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1.
JAMA Netw Open ; 5(3): e222735, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1748801

ABSTRACT

Importance: SARS-CoV-2 viral entry may disrupt angiotensin II (AII) homeostasis, contributing to COVID-19 induced lung injury. AII type 1 receptor blockade mitigates lung injury in preclinical models, although data in humans with COVID-19 remain mixed. Objective: To test the efficacy of losartan to reduce lung injury in hospitalized patients with COVID-19. Design, Setting, and Participants: This blinded, placebo-controlled randomized clinical trial was conducted in 13 hospitals in the United States from April 2020 to February 2021. Hospitalized patients with COVID-19 and a respiratory sequential organ failure assessment score of at least 1 and not already using a renin-angiotensin-aldosterone system (RAAS) inhibitor were eligible for participation. Data were analyzed from April 19 to August 24, 2021. Interventions: Losartan 50 mg orally twice daily vs equivalent placebo for 10 days or until hospital discharge. Main Outcomes and Measures: The primary outcome was the imputed arterial partial pressure of oxygen to fraction of inspired oxygen (Pao2:Fio2) ratio at 7 days. Secondary outcomes included ordinal COVID-19 severity; days without supplemental o2, ventilation, or vasopressors; and mortality. Losartan pharmacokinetics and RAAS components (AII, angiotensin-[1-7] and angiotensin-converting enzymes 1 and 2)] were measured in a subgroup of participants. Results: A total of 205 participants (mean [SD] age, 55.2 [15.7] years; 123 [60.0%] men) were randomized, with 101 participants assigned to losartan and 104 participants assigned to placebo. Compared with placebo, losartan did not significantly affect Pao2:Fio2 ratio at 7 days (difference, -24.8 [95%, -55.6 to 6.1]; P = .12). Compared with placebo, losartan did not improve any secondary clinical outcomes and led to fewer vasopressor-free days than placebo (median [IQR], 9.4 [9.1-9.8] vasopressor-free days vs 8.7 [8.2-9.3] vasopressor-free days). Conclusions and Relevance: This randomized clinical trial found that initiation of orally administered losartan to hospitalized patients with COVID-19 and acute lung injury did not improve Pao2:Fio2 ratio at 7 days. These data may have implications for ongoing clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT04312009.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/therapeutic use , COVID-19/complications , COVID-19/drug therapy , Losartan/therapeutic use , Lung Injury/prevention & control , Lung Injury/virology , Adult , Aged , COVID-19/diagnosis , Double-Blind Method , Female , Hospitalization , Humans , Lung Injury/diagnosis , Male , Middle Aged , Organ Dysfunction Scores , Respiratory Function Tests , United States
2.
Iran Biomed J ; 25(6): 381-9, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1599259

ABSTRACT

Background: Lung injury is common in coronavirus disease 2019 (COVID-19) patients. The severity of lung injury appears to be reflected in serum Krebs von den Lungen-6 (KL-6), a glycoprotein expressed on type II alveolar epithelium. This study aims to assess the role of serum KL-6 in reflecting the severity of lung injury in COVID-19 patients. Methods: A systematic search was conducted in Scopus, PubMed, Wiley Online Library, and ProQuest. Articles were screened based on several eligibility criteria and assessed for study quality using Newcastle-Ottawa Scale. Results: This systematic review included four studies involving a total of 151 adult COVID-19 patients. Pooled analysis revealed that serum KL-6 was significantly higher in severe patients (SMD = 1.16; 95% CI = 0.69­1.63) with moderately high pooled sensitivity (79%; 95% CI = 61­91%) and specificity (86%; 95% CI = 72­95%). Conclusion: High serum KL-6 may depict more severe lung injury in COVID-19 patients with moderately high sensitivity and specificity.


