , Radiation Injuries/physiopathology , SARS-CoV-2/pathogenicity , Acute Lung Injury/etiology , Acute Lung Injury/physiopathology , Angiotensin-Converting Enzyme 2/deficiency , Angiotensin-Converting Enzyme 2/physiology , Animals , Anti-Bacterial Agents/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Antioxidants/therapeutic use , Biomarkers/blood , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/etiology , Blood Coagulation Disorders/physiopathology , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19/immunology , Clinical Trials as Topic , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/physiopathology , Hematologic Diseases/etiology , Hematologic Diseases/physiopathology , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Inflammation/etiology , Inflammation/physiopathology , Intercellular Signaling Peptides and Proteins/therapeutic use , Mesenchymal Stem Cell Transplantation , Mice , Organ Specificity , Pyroptosis , Radiation Injuries/blood , Radiation Injuries/drug therapy , Radiation Injuries/immunology , Receptors, Virus/physiology , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , SARS-CoV-2/isolation & purification , Vascular Diseases/drug therapy , Vascular Diseases/etiology , Vascular Diseases/physiopathology
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