Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 10 de 10
Filter
1.
Oxid Med Cell Longev ; 2022: 2523066, 2022.
Article in English | MEDLINE | ID: covidwho-1662340

ABSTRACT

Pneumoconiosis is one of the most common occupational diseases in the world, and specific treatment methods of pneumoconiosis are lacking at present, so it carries great social and economic burdens. Pneumoconiosis, coronavirus disease 2019, and idiopathic pulmonary fibrosis all have similar typical pathological changes-pulmonary fibrosis. Pulmonary fibrosis is a chronic lung disease characterized by excessive deposition of the extracellular matrix and remodeling of the lung tissue structure. Clarifying the pathogenesis of pneumoconiosis plays an important guiding role in its treatment. The occurrence and development of pneumoconiosis are accompanied by epigenetic factors (e.g., DNA methylation and noncoding RNA) changes, which in turn can promote or inhibit the process of pneumoconiosis. Here, we summarize epigenetic changes and functions in the several kinds of evidence classification (epidemiological investigation, in vivo, and in vitro experiments) and main types of cells (macrophages, fibroblasts, and alveolar epithelial cells) to provide some clues for finding specific therapeutic targets for pneumoconiosis and even for pulmonary fibrosis.


Subject(s)
Epigenesis, Genetic , Pneumoconiosis/genetics , COVID-19/genetics , COVID-19/pathology , DNA Methylation , Humans , Idiopathic Pulmonary Fibrosis/genetics , Idiopathic Pulmonary Fibrosis/pathology , Macrophages/cytology , Macrophages/immunology , Macrophages/metabolism , Pneumoconiosis/pathology , RNA, Untranslated/metabolism , SARS-CoV-2/isolation & purification
2.
PLoS One ; 17(1): e0262737, 2022.
Article in English | MEDLINE | ID: covidwho-1631070

ABSTRACT

INTRODUCTION: The coronavirus disease 2019 (COVID-19), emerged in late 2019, was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The risk factors for idiopathic pulmonary fibrosis (IPF) and COVID-19 are reported to be common. This study aimed to determine the potential role of differentially expressed genes (DEGs) common in IPF and COVID-19. MATERIALS AND METHODS: Based on GEO database, we obtained DEGs from one SARS-CoV-2 dataset and five IPF datasets. A series of enrichment analysis were performed to identify the function of upregulated and downregulated DEGs, respectively. Two plugins in Cytoscape, Cytohubba and MCODE, were utilized to identify hub genes after a protein-protein interaction (PPI) network. Finally, candidate drugs were predicted to target the upregulated DEGs. RESULTS: A total of 188 DEGs were found between COVID-19 and IPF, out of which 117 were upregulated and 71 were downregulated. The upregulated DEGs were involved in cytokine function, while downregulated DEGs were associated with extracellular matrix disassembly. Twenty-two hub genes were upregulated in COVID-19 and IPF, for which 155 candidate drugs were predicted (adj.P.value < 0.01). CONCLUSION: Identifying the hub genes aberrantly regulated in both COVID-19 and IPF may enable development of molecules, encoded by those genes, as therapeutic targets for preventing IPF progression and SARS-CoV-2 infections.


Subject(s)
COVID-19/genetics , Idiopathic Pulmonary Fibrosis/genetics , COVID-19/pathology , COVID-19/virology , Databases, Genetic , Down-Regulation/drug effects , Down-Regulation/genetics , Humans , Idiopathic Pulmonary Fibrosis/drug therapy , Idiopathic Pulmonary Fibrosis/pathology , Protein Interaction Maps/drug effects , Protein Interaction Maps/genetics , SARS-CoV-2/isolation & purification , Suloctidil/pharmacology , Suloctidil/therapeutic use , Up-Regulation/drug effects , Up-Regulation/genetics , Vasodilator Agents/pharmacology , Vasodilator Agents/therapeutic use
3.
Cell ; 184(26): 6243-6261.e27, 2021 12 22.
Article in English | MEDLINE | ID: covidwho-1536467