Subject(s)
COVID-19/complications , Lung Injury/diagnosis , Lung Injury/virology , Mucin-1/blood , Severity of Illness Index , Biomarkers/blood , COVID-19/blood , COVID-19/diagnosis , Humans , Lung Injury/blood , Sensitivity and Specificity
3.
Signal Transduct Target Ther ; 6(1): 428, 2021 12 17.
Article in English | MEDLINE | ID: covidwho-1585884

ABSTRACT

SARS-CoV-2 infection-induced hyper-inflammation links to the acute lung injury and COVID-19 severity. Identifying the primary mediators that initiate the uncontrolled hypercytokinemia is essential for treatments. Mast cells (MCs) are strategically located at the mucosa and beneficially or detrimentally regulate immune inflammations. In this study, we showed that SARS-CoV-2-triggered MC degranulation initiated alveolar epithelial inflammation and lung injury. SARS-CoV-2 challenge induced MC degranulation in ACE-2 humanized mice and rhesus macaques, and a rapid MC degranulation could be recapitulated with Spike-RBD binding to ACE2 in cells; MC degranulation altered various signaling pathways in alveolar epithelial cells, particularly, the induction of pro-inflammatory factors and consequential disruption of tight junctions. Importantly, the administration of clinical MC stabilizers for blocking degranulation dampened SARS-CoV-2-induced production of pro-inflammatory factors and prevented lung injury. These findings uncover a novel mechanism for SARS-CoV-2 initiating lung inflammation, and suggest an off-label use of MC stabilizer as immunomodulators for COVID-19 treatments.


Subject(s)
COVID-19/metabolism , Cell Degranulation , Lung Injury/metabolism , Mast Cells/metabolism , Pulmonary Alveoli/metabolism , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/genetics , Cell Line, Tumor , Female , Humans , Lung Injury/genetics , Lung Injury/virology , Macaca mulatta , Male , Mice, Inbred BALB C , Mice, Transgenic , Pulmonary Alveoli/virology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
4.
Front Biosci (Landmark Ed) ; 26(10): 948-961, 2021 10 30.
Article in English | MEDLINE | ID: covidwho-1498509

ABSTRACT

Background: Corona Virus Disease 2019 (COVID-19) is an acute respiratory infectious disease caused by severe respiratory syndrome coronavirus 2 (SARS-CoV-2). The primary pathogenesis is over-activation of the immune system. SARS-CoV-2 continues to mutate and spread rapidly and no effective treatment options are yet available. Mesenchymal stem cells (MSCs) are known to induce anti-inflammatory macrophages, regulatory T cells and dendritic cells. There are a rapidly increasing number of clinical investigations of cell-based therapy approaches for COVID-19. Objective: To summarize the pathogenic mechanism of SARS-CoV-2, and systematically formulated the immunomodulation of COVID-19 by MSCs and their exosomes, as well as research progress. Method: Searching PubMed, clinicaltrials.gov and Chictr.cn for eligible studies to be published or registered by May 2021. Main keywords and search strategies were as follows: ((Mesenchymal stem cells) OR (MSCs)) AND (COVID-19). Results: MSCs regulate the immune system to prevent cytokine release syndrome (CRS) and to promote endogenous repair by releasing various paracrine factors and exosomes. Conclusions: MSC therapy is thus a promising candidate for COVID-19.


Subject(s)
COVID-19/therapy , Exosomes/transplantation , Immunomodulation/immunology , Lung Injury/therapy , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/metabolism , COVID-19/epidemiology , COVID-19/virology , Clinical Trials as Topic , Exosomes/immunology , Exosomes/metabolism , Humans , Lung Injury/physiopathology , Lung Injury/virology , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/immunology , Outcome Assessment, Health Care/methods , Outcome Assessment, Health Care/statistics & numerical data , Pandemics , Regeneration/immunology , Regeneration/physiology , SARS-CoV-2/immunology , SARS-CoV-2/physiology
5.
Physiology (Bethesda) ; 37(2): 88-100, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1484087

ABSTRACT

The lung is the major target organ of SARS-CoV-2 infection, which causes COVID-19. Here, we outline the multistep mechanisms of lung epithelial and endothelial injury induced by SARS-CoV-2: direct viral infection, chemokine/cytokine-mediated damage, and immune cell-mediated lung injury. Finally, we discuss the recent progress in terms of antiviral therapeutics as well as the development of anti-inflammatory or immunomodulatory therapeutic approaches. This review also provides a systematic overview of the models for studying SARS-CoV-2 infection and discusses how an understanding of mechanisms of lung injury will help identify potential targets for future drug development to mitigate lung injury.


