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1.
Eur J Neurol ; 29(12): 3676-3692, 2022 12.
Статья в английский | MEDLINE | ID: covidwho-2052437

Реферат

BACKGROUND AND PURPOSE: In the central nervous system, a multitude of changes have been described associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, such as microglial activation, perivascular lymphocyte cuffing, hypoxic-ischaemic changes, microthrombosis, infarcts or haemorrhages. It was sought here to assess the vascular basement membranes (vBMs) and surrounding perivascular astrocytes for any morphological changes in acute respiratory syndrome (coronavirus disease 2019, COVID-19) patients. METHODS: The light microscopy morphology of the vBMs and perivascular astrocytes from brains of 14 patients with confirmed SARS-CoV-2 infection was analysed and compared to four control patients utilizing fluorescent immunohistochemistry for collagen IV and astrocytes (GFAP), endothelia (CD31), tight junction 1 (TJ1) adhesion protein, as well as the aquaporin 4 (AQP4) water channel. On 2D and 3D deconvoluted images from the cortex and white matter, vessel densities, diameters, degree of gliosis, collagen IV/GFAP and GFAP/AQP4 colocalizations were calculated, as well as the fractal dimension of astrocytes and vBMs viewed in tangential planes. RESULTS: Fractal dimension analysis of the GFAP-stained astrocytes revealed lower branching complexities and decreased GFAP/collagen IV colocalization for COVID-19 patients. Interestingly, vBMs showed significantly increased irregularities (fractal dimension values) compared to controls. Vessel diameters were increased in COVID-19 cases, especially for the white matter, TJ1 protein decreased its colocalization with the endothelia, and AQP4 reduced its co-expression in astrocytes. CONCLUSIONS: Our data on the irregularity of the basement membranes, loss of endothelial tight junction, reduction of the astrocyte end-feet and decrease of AQP4 suggest subtle morphological changes of the blood-brain barrier in COVID-19 brains that could be linked with indirect inflammatory signalling or hypoxia/hypercapnia.


Тема - темы
Astrocytes , COVID-19 , Humans , SARS-CoV-2 , Aquaporin 4 , Brain/metabolism , Collagen/metabolism , Glial Fibrillary Acidic Protein
2.
Int J Mol Sci ; 23(17)2022 Aug 26.
Статья в английский | MEDLINE | ID: covidwho-2023746

Реферат

Although interstitial lung disease (ILD) is a life-threatening pathological condition that causes respiratory failure, the efficiency of current therapies is limited. This study aimed to investigate the effects of human MIKO-1 (hMIKO-1), a hybrid protein that suppresses the abnormal activation of macrophages, on murine macrophage function and its therapeutic effect in a mouse model of bleomycin-induced ILD (BLM-ILD). To this end, the phenotype of thioglycolate-induced murine peritoneal macrophages co-cultured with hMIKO-1 was examined. The mice were assigned to normal, BLM-alone, or BLM + hMIKO-1 groups, and hMIKO-1 (0.1 mg/mouse) was administered intraperitoneally from day 0 to 14. The mice were sacrificed on day 28, and their lungs were evaluated by histological examination, collagen content, and gene expression levels. hMIKO-1 suppressed the polarization of murine macrophages to M2 predominance in vitro. The fibrosis score of lung pathology and lung collagen content of the BLM + hMIKO-1 group were significantly lower than those in the BLM-alone group. The expression levels of TNF-α, IL-6, IL-1ß, F4/80, and TIMP-1 in the lungs of the BLM + hMIKO-1 group were significantly lower than those in the BLM-alone group. These findings indicate that hMIKO-1 reduces lung fibrosis and may be a future therapeutic candidate for ILD treatment.


Тема - темы
Lung Diseases, Interstitial , Pulmonary Fibrosis , Animals , Bleomycin/toxicity , Collagen/metabolism , Disease Models, Animal , Humans , Lung/pathology , Lung Diseases, Interstitial/chemically induced , Lung Diseases, Interstitial/drug therapy , Lung Diseases, Interstitial/metabolism , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/metabolism
3.
Peptides ; 157: 170848, 2022 11.
Статья в английский | MEDLINE | ID: covidwho-1967000