ABSTRACT

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


Subject(s)
COVID-19/pathology , COVID-19/virology , Idiopathic Pulmonary Fibrosis/pathology , Idiopathic Pulmonary Fibrosis/virology , Macrophages/pathology , Macrophages/virology , SARS-CoV-2/physiology , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , COVID-19/diagnostic imaging , Cell Communication , Cohort Studies , Fibroblasts/pathology , Gene Expression Regulation , Humans , Idiopathic Pulmonary Fibrosis/diagnostic imaging , Idiopathic Pulmonary Fibrosis/genetics , Mesenchymal Stem Cells/pathology , Phenotype , Proteome/metabolism , Receptors, Cell Surface/metabolism , Respiratory Distress Syndrome/diagnostic imaging , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , Tomography, X-Ray Computed , Transcription, Genetic
4.
Nat Commun ; 12(1): 4314, 2021 07 14.
Article in English | MEDLINE | ID: covidwho-1310804

ABSTRACT

Patients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 (COVID-19) and poor outcomes. Here, we analyze the transcriptomes of 611,398 single cells isolated from healthy and CLD lungs to identify molecular characteristics of lung cells that may account for worse COVID-19 outcomes in patients with chronic lung diseases. We observe a similar cellular distribution and relative expression of SARS-CoV-2 entry factors in control and CLD lungs. CLD AT2 cells express higher levels of genes linked directly to the efficiency of viral replication and the innate immune response. Additionally, we identify basal differences in inflammatory gene expression programs that highlight how CLD alters the inflammatory microenvironment encountered upon viral exposure to the peripheral lung. Our study indicates that CLD is accompanied by changes in cell-type-specific gene expression programs that prime the lung epithelium for and influence the innate and adaptive immune responses to SARS-CoV-2 infection.


Subject(s)
Lung Diseases/genetics , SARS-CoV-2/physiology , Transcriptome , Virus Internalization , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/pathology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/genetics , COVID-19/pathology , Chronic Disease , Humans , Idiopathic Pulmonary Fibrosis/genetics , Idiopathic Pulmonary Fibrosis/pathology , Immunity, Innate/genetics , Inflammation/genetics , Lung/metabolism , Lung/pathology , Lung Diseases/pathology , SARS-CoV-2/pathogenicity , Virus Replication/genetics
5.
J Pathol Clin Res ; 7(5): 446-458, 2021 09.
Article in English | MEDLINE | ID: covidwho-1224964

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious threat to healthcare systems worldwide. Binding of the virus to angiotensin-converting enzyme 2 (ACE2) is an important step in the infection mechanism. However, it is unknown if ACE2 expression in patients with chronic lung diseases (CLDs), such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary arterial hypertension (IPAH), or pulmonary fibrosis (PF), is changed as compared to controls. We used lung samples from patients with COPD (n = 28), IPAH (n = 10), and PF (n = 10) as well as healthy control donor (n = 10) tissue samples to investigate the expression of ACE2 and related cofactors that might influence the course of SARS-CoV-2 infection. Expression levels of the ACE2 receptor, the putative receptor CD147/BSG, and the viral entry cofactors TMPRSS2 (transmembrane serine protease 2), EZR, and FURIN were determined by quantitative PCR and in open-access RNA sequencing datasets. Immunohistochemical and single-cell RNA sequencing (scRNAseq) analyses were used for localization and coexpression, respectively. Soluble ACE2 (sACE2) plasma levels were analyzed by enzyme-linked immunosorbent assay. In COPD as compared to donor, IPAH, and PF lung tissue, gene expression of ACE2, TMPRSS2, and EZR was significantly elevated, but circulating sACE2 levels were significantly reduced in COPD and PF plasma compared to healthy control and IPAH plasma samples. Lung tissue expressions of FURIN and CD147/BSG were downregulated in COPD. None of these changes were associated with changes in pulmonary hemodynamics. Histological analysis revealed coexpression of ACE2, TMPRSS2, and Ezrin in bronchial regions and epithelial cells. This was confirmed by scRNAseq analysis. There were no significant expression changes of the analyzed molecules in the lung tissue of IPAH and idiopathic PF as compared to control. In conclusion, we reveal increased ACE2 and TMPRSS2 expression in lung tissue with a concomitant decrease of protective sACE2 in COPD patients. These changes represent the possible risk factors for an increased susceptibility of COPD patients to SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , Familial Primary Pulmonary Hypertension/pathology , Idiopathic Pulmonary Fibrosis/pathology , Pulmonary Disease, Chronic Obstructive/pathology , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism , Adult , Aged , Angiotensin-Converting Enzyme 2/genetics , Basigin/genetics , Basigin/metabolism , COVID-19/metabolism , COVID-19/virology , Disease Susceptibility , Familial Primary Pulmonary Hypertension/enzymology , Familial Primary Pulmonary Hypertension/virology , Female , Furin/genetics , Furin/metabolism , Gene Expression Regulation , Humans , Idiopathic Pulmonary Fibrosis/metabolism , Idiopathic Pulmonary Fibrosis/virology , Lung/metabolism , Lung/pathology , Lung/virology , Male , Middle Aged , Pulmonary Disease, Chronic Obstructive/metabolism , Pulmonary Disease, Chronic Obstructive/virology , Risk Factors , Serine Endopeptidases/genetics , Virus Internalization
6.
Cells ; 10(4)2021 04 14.
Article in English | MEDLINE | ID: covidwho-1186898