Subject(s)
COVID-19 , Lung Injury , Antiviral Agents/therapeutic use , COVID-19/complications , Humans , Lung , Lung Injury/drug therapy , Lung Injury/virology , SARS-CoV-2
6.
Front Immunol ; 12: 735922, 2021.
Article in English | MEDLINE | ID: covidwho-1477823

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major public health issue. COVID-19 is considered an airway/multi-systemic disease, and demise has been associated with an uncontrolled immune response and a cytokine storm in response to the virus. However, the lung pathology, immune response, and tissue damage associated with COVID-19 demise are poorly described and understood due to safety concerns. Using post-mortem lung tissues from uninfected and COVID-19 deadly cases as well as an unbiased combined analysis of histology, multi-viral and host markers staining, correlative microscopy, confocal, and image analysis, we identified three distinct phenotypes of COVID-19-induced lung damage. First, a COVID-19-induced hemorrhage characterized by minimal immune infiltration and large thrombus; Second, a COVID-19-induced immune infiltration with excessive immune cell infiltration but no hemorrhagic events. The third phenotype correspond to the combination of the two previous ones. We observed the loss of alveolar wall integrity, detachment of lung tissue pieces, fibroblast proliferation, and extensive fibrosis in all three phenotypes. Although lung tissues studied were from lethal COVID-19, a strong immune response was observed in all cases analyzed with significant B cell and poor T cell infiltrations, suggesting an exhausted or compromised immune cellular response in these patients. Overall, our data show that SARS-CoV-2-induced lung damage is highly heterogeneous. These individual differences need to be considered to understand the acute and long-term COVID-19 consequences.


Subject(s)
COVID-19/mortality , COVID-19/pathology , Lung Injury/pathology , Pulmonary Alveoli/pathology , Pulmonary Fibrosis/pathology , Aged , Aged, 80 and over , Autopsy , CD8-Positive T-Lymphocytes/immunology , Cytokine Release Syndrome/mortality , Cytokine Release Syndrome/pathology , Epithelial Cells/pathology , Female , Hemorrhage/pathology , Humans , Inflammation/pathology , Lung/pathology , Lung Injury/virology , Lymphopenia/pathology , Macrophage Activation/immunology , Macrophages/immunology , Male , Middle Aged , Myocytes, Smooth Muscle/pathology , Neutrophils/immunology , SARS-CoV-2 , Thrombosis/pathology
7.
Phytother Res ; 35(9): 4988-5006, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1432473

ABSTRACT

The SARS-CoV-2 virus, responsible for COVID-19, spread rapidly worldwide and became a pandemic in 2020. In some patients, the virus remains in the respiratory tract, causing pneumonia, respiratory failure, acute respiratory distress syndrome (ARDS), and sepsis, leading to death. Natural flavonoids (aglycone and glycosides) possess broad biological activities encompassing antiinflammatory, antiviral, antitumoral, antiallergic, antiplatelet, and antioxidant effects. While many studies have focused on the effects of natural flavonoids in experimental models, reports based on clinical trials are still insufficient. In this review, we highlight the effects of flavonoids in controlling pulmonary diseases, particularly the acute respiratory distress syndrome, a consequence of COVID-19, and their potential use in coronavirus-related diseases. Furthermore, we also focus on establishing a relationship between biological potential and chemical aspects of related flavonoids and discuss several possible mechanisms of action, pointing out some possible effects on COVID-19.


Subject(s)
COVID-19 , Flavonoids , Lung Injury , COVID-19/complications , Flavonoids/pharmacology , Humans , Lung Injury/drug therapy , Lung Injury/virology , Pandemics
8.
Cell Rep ; 37(1): 109798, 2021 10 05.
Article in English | MEDLINE | ID: covidwho-1415262