Реферат

Angiotensin (Ang) II, the main active member of the renin angiotensin system (RAS), is essential for the maintenance of cardiovascular homeostasis. However, hyperactivation of the RAS causes fibrotic diseases. Ang II has pro-inflammatory actions, and moreover activates interstitial fibroblasts and/or dysregulates extracellular matrix degradation. The discovery of new RAS pathways has revealed the complexity of this system. Among the RAS peptides, alamandine (ALA, Ala1 Ang 1-7) has been identified in humans, rats, and mice, with protective actions in different pathological conditions. ALA has similar effects to its well-known congener, Ang-(1-7), as a vasodilator, anti-inflammatory, and antifibrotic. Its protective role against cardiovascular diseases is well-reviewed in the literature. However, the protective actions of ALA in fibrotic conditions have been little explored. Therefore, in this article, we review the ability of ALA to modulate the inflammatory process and collagen deposition, to serve as an antioxidant, and to mediate protection against functional disorders. In this scenario, we also explore ALA as a promising therapy for pulmonary fibrosis after COVID-19 infection.


Тема - темы
COVID-19 , Peptidyl-Dipeptidase A , Angiotensin II/metabolism , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antioxidants/pharmacology , COVID-19/drug therapy , Collagen/metabolism , Fibrosis , Humans , Mice , Oligopeptides , Peptidyl-Dipeptidase A/metabolism , Rats , Receptors, G-Protein-Coupled/metabolism , Renin-Angiotensin System , Vasodilator Agents/pharmacology
4.
Clin Transl Med ; 12(5): e831, 2022 05.
Статья в английский | MEDLINE | ID: covidwho-1858584

Реферат

Tissue damage caused by an infection oran autoimmune disease triggers degradation of collagen in the extracellular matrix (ECM), which further enhances inflammation. Therefore, improving ECM in aninflamed tissue can be exploited as a potential therapeutic target. A recentstudy emphasised an innovative approach against COVID-19 using polymerised type I collagen (PTIC) that improves disease severity through a hitherto unknownmechanism. In this paper, we provide an overview of potential mechanism thatmay explain the anti-inflammatory effect of collagen peptides. In addition,the paper includes a brief summary of possible side effect of collagendeposition in inflammatory diseases. Altogether, current knowledge suggeststhat collagen may potentially reduce the residual risk in inflammatorydiseases; however, the detailed mechanism remains elusive.


Тема - темы
COVID-19 , COVID-19/drug therapy , Collagen/metabolism , Collagen/pharmacology , Collagen Type I/metabolism , Collagen Type I/pharmacology , Extracellular Matrix/metabolism , Humans , Inflammation/drug therapy , Inflammation/metabolism
5.
Int J Mol Sci ; 23(2)2022 Jan 15.
Статья в английский | MEDLINE | ID: covidwho-1631216

Реферат

Angiotensin II receptor type 1 (AT1R) and endothelin-1 receptor type A (ETAR) are G-protein-coupled receptors (GPCRs) expressed on the surface of a great variety of cells: immune cells, vascular smooth cells, endothelial cells, and fibroblasts express ETAR and AT1R, which are activated by endothelin 1 (ET1) and angiotensin II (AngII), respectively. Certain autoantibodies are specific for these receptors and can regulate their function, thus being known as functional autoantibodies. The function of these antibodies is similar to that of natural ligands, and it involves not only vasoconstriction, but also the secretion of proinflammatory cytokines (such as interleukin-6 (IL6), IL8 and TNF-α), collagen production by fibroblasts, and reactive oxygen species (ROS) release by fibroblasts and neutrophils. The role of autoantibodies against AT1R and ETAR (AT1R-AAs and ETAR-AAs, respectively) is well described in the pathogenesis of many medical conditions (e.g., systemic sclerosis (SSc) and SSc-associated pulmonary hypertension, cystic fibrosis, and allograft dysfunction), but their implications in cardiovascular diseases are still unclear. This review summarizes the current evidence regarding the effects of AT1R-AAs and ETAR-AAs in cardiovascular pathologies, highlighting their roles in heart transplantation and mechanical circulatory support, preeclampsia, and acute coronary syndromes.