ABSTRACT

Macrophages play an important role in the innate and adaptive immune responses of organ systems, including the lungs, to particles and pathogens. Cumulative results show that macrophages contribute to the development and progression of acute or chronic inflammatory responses through the secretion of inflammatory cytokines/chemokines and the activation of transcription factors in the pathogenesis of inflammatory lung diseases, such as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), ARDS related to COVID-19 (coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), allergic asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). This review summarizes the functions of macrophages and their associated underlying mechanisms in the development of ALI, ARDS, COVID-19-related ARDS, allergic asthma, COPD, and IPF and briefly introduces the acute and chronic experimental animal models. Thus, this review suggests an effective therapeutic approach that focuses on the regulation of macrophage function in the context of inflammatory lung diseases.


Subject(s)
Acute Lung Injury/pathology , COVID-19/pathology , Macrophages/pathology , Pneumonia/pathology , Pulmonary Disease, Chronic Obstructive/pathology , Respiratory Distress Syndrome/pathology , Acute Lung Injury/immunology , Animals , Asthma/immunology , Asthma/pathology , COVID-19/immunology , Chronic Disease , Humans , Idiopathic Pulmonary Fibrosis/immunology , Idiopathic Pulmonary Fibrosis/pathology , Lung/immunology , Lung/pathology , Macrophages/immunology , Pneumonia/immunology , Pulmonary Disease, Chronic Obstructive/immunology , Respiratory Distress Syndrome/immunology , SARS-CoV-2/immunology
7.
EBioMedicine ; 65: 103277, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1131243