ABSTRACT

Despite the worldwide effect of the coronavirus disease 2019 (COVID-19) pandemic, the underlying mechanisms of fatal viral pneumonia remain elusive. Here, we show that critical COVID-19 is associated with enhanced eosinophil-mediated inflammation when compared to non-critical cases. In addition, we confirm increased T helper (Th)2-biased adaptive immune responses, accompanying overt complement activation, in the critical group. Moreover, enhanced antibody responses and complement activation are associated with disease pathogenesis as evidenced by formation of immune complexes and membrane attack complexes in airways and vasculature of lung biopsies from six fatal cases, as well as by enhanced hallmark gene set signatures of Fcγ receptor (FcγR) signaling and complement activation in myeloid cells of respiratory specimens from critical COVID-19 patients. These results suggest that SARS-CoV-2 infection may drive specific innate immune responses, including eosinophil-mediated inflammation, and subsequent pulmonary pathogenesis via enhanced Th2-biased immune responses, which might be crucial drivers of critical disease in COVID-19 patients.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , Complement System Proteins/immunology , Eosinophils/immunology , Inflammation/immunology , Pneumonia, Viral/immunology , SARS-CoV-2/immunology , Adaptive Immunity , Adult , Aged , Aged, 80 and over , Antigen-Antibody Complex/metabolism , COVID-19/metabolism , COVID-19/virology , Complement Activation , Complement Membrane Attack Complex/metabolism , Eosinophils/virology , Female , Humans , Inflammation/metabolism , Inflammation/virology , Lung Injury/immunology , Lung Injury/pathology , Lung Injury/virology , Male , Middle Aged , Pneumonia, Viral/metabolism , Receptors, IgG/immunology , Receptors, IgG/metabolism , Severity of Illness Index , Signal Transduction , Th2 Cells/immunology , Viral Load , Young Adult
9.
Signal Transduct Target Ther ; 6(1): 339, 2021 09 08.
Article in English | MEDLINE | ID: covidwho-1402052

ABSTRACT

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has placed a global public burden on health authorities. Although the virological characteristics and pathogenesis of COVID-19 has been largely clarified, there is currently no specific therapeutic measure. In severe cases, acute SARS-CoV-2 infection leads to immune disorders and damage to both the adaptive and innate immune responses. Having roles in immune regulation and regeneration, mesenchymal stem cells (MSCs) serving as a therapeutic option may regulate the over-activated inflammatory response and promote recovery of lung damage. Since the outbreak of the COVID-19 pandemic, a series of MSC-therapy clinical trials has been conducted. The findings indicate that MSC treatment not only significantly reduces lung damage, but also improves patient recovery with safety and good immune tolerance. Herein, we summarize the recent progress in MSC therapy for COVID-19 and highlight the challenges in the field.


Subject(s)
COVID-19/therapy , Lung Injury/therapy , Lung/immunology , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/immunology , SARS-CoV-2/immunology , Animals , COVID-19/immunology , COVID-19/pathology , Humans , Lung/pathology , Lung/virology , Lung Injury/immunology , Lung Injury/virology , Mesenchymal Stem Cells/pathology
10.
Dis Markers ; 2021: 5566826, 2021.
Article in English | MEDLINE | ID: covidwho-1341351

ABSTRACT

An excess formation of neutrophil extracellular traps (NETs), previously shown to be strongly associated with cytokine storm and acute respiratory distress syndrome (ARDS) with prevalent endothelial dysfunction and thrombosis, has been postulated to be a central factor influencing the pathophysiology and clinical presentation of severe COVID-19. A growing number of serological and morphological evidence has added to this assumption, also in regard to potential treatment options. In this study, we used immunohistochemistry and histochemistry to trace NETs and their molecular markers in autopsy lung tissue from seven COVID-19 patients. Quantification of key immunomorphological features enabled comparison with non-COVID-19 diffuse alveolar damage. Our results strengthen and extend recent findings, confirming that NETs are abundantly present in seriously damaged COVID-19 lung tissue, especially in association with microthrombi of the alveolar capillaries. In addition, we provide evidence that low-density neutrophils (LDNs), which are especially prone to NETosis, contribute substantially to COVID-19-associated lung damage in general and vascular blockages in particular.


Subject(s)
COVID-19/pathology , Extracellular Traps , Lung Injury/pathology , Neutrophils/pathology , Aged , Aged, 80 and over , Antigens, CD/metabolism , Autopsy , Cell Adhesion Molecules/metabolism , Extracellular Traps/virology , Female , GPI-Linked Proteins/metabolism , Humans , Immunohistochemistry , Lung/pathology , Lung/virology , Lung Injury/virology , Male , Neutrophils/metabolism , Neutrophils/virology , Peroxidase/metabolism
11.
Crit Care ; 25(1): 276, 2021 08 04.
Article in English | MEDLINE | ID: covidwho-1339145

ABSTRACT

BACKGROUND: Typical features differentiate COVID-19-associated lung injury from acute respiratory distress syndrome. The clinical role of chest computed tomography (CT) in describing the progression of COVID-19-associated lung injury remains to be clarified. We investigated in COVID-19 patients the regional distribution of lung injury and the influence of clinical and laboratory features on its progression. METHODS: This was a prospective study. For each CT, twenty images, evenly spaced along the cranio-caudal axis, were selected. For regional analysis, each CT image was divided into three concentric subpleural regions of interest and four quadrants. Hyper-, normally, hypo- and non-inflated lung compartments were defined. Nonparametric tests were used for hypothesis testing (α = 0.05). Spearman correlation test was used to detect correlations between lung compartments and clinical features. RESULTS: Twenty-three out of 111 recruited patients were eligible for further analysis. Five hundred-sixty CT images were analyzed. Lung injury, composed by hypo- and non-inflated areas, was significantly more represented in subpleural than in core lung regions. A secondary, centripetal spread of lung injury was associated with exposure to mechanical ventilation (p < 0.04), longer spontaneous breathing (more than 14 days, p < 0.05) and non-protective tidal volume (p < 0.04). Positive fluid balance (p < 0.01), high plasma D-dimers (p < 0.01) and ferritin (p < 0.04) were associated with increased lung injury. CONCLUSIONS: In a cohort of COVID-19 patients with severe respiratory failure, a predominant subpleural distribution of lung injury is observed. Prolonged spontaneous breathing and high tidal volumes, both causes of patient self-induced lung injury, are associated to an extensive involvement of more central regions. Positive fluid balance, inflammation and thrombosis are associated with lung injury. Trial registration Study registered a priori the 20th of March, 2020. Clinical Trials ID NCT04316884.


Subject(s)
COVID-19/diagnostic imaging , Lung Injury/diagnostic imaging , Aged , COVID-19/complications , Female , Humans , Lung Injury/virology , Male , Middle Aged , Prospective Studies , Respiration, Artificial , Sweden , Tidal Volume , Tomography, X-Ray Computed
12.
J Med Virol ; 93(10): 6008-6015, 2021 10.
Article in English | MEDLINE | ID: covidwho-1298507

ABSTRACT

INTRODUCTION: Coronavirus disease-2019 (COVID-19) is a respiratory disease whose clinical manifestation ranges from asymptomatic to severe respiratory failure. The purpose of this study was to investigate the place of serum surfactant-D (SP-D) and angiopoetin-2 (Ang-2) levels in predicting severity of disease in patients diagnosed with COVID-19. METHODS: Sixty-four patients diagnosed with COVID-19 between September 2020 and February 2021, 50 patients diagnosed with community-acquired pneumonia and a 50-member healthy control group were included in the study. Plasma samples and clinical data were collected within 72 h after admission, during hospital stay. Serum SP-D and Ang-2 concentrations were measured using the enzyme-linked immunosorbent assay. RESULTS: SP-D and Ang-2 levels were significantly higher in the mild-moderate pneumonia and severe/critical patient groups compared to the asymptomatic and noncomplicated COVID-19 patients (p < 0.001 for all groups). Serum SP-D and Ang-2 levels of severe-critical COVID-19 patients were significantly higher than CAP patients (p < 0.001). Powerful correlation was present between clinical severity of COVID-19 and SP-D and Ang-2 levels (r = 0.885 p < 0.001 and r = 0.913 p < 0.001, respectively). Cut-off values of 37.7 ng/ml (AUC = 0.763, p < 0.001, 95% confidence interval [CI] = 0.667-0.860) for SP-D and 4208.3 pg/ml (AUC = 0.659, p = 0.004, 95% CI = 0.554-0.763) for Ang-2 were identified as predictors of COVID-19 disease at receiver operating characteristic curve analysis. CONCLUSION: SP-D and Ang-2 are predictive factors in differentiating COVID-19 patients and determining severity of disease. These data may be important for the initiation of treatment in the early stage of the disease in patients with COVID-19.


Subject(s)
Angiopoietin-2/metabolism , COVID-19/diagnosis , COVID-19/metabolism , Lung Injury/metabolism , Pulmonary Surfactant-Associated Protein D/metabolism , Adult , Aged , Biomarkers/blood , Community-Acquired Infections/diagnosis , Community-Acquired Infections/virology , Diagnostic Tests, Routine , Female , Humans , Lung Injury/virology , Male , Middle Aged , Prognosis , Prospective Studies , ROC Curve , Severity of Illness Index
13.
Nat Nanotechnol ; 16(8): 942-951, 2021 08.
Article in English | MEDLINE | ID: covidwho-1275929

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has grown into a global pandemic, and only a few antiviral treatments have been approved to date. Angiotensin-converting enzyme 2 (ACE2) plays a fundamental role in SARS-CoV-2 pathogenesis because it allows viral entry into host cells. Here we show that ACE2 nanodecoys derived from human lung spheroid cells (LSCs) can bind and neutralize SARS-CoV-2 and protect the host lung cells from infection. In mice, these LSC-nanodecoys were delivered via inhalation therapy and resided in the lungs for over 72 h post-delivery. Furthermore, inhalation of the LSC-nanodecoys accelerated clearance of SARS-CoV-2 mimics from the lungs, with no observed toxicity. In cynomolgus macaques challenged with live SARS-CoV-2, four doses of these nanodecoys delivered by inhalation promoted viral clearance and reduced lung injury. Our results suggest that LSC-nanodecoys can serve as a potential therapeutic agent for treating COVID-19.


Subject(s)
COVID-19/drug therapy , Lung Injury/prevention & control , Nanostructures/administration & dosage , SARS-CoV-2/drug effects , Administration, Inhalation , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/virology , Cell-Derived Microparticles/metabolism , Cell-Derived Microparticles/transplantation , Disease Models, Animal , Humans , Lung Injury/virology , Macaca fascicularis , Mice , Protein Binding , SARS-CoV-2/metabolism , Spheroids, Cellular/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Viral Load/drug effects
14.
PLoS One ; 16(5): e0251819, 2021.
Article in English | MEDLINE | ID: covidwho-1234591

ABSTRACT

The multifunctional role of neuron-specific enolase (NSE) in lung diseases is well established. As the lungs are greatly affected in COVID-19, we evaluated serum NSE levels in COVID-19 patients with and without dyspnea. In this study, we evaluated both SARS-CoV-2-infected and uninfected patients aged >18 years who were referred to hospitals in Catanzaro, Italy from March 30 to July 30, 2020. Epidemiological, clinical, and radiological characteristics, treatment, and outcome data were recorded and reviewed by a trained team of physicians. In total, 323 patients (178 men, 55.1% and 145 women, 44.9%) were enrolled; of these, 128 were COVID-19 patients (39.6%) and 195 were control patients (60.4%). Westergren's method was used to determine erythroid sedimentation rate. A chemiluminescence assay was used for measurement of interleukin-6, procalcitonin, C-reactive protein, and NSE. We detected significantly higher NSE values (P<0.05) in COVID-19 patients than in controls. Interestingly, within the COVID-19 group, we also observed a further significant increase in dyspnea (Dyspnea Scale and Exercise score: 8.2 ± 0.8; scores ranging from 0 to 10, with higher numbers indicating very severe shortness of breath). These data provide the background for further investigations into the potential role of NSE as a clinical marker of COVID-19 progression.


Subject(s)
COVID-19/enzymology , Lung Injury/enzymology , Lung Injury/virology , Phosphopyruvate Hydratase/blood , Adult , Biomarkers/blood , COVID-19/blood , Female , Humans , Immunologic Tests , Italy/epidemiology , Lung Injury/blood , Male , Middle Aged , SARS-CoV-2/isolation & purification , Severity of Illness Index
15.
Cells ; 10(4)2021 03 24.
Article in English | MEDLINE | ID: covidwho-1232574

ABSTRACT

Despite vaccination and antivirals, influenza remains a communicable disease of high burden, with limited therapeutic options available to patients that develop complications. Here, we report the development and preclinical characterization of Adipose Stromal Cell (ASC) concentrated secretome (CS), generated by process adaptable to current Good Manufacturing Practices (cGMP) standards. We demonstrate that ASC-CS limits pulmonary histopathological changes, infiltration of inflammatory cells, protein leak, water accumulation, and arterial oxygen saturation (spO2) reduction in murine model of lung infection with influenza A virus (IAV) when first administered six days post-infection. The ability to limit lung injury is sustained in ASC-CS preparations stored at -80 °C for three years. Priming of the ASC with inflammatory factors TNFα and IFNγ enhances ASC-CS ability to suppress lung injury. IAV infection is associated with dramatic increases in programmed cell death ligand (PDL1) and angiopoietin 2 (Angpt2) levels. ASC-CS application significantly reduces both PDL1 and Angpt2 levels. Neutralization of PDL1 with anti-mouse PDL1 antibody starting Day6 onward effectively ablates lung PDL1, but only non-significantly reduces Angpt2 release. Most importantly, late-phase PDL1 neutralization results in negligible suppression of protein leakage and inflammatory cell infiltration, suggesting that suppression of PDL1 does not play a critical role in ASC-CS therapeutic effects.


Subject(s)
Adipose Tissue/cytology , Influenza A virus/physiology , Lung Injury/therapy , Lung Injury/virology , Orthomyxoviridae Infections/therapy , Orthomyxoviridae Infections/virology , Angiopoietin-2/metabolism , Animals , B7-H1 Antigen/metabolism , Bronchoalveolar Lavage , Cryopreservation , Culture Media, Conditioned/pharmacology , Cytokines/metabolism , Disease Models, Animal , Female , Humans , Inflammation/complications , Inflammation/pathology , Lung Injury/complications , Lung Injury/pathology , Male , Mice , Orthomyxoviridae Infections/complications , Orthomyxoviridae Infections/pathology , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , Sex Characteristics , Stromal Cells/metabolism
16.
JCI Insight ; 6(12)2021 06 22.
Article in English | MEDLINE | ID: covidwho-1223641

ABSTRACT

Mice are normally unaffected by SARS coronavirus 2 (SARS-CoV-2) infection since the virus does not bind effectively to the murine version of the angiotensin-converting enzyme 2 (ACE2) receptor molecule. Here, we report that induced mild pulmonary morbidities rendered SARS-CoV-2-refractive CD-1 mice susceptible to this virus. Specifically, SARS-CoV-2 infection after application of low doses of the acute lung injury stimulants bleomycin or ricin caused severe disease in CD-1 mice, manifested by sustained body weight loss and mortality rates greater than 50%. Further studies revealed markedly higher levels of viral RNA in the lungs, heart, and serum of low-dose ricin-pretreated mice compared with non-pretreated mice. Furthermore, lung extracts prepared 2-3 days after viral infection contained subgenomic mRNA and virus particles capable of replication only when derived from the pretreated mice. The deleterious effects of SARS-CoV-2 infection were effectively alleviated by passive transfer of polyclonal or monoclonal antibodies generated against the SARS-CoV-2 receptor binding domain (RBD). Thus, viral cell entry in the sensitized mice seems to depend on viral RBD binding, albeit by a mechanism other than the canonical ACE2-mediated uptake route. This unique mode of viral entry, observed over a mildly injured tissue background, may contribute to the exacerbation of coronavirus disease 2019 (COVID-19) pathologies in patients with preexisting morbidities.


Subject(s)
Bleomycin/toxicity , COVID-19/pathology , Lung Injury , Ricin/toxicity , Animals , Chlorocebus aethiops , Comorbidity , Disease Models, Animal , Female , Lung Injury/chemically induced , Lung Injury/virology , Mice , Vero Cells , Virus Attachment , Virus Internalization/drug effects
17.
Pharmacol Rep ; 73(3): 712-727, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1195205

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes pulmonary injury or multiple-organ injury by various pathological pathways. Transforming growth factor-beta (TGF-ß) is a key factor that is released during SARS-CoV-2 infection. TGF-ß, by internalization of the epithelial sodium channel (ENaC), suppresses the anti-oxidant system, downregulates the cystic fibrosis transmembrane conductance regulator (CFTR), and activates the plasminogen activator inhibitor 1 (PAI-1) and nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-kB). These changes cause inflammation and lung injury along with coagulopathy. Moreover, reactive oxygen species play a significant role in lung injury, which levels up during SARS-CoV-2 infection. DRUG SUGGESTION: Pirfenidone is an anti-fibrotic drug with an anti-oxidant activity that can prevent lung injury during SARS-CoV-2 infection by blocking the maturation process of transforming growth factor-beta (TGF-ß) and enhancing the protective role of peroxisome proliferator-activated receptors (PPARs). Pirfenidone is a safe drug for patients with hypertension or diabetes and its side effect tolerated well. CONCLUSION: The drug as a theoretical perspective may be an effective and safe choice for suppressing the inflammatory response during COVID-19. The recommendation would be a combination of pirfenidone and N-acetylcysteine to achieve maximum benefit during SARS-CoV-2 treatment.


Subject(s)
COVID-19/drug therapy , COVID-19/metabolism , Inflammation/drug therapy , Lung Injury/metabolism , Pyridones/therapeutic use , Signal Transduction/drug effects , Transforming Growth Factor beta/metabolism , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , COVID-19/virology , Humans , Inflammation/metabolism , Lung Injury/virology , SARS-CoV-2/pathogenicity
18.
Clin Microbiol Rev ; 34(3)2021 06 16.
Article in English | MEDLINE | ID: covidwho-1166352

ABSTRACT

Several viruses target the human respiratory tract, causing different clinical manifestations spanning from mild upper airway involvement to life-threatening acute respiratory distress syndrome (ARDS). As dramatically evident in the ongoing SARS-CoV-2 pandemic, the clinical picture is not always easily predictable due to the combined effect of direct viral and indirect patient-specific immune-mediated damage. In this review, we discuss the main RNA (orthomyxoviruses, paramyxoviruses, and coronaviruses) and DNA (adenoviruses, herpesviruses, and bocaviruses) viruses with respiratory tropism and their mechanisms of direct and indirect cell damage. We analyze the thin line existing between a protective immune response, capable of limiting viral replication, and an unbalanced, dysregulated immune activation often leading to the most severe complication. Our comprehension of the molecular mechanisms involved is increasing and this should pave the way for the development and clinical use of new tailored immune-based antiviral strategies.


Subject(s)
DNA Viruses , Lung Injury , RNA Viruses , Respiratory Tract Infections , Virus Diseases , Adult , Aged , Antiviral Agents/therapeutic use , COVID-19 , Child , Child, Preschool , Female , Humans , Immunologic Factors/therapeutic use , Infant , Infant, Newborn , Interferons/therapeutic use , Lung/immunology , Lung/virology , Lung Injury/diagnosis , Lung Injury/drug therapy , Lung Injury/immunology , Lung Injury/virology , Male , Middle Aged , Pandemics , SARS-CoV-2
19.
Clin Immunol ; 226: 108716, 2021 05.
Article in English | MEDLINE | ID: covidwho-1152310

ABSTRACT

Lung inflammation and damage is prominent in people infected with SARS-Cov-2 and a major determinant of morbidity and mortality. We report the deposition of complement components in the lungs of people who succumbed to COVID-19 consistent with the activation of the classical and the alternative pathways. Our study provides strong rationale for the expansion of trials involving the use of complement inhibitors to treat patients with COVID-19.


Subject(s)
COVID-19/immunology , Complement Activation/immunology , Complement Pathway, Alternative/immunology , Lung Injury/immunology , Aged , Aged, 80 and over , COVID-19/complications , Complement Inactivating Agents/pharmacology , Complement Inactivating Agents/therapeutic use , Epithelial Cells/metabolism , Epithelial Cells/pathology , Female , Humans , Immunohistochemistry , Lung/diagnostic imaging , Lung/immunology , Lung/pathology , Lung Injury/complications , Lung Injury/pathology , Lung Injury/virology , Male , Middle Aged
20.
Life Sci ; 274: 119341, 2021 Jun 01.
Article in English | MEDLINE | ID: covidwho-1126966

ABSTRACT

The COVID-19 pandemic surges on as vast research is produced to study the novel SARS-CoV-2 virus and the disease state it induces. Still, little is known about the impact of COVID-19-induced microscale damage in the lung on global lung dynamics. This review summarizes the key histological features of SARS-CoV-2 infected alveoli and links the findings to structural tissue changes and surfactant dysfunction affecting tissue mechanical behavior similar to changes seen in other lung injury. Along with typical findings of diffuse alveolar damage affecting the interstitium of the alveolar walls and blood-gas barrier in the alveolar airspace, COVID-19 can cause extensive microangiopathy in alveolar capillaries that further contribute to mechanical changes in the tissues and may differentiate it from previously studied infectious lung injury. Understanding microlevel damage impact on tissue mechanics allows for better understanding of macroscale respiratory dynamics. Knowledge gained from studies into the relationship between microscale and macroscale lung mechanics can allow for optimized treatments to improve patient outcomes in case of COVID-19 and future respiratory-spread pandemics.


Subject(s)
COVID-19/complications , Lung Injury/pathology , Lung Injury/virology , Pulmonary Ventilation , SARS-CoV-2/isolation & purification , COVID-19/transmission , COVID-19/virology , Humans
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