Тема - темы
Autoantibodies/metabolism , Cardiovascular Diseases/immunology , Receptor, Angiotensin, Type 1/immunology , Receptor, Endothelin A/immunology , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/pathology , Collagen/metabolism , Humans , Interleukin-6/metabolism , Interleukin-8/metabolism , Reactive Oxygen Species/metabolism , Receptor, Angiotensin, Type 1/metabolism , Tumor Necrosis Factor-alpha/metabolism
6.
Front Immunol ; 12: 748417, 2021.
Статья в английский | MEDLINE | ID: covidwho-1528820

Реферат

Rationale: Myocardial injury associates significantly and independently with mortality in COVID-19 patients. However, the pathogenesis of myocardial injury in COVID-19 remains unclear, and cardiac involvement by SARS-CoV-2 presents a major challenge worldwide. Objective: This histological and immunohistochemical study sought to clarify the pathogenesis and propose a mechanism with pathways involved in COVID-19 myocardial injury. Methods and Results: Postmortem minimally invasive autopsies were performed in six patients who died from COVID-19, and the myocardium samples were compared to a control group (n=11). Histological analysis was performed using hematoxylin-eosin and toluidine blue staining. Immunohistochemical (IHC) staining was performed using monoclonal antibodies against targets: caspase-1, caspase-9, gasdermin-d, ICAM-1, IL-1ß, IL-4, IL-6, CD163, TNF-α, TGF-ß, MMP-9, type 1 and type 3 collagen. The samples were also assessed for apoptotic cells by TUNEL. Histological analysis showed severe pericardiocyte interstitial edema and higher mast cells counts per high-power field in all COVID-19 myocardium samples. The IHC analysis showed increased expression of caspase-1, ICAM-1, IL-1ß, IL-6, MMP-9, TNF-α, and other markers in the hearts of COVID-19 patients. Expression of caspase-9 did not differ from the controls, while gasdermin-d expression was less. The TUNEL assay was positive in all the COVID-19 samples supporting endothelial apoptosis. Conclusions: The pathogenesis of COVID-19 myocardial injury does not seem to relate to primary myocardiocyte involvement but to local inflammation with associated interstitial edema. We found heightened TGF-ß and interstitial collagen expression in COVID-affected hearts, a potential harbinger of chronic myocardial fibrosis. These results suggest a need for continued clinical surveillance of patients for myocardial dysfunction and arrythmias after recovery from the acute phase of COVID-19.


Тема - темы
COVID-19/metabolism , Heart Injuries/metabolism , SARS-CoV-2 , Aged , Apoptosis , Biopsy , COVID-19/pathology , Caspase 1/metabolism , Collagen/metabolism , Cytokines/metabolism , Female , Heart Injuries/pathology , Humans , Immunohistochemistry , Intercellular Adhesion Molecule-1/metabolism , Male , Matrix Metalloproteinase 9/metabolism , Myocardium/metabolism , Myocardium/pathology
7.
Int J Mol Sci ; 22(14)2021 Jul 13.
Статья в английский | MEDLINE | ID: covidwho-1314665

Реферат

Lung fibrosis has specific computed tomography (CT) findings and represents a common finding in advanced COVID-19 pneumonia whose reversibility has been poorly investigated. The aim of this study was to quantify the extension of collagen deposition and aeration in postmortem cryobiopsies of critically ill COVID-19 patients and to describe the correlations with qualitative and quantitative analyses of lung CT. Postmortem transbronchial cryobiopsy samples were obtained, formalin fixed, paraffin embedded and stained with Sirius red to quantify collagen deposition, defining fibrotic samples as those with collagen deposition above 10%. Lung CT images were analyzed qualitatively with a radiographic score and quantitatively with computer-based analysis at the lobe level. Thirty samples from 10 patients with COVID-19 pneumonia deceased during invasive mechanical ventilation were included in this study. The median [interquartile range] percent collagen extension was 6.8% (4.6-16.2%). In fibrotic compared to nonfibrotic samples, the qualitative score was higher (260 (250-290) vs. 190 (120-270), p = 0.036) while the gas fraction was lower (0.46 (0.32-0.47) vs. 0.59 (0.37-0.68), p = 0.047). A radiographic score above 230 had 100% sensitivity (95% confidence interval, CI: 66.4% to 100%) and 66.7% specificity (95% CI: 41.0% to 92.3%) to detect fibrotic samples, while a gas fraction below 0.57 had 100% sensitivity (95% CI: 66.4% to 100%) and 57.1% specificity (95% CI: 26.3% to 88.0%). In COVID-19 pneumonia, qualitative and quantitative analyses of lung CT images have high sensitivity but moderate to low specificity to detect histopathological fibrosis. Pseudofibrotic CT findings do not always correspond to increased collagen deposition.