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease, characterized by progressive lung scarring. Severe COVID-19 is associated with substantial pneumonitis and has a number of shared major risk factors with IPF. This study aimed to determine the genetic correlation between IPF and severe COVID-19 and assess a potential causal role of genetically increased risk of IPF on COVID-19 severity. METHODS: The genetic correlation between IPF and COVID-19 severity was estimated with linkage disequilibrium (LD) score regression. We performed a Mendelian randomization (MR) study for IPF causality in COVID-19. Genetic variants associated with IPF susceptibility (P<5 × 10-8) in previous genome-wide association studies (GWAS) were used as instrumental variables (IVs). Effect estimates of those IVs on COVID-19 severity were gathered from the GWAS meta-analysis by the COVID-19 Host Genetics Initiative (4,336 cases & 623,902 controls). FINDINGS: We detected a positive genetic correlation of IPF with COVID-19 severity (rg=0·31 [95% CI 0·04-0·57], P = 0·023). The MR estimates for severe COVID-19 did not reveal any genetic association (OR 1·05, [95% CI 0·92-1·20], P = 0·43). However, outlier analysis revealed that the IPF risk allele rs35705950 at MUC5B had a different effect compared with the other variants. When rs35705950 was excluded, MR results provided evidence that genetically increased risk of IPF has a causal effect on COVID-19 severity (OR 1·21, [95% CI 1·06-1·38], P = 4·24 × 10-3). Furthermore, the IPF risk-allele at MUC5B showed an apparent protective effect against COVID-19 hospitalization only in older adults (OR 0·86, [95% CI 0·73-1·00], P = 2·99 × 10-2) . INTERPRETATION: The strongest genetic determinant of IPF, rs35705950 at MUC5B, seems to confer protection against COVID-19, whereas the combined effect of all other IPF risk loci seem to confer risk of COVID-19 severity. The observed effect of rs35705950 could either be due to protective effects of mucin over-production on the airways or a consequence of selection bias due to (1) a patient group that is heavily enriched for the rs35705950 T undertaking strict self-isolation and/or (2) due to survival bias of the rs35705950 non-IPF risk allele carriers. Due to the diverse impact of IPF causal variants on SARS-CoV-2 infection, with a possible selection bias as an explanation, further investigation is needed to address this apparent paradox between variance at MUC5B and other IPF genetic risk factors. FUNDING: Novo Nordisk Foundation and Oak Foundation.


Subject(s)
COVID-19/pathology , Genetic Predisposition to Disease/genetics , Idiopathic Pulmonary Fibrosis/pathology , COVID-19/genetics , Genome-Wide Association Study , Humans , Idiopathic Pulmonary Fibrosis/genetics , Lung/pathology , Mucin-5B/genetics , Polymorphism, Single Nucleotide/genetics , Risk , SARS-CoV-2 , Severity of Illness Index
8.
Am J Physiol Lung Cell Mol Physiol ; 320(1): L152-L157, 2021 01 01.
Article in English | MEDLINE | ID: covidwho-1054733

ABSTRACT

The COVID-19 pandemic is associated with severe pneumonia and acute respiratory distress syndrome leading to death in susceptible individuals. For those who recover, post-COVID-19 complications may include development of pulmonary fibrosis. Factors contributing to disease severity or development of complications are not known. Using computational analysis with experimental data, we report that idiopathic pulmonary fibrosis (IPF)- and chronic obstructive pulmonary disease (COPD)-derived lung fibroblasts express higher levels of angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2 entry and part of the renin-angiotensin system that is antifibrotic and anti-inflammatory. In preclinical models, we found that chronic exposure to cigarette smoke, a risk factor for both COPD and IPF and potentially for SARS-CoV-2 infection, significantly increased pulmonary ACE2 protein expression. Further studies are needed to understand the functional implications of ACE2 on lung fibroblasts, a cell type that thus far has received relatively little attention in the context of COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/biosynthesis , COVID-19/pathology , Fibroblasts/metabolism , Idiopathic Pulmonary Fibrosis/pathology , Pulmonary Disease, Chronic Obstructive/pathology , Adult , Animals , Female , Gene Expression Regulation/drug effects , Humans , Male , Mice , Mice, Inbred C57BL , Middle Aged , Receptors, Virus/biosynthesis , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , SARS-CoV-2/metabolism , Smoke/adverse effects
9.
Mol Med ; 26(1): 95, 2020 10 14.
Article in English | MEDLINE | ID: covidwho-873932

ABSTRACT

Pulmonary fibrosis arises from the repeated epithelial mild injuries and insufficient repair lead to over activation of fibroblasts and excessive deposition of extracellular matrix, which result in a mechanical stretched niche. However, increasing mechanical stress likely exists before the establishment of fibrosis since early micro injuries increase local vascular permeability and prompt cytoskeletal remodeling which alter cellular mechanical forces. It is noteworthy that COVID-19 patients with severe hypoxemia will receive mechanical ventilation as supportive treatment and subsequent pathology studies indicate lung fibrosis pattern. At advanced stages, mechanical stress originates mainly from the stiff matrix since boundaries between stiff and compliant parts of the tissue could generate mechanical stress. Therefore, mechanical stress has a significant role in the whole development process of pulmonary fibrosis. The alveoli are covered by abundant capillaries and function as the main gas exchange unit. Constantly subject to variety of damages, the alveolar epithelium injuries were recently recognized to play a vital role in the onset and development of idiopathic pulmonary fibrosis. In this review, we summarize the literature regarding the effects of mechanical stress on the fundamental cells constituting the alveoli in the process of pulmonary fibrosis, particularly on epithelial cells, capillary endothelial cells, fibroblasts, mast cells, macrophages and stem cells. Finally, we briefly review this issue from a more comprehensive perspective: the metabolic and epigenetic regulation.