Тема - темы
COVID-19/complications , Collagen/metabolism , Pulmonary Fibrosis/diagnosis , SARS-CoV-2/isolation & purification , Tomography, X-Ray Computed/methods , Aged , Autopsy , COVID-19/epidemiology , COVID-19/virology , Female , Humans , Italy/epidemiology , Male , Middle Aged , Pulmonary Fibrosis/diagnostic imaging , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/virology , Retrospective Studies
8.
Angiogenesis ; 24(3): 407-411, 2021 08.
Статья в английский | MEDLINE | ID: covidwho-1222775

Реферат

BACKGROUND: Microthrombosis is a hallmark of COVID-19. We previously described von willebrand factor (VWF) and their high molecular weight multimers (HMWMs) as potential trigger of microthrombosis. OBJECTIVES: Investigate VWF activity with collagen-binding assay and ADAMTS13 in COVID-19. METHODS AND RESULTS: Our study enrolled 77 hospitalized COVID-19 patients including 37 suffering from a non-critical form and 40 with critical form. Plasma levels of VWF collagen-binding ability (VWF:CB) and ADAMTS13 activity (ADAMTS13:Act) were measured in the first 48 hours following admission. VWF:CB was increased in critical (631% IQR [460-704]) patients compared to non-critical patients (259% [235-330], p < 0.005). VWF:CB was significantly associated (r = 0.564, p < 0.001) with HMWMs. Moreover, median ADAMTS13:Act was lower in critical (64.8 IU/dL IQR 50.0-77.7) than non-critical patients (85.0 IU/dL IQR 75.8-94.7, p < 0.001), even if no patients displayed majors deficits. VWF:Ag-to-ADAMTS13:Act ratio was highly associated with VWF:CB (r = 0.916, p < 0.001). Moreover, VWF:CB level was highly predictive of COVID-19 in-hospital mortality as shown by the ROC curve analysis (AUC = 0.92, p < 0.0001) in which we identified a VWF:CB cut-off of 446% as providing the best predictor sensitivity-specificity balance. We confirmed this cut-off thanks to a Kaplan-Meier estimator analysis (log-rank p < 0.001) and a Cox-proportional Hazard model (HR = 49.1, 95% CI 1.81-1328.2, p = 0.021) adjusted on, BMI, C-reactive protein, and D-dimer levels. CONCLUSION: VWF:CB levels could summarize both VWF increased levels and hyper-reactivity subsequent to ADAMTS13 overflow and, therefore, be a valuable and easy to perform clinical biomarker of microthrombosis and COVID-19 severity.


Тема - темы
ADAMTS13 Protein/blood , COVID-19/blood , COVID-19/mortality , Pandemics , SARS-CoV-2 , von Willebrand Factor/metabolism , Aged , Biomarkers/blood , Collagen/metabolism , Cross-Sectional Studies , Female , Hospital Mortality , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Paris/epidemiology , Proportional Hazards Models , Protein Binding , Severity of Illness Index
9.
Commun Biol ; 4(1): 290, 2021 03 05.
Статья в английский | MEDLINE | ID: covidwho-1118820

Реферат

SARS-CoV-2 virus has infected more than 92 million people worldwide resulting in the Coronavirus disease 2019 (COVID-19). Using a rhesus macaque model of SARS-CoV-2 infection, we have characterized the transcriptional signatures induced in the lungs of juvenile and old macaques following infection. Genes associated with Interferon (IFN) signaling, neutrophil degranulation and innate immune pathways are significantly induced in macaque infected lungs, while pathways associated with collagen formation are downregulated, as also seen in lungs of macaques with tuberculosis. In COVID-19, increasing age is a significant risk factor for poor prognosis and increased mortality. Type I IFN and Notch signaling pathways are significantly upregulated in lungs of juvenile infected macaques when compared with old infected macaques. These results are corroborated with increased peripheral neutrophil counts and neutrophil lymphocyte ratio in older individuals with COVID-19 disease. Together, our transcriptomic studies have delineated disease pathways that improve our understanding of the immunopathogenesis of COVID-19.


Тема - темы
COVID-19/immunology , Cell Degranulation , Interferons/physiology , Neutrophils/physiology , SARS-CoV-2 , Aged , Animals , CD36 Antigens/physiology , COVID-19/etiology , Collagen/metabolism , Disease Models, Animal , Female , Gene Expression Regulation , Humans , Lung/metabolism , Macaca mulatta , Male , Middle Aged , Receptors, Notch/physiology , Signal Transduction/physiology , Transforming Growth Factor beta/physiology , Vascular Endothelial Growth Factor A/blood , Vascular Endothelial Growth Factor A/physiology
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