Subject(s)
Coronavirus Infections/immunology , Epigenesis, Genetic/immunology , Idiopathic Pulmonary Fibrosis/immunology , Mechanotransduction, Cellular/immunology , Pneumonia, Viral/immunology , Pulmonary Embolism/immunology , Respiratory Insufficiency/immunology , Alveolar Epithelial Cells/immunology , Alveolar Epithelial Cells/pathology , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , Biomechanical Phenomena , COVID-19 , Coronavirus Infections/genetics , Coronavirus Infections/pathology , Coronavirus Infections/virology , Cytokines/genetics , Cytokines/immunology , Endothelial Cells/immunology , Endothelial Cells/pathology , Fibroblasts/immunology , Fibroblasts/pathology , Humans , Idiopathic Pulmonary Fibrosis/genetics , Idiopathic Pulmonary Fibrosis/pathology , Idiopathic Pulmonary Fibrosis/virology , Lung/blood supply , Lung/immunology , Lung/pathology , Macrophages/immunology , Macrophages/pathology , Mechanotransduction, Cellular/genetics , Pandemics , Pneumonia, Viral/genetics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Pulmonary Embolism/genetics , Pulmonary Embolism/pathology , Pulmonary Embolism/virology , Respiratory Insufficiency/genetics , Respiratory Insufficiency/pathology , Respiratory Insufficiency/virology , SARS-CoV-2 , Stress, Mechanical
10.
Expert Rev Clin Immunol ; 16(8): 751-770, 2020 08.
Article in English | MEDLINE | ID: covidwho-684487

ABSTRACT

INTRODUCTION: Main clinical manifestations of SARS-CoV-2 infection are characterized by fever, dyspnea, and interstitial pneumonia, frequently evolving in acute respiratory distress syndrome (ARDS). AREAS COVERED: Features of coronavirus disease 2019 (COVID-19) presents some common points with interstitial lung disease (ILD) both idiopathic and related to rheumatoid arthritis (RA), typically characterized by a chronic progression over time and possibly complicated by acute exacerbation (AE). The study of common pathogenetic mechanisms, such as the involvement of toll-like receptor 4, could contribute to the knowledge and treatment of idiopathic and RA-ILD. Moreover, hyperinflammation, mainly characterized by increase of effector T-cells and inflammatory cytokines, and activation of coagulation cascade, observed in COVID-19 related ARDS have been already shown in patients with AE of idiopathic and RA-ILD. A literature search was performed in PubMed, Embase, Scopus, and Web of Science, together with a manual search in COVID-resource centers of the main journals. EXPERT OPINION: Despite the uncertainty about pathogenetic aspects about COVID-19- pneumonia, it could be a possible model for other forms of ILD and AE. The great amount of data from studies on COVID-19 could be helpful in proposing safe therapeutic approaches for RA-ILD, in understanding pathogenesis of usual interstitial pneumonia and to develop new therapeutic strategies for AE.


Subject(s)
Arthritis, Rheumatoid/pathology , Coronavirus Infections/pathology , Lung Diseases, Interstitial/pathology , Pneumonia, Viral/pathology , Arthritis, Rheumatoid/therapy , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/therapy , Disease Progression , Humans , Idiopathic Pulmonary Fibrosis/pathology , Idiopathic Pulmonary Fibrosis/therapy , Lung/pathology , Lung Diseases, Interstitial/therapy , Pandemics , Pneumonia, Viral/therapy , SARS-CoV-2 , Symptom Flare Up , Toll-Like Receptor 4/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL