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1.
Int J Mol Sci ; 23(3)2022 Jan 29.
Article in English | MEDLINE | ID: covidwho-1667195

ABSTRACT

(1) Background: In COVID-19 survivors there is an increased prevalence of pulmonary fibrosis of which the underlying molecular mechanisms are poorly understood; (2) Methods: In this multicentric study, n = 12 patients who succumbed to COVID-19 due to progressive respiratory failure were assigned to an early and late group (death within ≤7 and >7 days of hospitalization, respectively) and compared to n = 11 healthy controls; mRNA and protein expression as well as biological pathway analysis were performed to gain insights into the evolution of pulmonary fibrogenesis in COVID-19; (3) Results: Median duration of hospitalization until death was 3 (IQR25-75, 3-3.75) and 14 (12.5-14) days in the early and late group, respectively. Fifty-eight out of 770 analyzed genes showed a significantly altered expression signature in COVID-19 compared to controls in a time-dependent manner. The entire study group showed an increased expression of BST2 and IL1R1, independent of hospitalization time. In the early group there was increased activity of inflammation-related genes and pathways, while fibrosis-related genes (particularly PDGFRB) and pathways dominated in the late group; (4) Conclusions: After the first week of hospitalization, there is a shift from pro-inflammatory to fibrogenic activity in severe COVID-19. IL1R1 and PDGFRB may serve as potential therapeutic targets in future studies.


Subject(s)
COVID-19/genetics , COVID-19/metabolism , Pulmonary Fibrosis/pathology , Aged , COVID-19/mortality , Female , Hospital Mortality/trends , Hospitalization , Humans , Lung/pathology , Male , Middle Aged , Pulmonary Fibrosis/metabolism , Respiratory Insufficiency/pathology , SARS-CoV-2/pathogenicity
2.
Am J Chin Med ; 49(8): 1965-1999, 2021.
Article in English | MEDLINE | ID: covidwho-1599109

ABSTRACT

Pulmonary fibrosis (PF) is a chronic and irreversible interstitial lung disease that even threatens the lives of some patients infected with COVID-19. PF is a multicellular pathological process, including the initial injuries of epithelial cells, recruitment of inflammatory cells, epithelial-mesenchymal transition, activation and differentiation of fibroblasts, etc. TGF-[Formula: see text]1 acts as a key effect factor that participates in these cellular processes of PF. Recently, much attention was paid to inhibiting TGF-[Formula: see text]1 mediated cell processes in the treatment of PF with Chinese herbal medicines (CHM), an important part of traditional Chinese medicine. Here, this review first summarized the effects of TGF-[Formula: see text]1 in different cellular processes of PF. Then, this review summarized the recent research on CHM (compounds, multi-components, single medicines and prescriptions) to directly and/or indirectly inhibit TGF-[Formula: see text]1 signaling (TLRs, PPARs, micrRNA, etc.) in PF. Most of the research focused on CHM natural compounds, including but not limited to alkaloids, flavonoids, phenols and terpenes. After review, the research perspectives of CHM on TGF-[Formula: see text]1 inhibition in PF were further discussed. This review hopes that revealing the inhibiting effects of CHM on TGF-[Formula: see text]1-mediated cellular processes of PF can promote CHM to be better understood and utilized, thus transforming the therapeutic activities of CHM into practice.


Subject(s)
Cell Physiological Phenomena/drug effects , Drugs, Chinese Herbal/therapeutic use , Pulmonary Fibrosis/drug therapy , Signal Transduction/drug effects , Transforming Growth Factor beta1/antagonists & inhibitors , COVID-19/complications , COVID-19/metabolism , COVID-19/virology , Humans , Medicine, Chinese Traditional/methods , Phytotherapy/methods , Pulmonary Fibrosis/complications , Pulmonary Fibrosis/metabolism , SARS-CoV-2/physiology , Transforming Growth Factor beta1/metabolism
3.
Int J Mol Sci ; 23(1)2021 Dec 24.
Article in English | MEDLINE | ID: covidwho-1580700

ABSTRACT

Acute respiratory distress syndrome (ARDS) followed by repair with lung remodeling is observed in COVID-19. These findings can lead to pulmonary terminal fibrosis, a form of irreversible sequelae. There is evidence that TGF-ß is intimately involved in the fibrogenic process. When activated, TGF-ß promotes the differentiation of fibroblasts into myofibroblasts and regulates the remodeling of the extracellular matrix (ECM). In this sense, the present study evaluated the histopathological features and immunohistochemical biomarkers (ACE-2, AKT-1, Caveolin-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-ß1 tissue expression) involved in the TGF-ß1 signaling pathways and pulmonary fibrosis. The study consisted of 24 paraffin lung samples from patients who died of COVID-19 (COVID-19 group), compared to 10 lung samples from patients who died of H1N1pdm09 (H1N1 group) and 11 lung samples from patients who died of different causes, with no lung injury (CONTROL group). In addition to the presence of alveolar septal fibrosis, diffuse alveolar damage (DAD) was found to be significantly increased in the COVID-19 group, associated with a higher density of Collagen I (mature) and III (immature). There was also a significant increase observed in the immunoexpression of tissue biomarkers ACE-2, AKT-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-ß1 in the COVID-19 group. A significantly lower expression of Caveolin-1 was also found in this group. The results suggest the participation of TGF-ß pathways in the development process of pulmonary fibrosis. Thus, it would be plausible to consider therapy with TGF-ß inhibitors in those patients recovered from COVID-19 to mitigate a possible development of pulmonary fibrosis and its consequences for post-COVID-19 life quality.


Subject(s)
COVID-19/metabolism , Pulmonary Fibrosis/metabolism , Signal Transduction , Transforming Growth Factor beta/metabolism , Actins/metabolism , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/complications , COVID-19/drug therapy , COVID-19/pathology , Caveolin 1/metabolism , Collagen Type I/metabolism , Collagen Type III/metabolism , Female , Humans , Hyaluronan Receptors/metabolism , Immunohistochemistry , Influenza A Virus, H1N1 Subtype/metabolism , Influenza, Human/metabolism , Influenza, Human/pathology , Interleukin-4/metabolism , Male , Matrix Metalloproteinase 9/metabolism , Middle Aged , Proto-Oncogene Proteins c-akt/metabolism , Pulmonary Fibrosis/complications , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/pathology , Retrospective Studies , Transforming Growth Factor beta1/metabolism
4.
Biochem Pharmacol ; 193: 114812, 2021 11.
Article in English | MEDLINE | ID: covidwho-1474355

ABSTRACT

Pulmonary fibrosis (PF) is characterised by several grades of chronic inflammation and collagen deposition in the interalveolar space and is a hallmark of interstitial lung diseases (ILDs). Recently, infectious agents have emerged as driving causes for PF development; however, the role of viral/bacterial infections in the initiation and propagation of PF is still debated. In this context, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the current coronavirus disease 2019 (COVID-19) pandemic, has been associated with acute respiratory distress syndrome (ARDS) and PF development. Although the infection by SARS-CoV-2 can be eradicated in most cases, the development of fibrotic lesions cannot be precluded; furthermore, whether these lesions are stable or progressive fibrotic events is still unknown. Herein, an overview of the main molecular mechanisms driving the fibrotic process together with the currently approved and newly proposed therapeutic solutions was given. Then, the most recent data that emerged from post-COVID-19 patients was discussed, in order to compare PF and COVID-19-dependent PF, highlighting shared and specific mechanisms. A better understanding of PF aetiology is certainly needed, also to develop effective therapeutic strategies and COVID-19 pathology is offering one more chance to do it. Overall, the work reported here could help to define new approaches for therapeutic intervention in the diversity of the ILD spectrum.


Subject(s)
COVID-19/complications , Pulmonary Fibrosis/immunology , Pulmonary Fibrosis/metabolism , Animals , COVID-19/etiology , COVID-19/immunology , COVID-19/metabolism , Humans , Inflammation Mediators/immunology , Inflammation Mediators/metabolism , Neutrophils/immunology , Neutrophils/metabolism , Pulmonary Fibrosis/etiology
5.
Sci Rep ; 11(1): 19161, 2021 09 27.
Article in English | MEDLINE | ID: covidwho-1440480

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated with fatal pulmonary fibrosis. Small interfering RNAs (siRNAs) can be developed to induce RNA interference against SARS-CoV-2, and their susceptible target sites can be inferred by Argonaute crosslinking immunoprecipitation sequencing (AGO CLIP). Here, by reanalysing AGO CLIP data in RNA viruses, we delineated putative AGO binding in the conserved non-structural protein 12 (nsp12) region encoding RNA-dependent RNA polymerase (RdRP) in SARS-CoV-2. We utilised the inferred AGO binding to optimise the local RNA folding parameter to calculate target accessibility and predict all potent siRNA target sites in the SARS-CoV-2 genome, avoiding sequence variants. siRNAs loaded onto AGO also repressed seed (positions 2-8)-matched transcripts by acting as microRNAs (miRNAs). To utilise this, we further screened 13 potential siRNAs whose seed sequences were matched to known antifibrotic miRNAs and confirmed their miRNA-like activity. A miR-27-mimicking siRNA designed to target the nsp12 region (27/RdRP) was validated to silence a synthesised nsp12 RNA mimic in lung cell lines and function as an antifibrotic miR-27 in regulating target transcriptomes related to TGF-ß signalling. siRNA sequences with an antifibrotic miRNA-like activity that could synergistically treat COVID-19 are available online ( http://clip.korea.ac.kr/covid19 ).


Subject(s)
Argonaute Proteins/genetics , COVID-19/prevention & control , MicroRNAs/genetics , RNA, Small Interfering/genetics , SARS-CoV-2/genetics , A549 Cells , Argonaute Proteins/metabolism , Base Sequence , Binding Sites/genetics , COVID-19/virology , Cell Line , Coronavirus RNA-Dependent RNA Polymerase/genetics , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Gene Expression Profiling/methods , HeLa Cells , Humans , Pulmonary Fibrosis/genetics , Pulmonary Fibrosis/metabolism , RNA Interference , RNA-Seq/methods , SARS-CoV-2/physiology , Sequence Homology, Nucleic Acid
6.
JCI Insight ; 6(14)2021 07 22.
Article in English | MEDLINE | ID: covidwho-1320461

ABSTRACT

BACKGROUNDIndividuals recovering from COVID-19 frequently experience persistent respiratory ailments, which are key elements of postacute sequelae of SARS-CoV-2 infection (PASC); however, little is known about the underlying biological factors that may direct lung recovery and the extent to which these are affected by COVID-19 severity.METHODSWe performed a prospective cohort study of individuals with persistent symptoms after acute COVID-19, collecting clinical data, pulmonary function tests, and plasma samples used for multiplex profiling of inflammatory, metabolic, angiogenic, and fibrotic factors.RESULTSSixty-one participants were enrolled across 2 academic medical centers at a median of 9 weeks (interquartile range, 6-10 weeks) after COVID-19 illness: n = 13 participants (21%) had mild COVID-19 and were not hospitalized, n = 30 participants (49%) were hospitalized but were considered noncritical, and n = 18 participants (30%) were hospitalized and in the intensive care unit (ICU). Fifty-three participants (85%) had lingering symptoms, most commonly dyspnea (69%) and cough (58%). Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and diffusing capacity for carbon monoxide (DLCO) declined as COVID-19 severity increased (P < 0.05) but these values did not correlate with respiratory symptoms. Partial least-squares discriminant analysis of plasma biomarker profiles clustered participants by past COVID-19 severity. Lipocalin-2 (LCN2), MMP-7, and HGF identified by our analysis were significantly higher in the ICU group (P < 0.05), inversely correlated with FVC and DLCO (P < 0.05), and were confirmed in a separate validation cohort (n = 53).CONCLUSIONSubjective respiratory symptoms are common after acute COVID-19 illness but do not correlate with COVID-19 severity or pulmonary function. Host response profiles reflecting neutrophil activation (LCN2), fibrosis signaling (MMP-7), and alveolar repair (HGF) track with lung impairment and may be novel therapeutic or prognostic targets.FundingNational Heart, Lung, and Blood Institute (K08HL130557 and R01HL142818), American Heart Association (Transformational Project Award), the DeLuca Foundation Award, a donation from Jack Levin to the Benign Hematology Program at Yale University, and Duke University.


Subject(s)
COVID-19/complications , Hepatocyte Growth Factor/analysis , Lipocalin-2/analysis , Matrix Metalloproteinase 7/analysis , Pulmonary Fibrosis , Respiratory Function Tests , COVID-19/diagnosis , COVID-19/immunology , COVID-19/physiopathology , Cough/diagnosis , Cough/etiology , Dyspnea/diagnosis , Dyspnea/etiology , Female , Humans , Lung/metabolism , Lung/pathology , Lung/physiopathology , Male , Middle Aged , Neutrophil Activation/immunology , Prognosis , Pulmonary Fibrosis/diagnosis , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/metabolism , Recovery of Function/immunology , Respiratory Function Tests/methods , Respiratory Function Tests/statistics & numerical data , SARS-CoV-2 , Severity of Illness Index
7.
Int J Mol Sci ; 22(14)2021 Jul 13.
Article in English | MEDLINE | ID: covidwho-1314665

ABSTRACT

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.


Subject(s)
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.
Front Immunol ; 12: 663303, 2021.
Article in English | MEDLINE | ID: covidwho-1291384

ABSTRACT

The release of neutrophil extracellular traps (NETs), a process termed NETosis, avoids pathogen spread but may cause tissue injury. NETs have been found in severe COVID-19 patients, but their role in disease development is still unknown. The aim of this study is to assess the capacity of NETs to drive epithelial-mesenchymal transition (EMT) of lung epithelial cells and to analyze the involvement of NETs in COVID-19. Bronchoalveolar lavage fluid of severe COVID-19 patients showed high concentration of NETs that correlates with neutrophils count; moreover, the analysis of lung tissues of COVID-19 deceased patients showed a subset of alveolar reactive pneumocytes with a co-expression of epithelial marker and a mesenchymal marker, confirming the induction of EMT mechanism after severe SARS-CoV2 infection. By airway in vitro models, cultivating A549 or 16HBE at air-liquid interface, adding alveolar macrophages (AM), neutrophils and SARS-CoV2, we demonstrated that to trigger a complete EMT expression pattern are necessary the induction of NETosis by SARS-CoV2 and the secretion of AM factors (TGF-ß, IL8 and IL1ß). All our results highlight the possible mechanism that can induce lung fibrosis after SARS-CoV2 infection.


Subject(s)
COVID-19/physiopathology , Epithelial-Mesenchymal Transition , Extracellular Traps/metabolism , Neutrophils/metabolism , Adult , Biopsy , Bronchoalveolar Lavage Fluid/cytology , COVID-19/complications , COVID-19/immunology , Cell Line , Epithelial Cells/pathology , Humans , Lung/pathology , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/metabolism
10.
J Med Virol ; 93(3): 1378-1386, 2021 03.
Article in English | MEDLINE | ID: covidwho-1196511

ABSTRACT

Since December 2019, coronavirus disease (COVID-19) has rapidly swept the world. So far, more than 30 million people have been infected and nearly one million have died. Although the world is still in the stage of COVID-19 pandemic, the treatment of new cases and critically ill patients is the focus of the current work. However, COVID-19 patients lead to pulmonary fibrosis, such a serious threat to the prognosis of complications were also worthy of our attention. First of all, we proposed the possible mechanism of pulmonary fibrosis caused by SARS-CoV-2, based on the published data of COVID-19 ((i) Direct evidence: pulmonary fibrosis was found in autopsy and pulmonary puncture pathology. (ii) Indirect evidence: increased levels of fibrosis-related cytokines[transforming growth factor [TGF]- ß, tumor necrosis factor [TNF]- α, interleukin [IL]-6, etc] in peripheral blood of severe patients.) What is more, we summarized the role of three fibrosis-related signaling pathways (TGF- ß signal pathway, WNT signal pathway and YAP/TAZ signal pathway) in pulmonary fibrosis. Finally, we suggested the therapeutic value of two drugs (pirfenidone and nintedanib) for idiopathic pulmonary fibrosis in COVID-19-induced pulmonary fibrosis.


Subject(s)
COVID-19/complications , Indoles/therapeutic use , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/etiology , Pyridones/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , COVID-19/metabolism , COVID-19/pathology , Humans , Lung/pathology , Patient Discharge , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology , Severity of Illness Index , Signal Transduction
11.
Front Immunol ; 12: 636118, 2021.
Article in English | MEDLINE | ID: covidwho-1190312

ABSTRACT

Following respiratory viral infections or local immunizations, lung resident-memory T cells (TRM) of the CD8 lineage provide protection against the same pathogen or related pathogens with cross-reactive T cell epitopes. Yet, it is now clear that, if homeostatic controls are lost following viral pneumonia, CD8 TRM cells can mediate pulmonary pathology. We recently showed that the aging process can result in loss of homeostatic controls on CD8 TRM cells in the respiratory tract. This may be germane to treatment modalities in both influenza and coronavirus disease 2019 (COVID-19) patients, particularly, the portion that present with symptoms linked to long-lasting lung dysfunction. Here, we review the developmental cues and functionalities of CD8 TRM cells in viral pneumonia models with a particular focus on their capacity to mediate heterogeneous responses of immunity and pathology depending on immune status.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , COVID-19/virology , Immunologic Memory , Lung/immunology , Lung/virology , SARS-CoV-2/immunology , Age Factors , Animals , Biomarkers , CD8-Positive T-Lymphocytes/metabolism , COVID-19/metabolism , COVID-19/pathology , Disease Resistance/immunology , Homeostasis , Host-Pathogen Interactions/immunology , Humans , Immunophenotyping , Lung/metabolism , Lung/pathology , Lymphocyte Count , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology
12.
Respir Res ; 22(1): 99, 2021 Apr 06.
Article in English | MEDLINE | ID: covidwho-1169963

ABSTRACT

BACKGROUND: COVID-19 pneumonia has been associated with severe acute hypoxia, sepsis-like states, thrombosis and chronic sequelae including persisting hypoxia and fibrosis. The molecular hypoxia response pathway has been associated with such pathologies and our recent observations on anti-hypoxic and anti-inflammatory effects of whole aqueous extract of Adhatoda Vasica (AV) prompted us to explore its effects on relevant preclinical mouse models. METHODS: In this study, we tested the effect of whole aqueous extract of AV, in murine models of bleomycin induced pulmonary fibrosis, Cecum Ligation and Puncture (CLP) induced sepsis, and siRNA induced hypoxia-thrombosis phenotype. The effect on lung of AV treated naïve mice was also studied at transcriptome level. We also determined if the extract may have any effect on SARS-CoV2 replication. RESULTS: Oral administration AV extract attenuates increased airway inflammation, levels of transforming growth factor-ß1 (TGF-ß1), IL-6, HIF-1α and improves the overall survival rates of mice in the models of pulmonary fibrosis and sepsis and rescues the siRNA induced inflammation and associated blood coagulation phenotypes in mice. We observed downregulation of hypoxia, inflammation, TGF-ß1, and angiogenesis genes and upregulation of adaptive immunity-related genes in the lung transcriptome. AV treatment also reduced the viral load in Vero cells infected with SARS-CoV2. CONCLUSION: Our results provide a scientific rationale for this ayurvedic herbal medicine in ameliorating the hypoxia-hyperinflammation features and highlights the repurposing potential of AV in COVID-19-like conditions.


Subject(s)
Anti-Inflammatory Agents/pharmacology , COVID-19/drug therapy , Drug Repositioning , Hypoxia/drug therapy , Justicia , Lung/drug effects , Plant Extracts/pharmacology , Pneumonia/prevention & control , Pulmonary Fibrosis/drug therapy , Sepsis/drug therapy , Animals , Anti-Inflammatory Agents/isolation & purification , Bleomycin , COVID-19/metabolism , COVID-19/virology , Cecum/microbiology , Cecum/surgery , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Hypoxia/genetics , Hypoxia/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor-Proline Dioxygenases/genetics , Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism , Inflammation Mediators/metabolism , Justicia/chemistry , Ligation , Lung/metabolism , Lung/microbiology , Lung/pathology , Male , Mice, Inbred BALB C , Mice, Inbred C57BL , Plant Extracts/isolation & purification , Pneumonia/genetics , Pneumonia/metabolism , Pneumonia/microbiology , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/genetics , Pulmonary Fibrosis/metabolism , RNA Interference , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Sepsis/genetics , Sepsis/metabolism , Sepsis/microbiology , Transcriptome
13.
Respir Res ; 22(1): 38, 2021 Feb 05.
Article in English | MEDLINE | ID: covidwho-1067230

ABSTRACT

Pulmonary fibrosis has been identified as a main factor leading to pulmonary dysfunction and poor quality of life in post-recovery Severe Acute Respiratory Syndrome (SARS) survivor's consequent to SARS-Cov-2 infection. Thus there is an urgent medical need for identification of readily available biomarkers that in patients with SARS-Cov-2 infection are able to; (1) identify patients in most need of medical care prior to admittance to an intensive care unit (ICU), and; (2) identify patients post-infection at risk of developing persistent fibrosis of lungs with subsequent impaired quality of life and increased morbidity and mortality. An intense amount of research have focused on wound healing and Extracellular Matrix (ECM) remodelling of the lungs related to lung function decline in pulmonary fibrosis (PF). A range of non-invasive serological biomarkers, reflecting tissue remodelling, and fibrosis have been shown to predict risk of acute exacerbations, lung function decline and mortality in PF and other interstitial lung diseases (Sand et al. in Respir Res 19:82, 2018). We suggest that lessons learned from such PF studies of the pathological processes leading to lung function decline could be used to better identify patients infected with SARS-Co-V2 at most risk of acute deterioration or persistent fibrotic damage of the lung and could consequently be used to guide treatment decisions.


Subject(s)
COVID-19/metabolism , Extracellular Matrix/metabolism , Pulmonary Fibrosis/metabolism , Wound Healing/physiology , Animals , Biomarkers/metabolism , COVID-19/diagnosis , Humans , Lung/metabolism , Pulmonary Fibrosis/diagnosis
14.
Sci Adv ; 7(1)2021 01.
Article in English | MEDLINE | ID: covidwho-1066781

ABSTRACT

Despite past extensive studies, the mechanisms underlying pulmonary fibrosis (PF) still remain poorly understood. Here, we demonstrated that lungs originating from different types of patients with PF, including coronavirus disease 2019, systemic sclerosis-associated interstitial lung disease, and idiopathic PF, and from mice following bleomycin (BLM)-induced PF are characterized by the altered methyl-CpG-binding domain 2 (MBD2) expression in macrophages. Depletion of Mbd2 in macrophages protected mice against BLM-induced PF. Mbd2 deficiency significantly attenuated transforming growth factor-ß1 (TGF-ß1) production and reduced M2 macrophage accumulation in the lung following BLM induction. Mechanistically, Mbd2 selectively bound to the Ship promoter in macrophages, by which it repressed Ship expression and enhanced PI3K/Akt signaling to promote the macrophage M2 program. Therefore, intratracheal administration of liposomes loaded with Mbd2 siRNA protected mice from BLM-induced lung injuries and fibrosis. Together, our data support the possibility that MBD2 could be a viable target against PF in clinical settings.


Subject(s)
COVID-19/metabolism , DNA-Binding Proteins/metabolism , Macrophages/metabolism , Pulmonary Fibrosis/metabolism , Animals , Bleomycin/pharmacology , Carcinoma, Non-Small-Cell Lung/metabolism , Fibrosis , Gene Expression Profiling , Gene Expression Regulation , Humans , Liposomes/chemistry , Lung Diseases, Interstitial/metabolism , Lung Neoplasms/metabolism , Macrophages/virology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Pulmonary Fibrosis/virology , RNA, Small Interfering/metabolism , Scleroderma, Systemic/metabolism , Signal Transduction , Transforming Growth Factor beta1/metabolism
15.
Med Sci Monit ; 26: e927240, 2020 Dec 01.
Article in English | MEDLINE | ID: covidwho-985826

ABSTRACT

BACKGROUND Infants and young children with acute respiratory distress syndrome (ARDS) have acute progressive hypoxic respiratory failure caused by a variety of extrapulmonary pathogenic factors and cardiogenic factors. Diffuse alveolar injury and pulmonary fibrosis both are pathological features of ARDS. This study investigated the effect of Rehmannia Radix extract (RRE) on pulmonary fibrosis of infants with ARDS. MATERIAL AND METHODS The human lung fibroblasts cell line HFL1 was treated with various concentrations of Rehmannia Radix extract in different groups for different times. Flow cytometry and TUNEL assay were performed to detect cell apoptosis, and CCK8 assay was utilized to analyze cell proliferation. TGF-ß1 expression was detected by real-time quantitative PCR, and protein-level expressions of Caspase3, TGF-ß1, Bcl-2, and Smad3 were measured by western blot and immunohistochemical staining in cells or tissues. TGF-ß1 was overexpressed by recombinant human TGF-ß1 (2 ng/mL) and the treated cells and culture supernatant were harvested for analysis in each step. Bleomycin was used to induce a mouse model of pulmonary fibrosis and was confirmed by HE pathological sections. RESULTS Flow cytometry and TUNEL results showed that RRE promoted the apoptosis of HFL1 cells in a concentration-dependent manner, and it inhibited the proliferation of HFL1 cells. Upregulation of TGF-ß1 reversed the effects of RRE in HFL1 cells. RRE alleviated pulmonary fibrosis in mice through downregulating Bcl-2, TGF-ß1, and Smad3 expression. CONCLUSIONS RRE promoted apoptosis and inhibited proliferation of HFL1, and then arrested the progression of pulmonary fibrosis. RRE had a significant inhibitory effect on TGF-ß1 and Smad3. These results suggest that RRE directly prevents the development of pulmonary fibrosis by affecting the expression of TGF-ß1 and Smad3.


Subject(s)
Plant Extracts/therapeutic use , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/drug therapy , Rehmannia/chemistry , Transforming Growth Factor beta1/metabolism , Animals , Apoptosis/drug effects , Bleomycin , Cell Line , Cell Proliferation/drug effects , Disease Progression , Humans , Mice , Plant Extracts/pharmacology , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology
16.
Eur J Clin Invest ; 51(1): e13443, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-901035

ABSTRACT

BACKGROUND: To reveal detailed histopathological changes, virus distributions, immunologic properties and multi-omic features caused by SARS-CoV-2 in the explanted lungs from the world's first successful lung transplantation of a COVID-19 patient. MATERIALS AND METHODS: A total of 36 samples were collected from the lungs. Histopathological features and virus distribution were observed by optical microscope and transmission electron microscope (TEM). Immune cells were detected by flow cytometry and immunohistochemistry. Transcriptome and proteome approaches were used to investigate main biological processes involved in COVID-19-associated pulmonary fibrosis. RESULTS: The histopathological changes of the lung tissues were characterized by extensive pulmonary interstitial fibrosis and haemorrhage. Viral particles were observed in the cytoplasm of macrophages. CD3+ CD4- T cells, neutrophils, NK cells, γ/δ T cells and monocytes, but not B cells, were abundant in the lungs. Higher levels of proinflammatory cytokines iNOS, IL-1ß and IL-6 were in the area of mild fibrosis. Multi-omics analyses revealed a total of 126 out of 20,356 significant different transcription and 114 out of 8,493 protein expression in lung samples with mild and severe fibrosis, most of which were related to fibrosis and inflammation. CONCLUSIONS: Our results provide novel insight that the significant neutrophil/ CD3+ CD4- T cell/ macrophage activation leads to cytokine storm and severe fibrosis in the lungs of COVID-19 patient and may contribute to a better understanding of COVID-19 pathogenesis.


Subject(s)
COVID-19/pathology , Hemorrhage/pathology , Lung Transplantation , Lung/pathology , Lymph Nodes/pathology , Pulmonary Fibrosis/pathology , B-Lymphocytes/pathology , B-Lymphocytes/ultrastructure , B-Lymphocytes/virology , COVID-19/genetics , COVID-19/metabolism , COVID-19/surgery , Chromatography, Liquid , Flow Cytometry , Gene Expression Profiling , Humans , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Killer Cells, Natural/pathology , Killer Cells, Natural/ultrastructure , Killer Cells, Natural/virology , Lung/metabolism , Lung/ultrastructure , Lung/virology , Lymph Nodes/metabolism , Lymph Nodes/ultrastructure , Lymph Nodes/virology , Macrophages, Alveolar/pathology , Macrophages, Alveolar/ultrastructure , Macrophages, Alveolar/virology , Male , Middle Aged , Monocytes/pathology , Monocytes/ultrastructure , Monocytes/virology , Neutrophils/pathology , Neutrophils/ultrastructure , Neutrophils/virology , Nitric Oxide Synthase Type II/metabolism , Proteomics , Pulmonary Fibrosis/genetics , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/surgery , RNA-Seq , SARS-CoV-2 , Severity of Illness Index , T-Lymphocytes/pathology , T-Lymphocytes/ultrastructure , T-Lymphocytes/virology , Tandem Mass Spectrometry
17.
J Med Virol ; 93(3): 1378-1386, 2021 03.
Article in English | MEDLINE | ID: covidwho-891893

ABSTRACT

Since December 2019, coronavirus disease (COVID-19) has rapidly swept the world. So far, more than 30 million people have been infected and nearly one million have died. Although the world is still in the stage of COVID-19 pandemic, the treatment of new cases and critically ill patients is the focus of the current work. However, COVID-19 patients lead to pulmonary fibrosis, such a serious threat to the prognosis of complications were also worthy of our attention. First of all, we proposed the possible mechanism of pulmonary fibrosis caused by SARS-CoV-2, based on the published data of COVID-19 ((i) Direct evidence: pulmonary fibrosis was found in autopsy and pulmonary puncture pathology. (ii) Indirect evidence: increased levels of fibrosis-related cytokines[transforming growth factor [TGF]- ß, tumor necrosis factor [TNF]- α, interleukin [IL]-6, etc] in peripheral blood of severe patients.) What is more, we summarized the role of three fibrosis-related signaling pathways (TGF- ß signal pathway, WNT signal pathway and YAP/TAZ signal pathway) in pulmonary fibrosis. Finally, we suggested the therapeutic value of two drugs (pirfenidone and nintedanib) for idiopathic pulmonary fibrosis in COVID-19-induced pulmonary fibrosis.


Subject(s)
COVID-19/complications , Indoles/therapeutic use , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/etiology , Pyridones/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , COVID-19/metabolism , COVID-19/pathology , Humans , Lung/pathology , Patient Discharge , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology , Severity of Illness Index , Signal Transduction
18.
Phytother Res ; 35(2): 974-986, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-804475

ABSTRACT

Pulmonary fibrosis is a key feature of COVID-19, Chinese herbal medicine Arenaria kansuensis has been used for curing pulmonary disease and antivirus for a long time and it has the potential against COVID-19. In this work, protective effect of A. kansuensis ethanol extract (AE) on pulmonary fibrosis was evaluated through paraquat (PQ)-induced pulmonary fibrosis animal model. Results showed that AE could significantly improve the survival rate, increase the body weight and reduce the lung index of mice at the raw drug doses of 700 and 350 mg/kg. Histopathological observation results showed that the destruction degree of lung tissue structure in mice was significantly improved with the increase of AE dosage. Collagen deposition in lung interstitium was significantly reduced. The marker protein alpha-SMA involved in PF were significantly inhibited through repressing TGF-beta1/Smads pathway. The degree of inflammatory infiltration was significantly reduced and inflammatory cytokines were significantly inhibited in mice through inhibiting the NF-kB-p65. Besides, oxidant stress level including upregulated ROS and down-regulated SOD and GSH was efficiently improved by AE through upregulation of Nrf2 and downregulation of NOX4. In summary, this study firstly showed that the protective effect of AE on pulmonary fibrosis was partly due to activation of Nrf2 pathway and the inhibition of NF-kB/TGF-beta1/Smad2/3 pathway.


Subject(s)
Arenaria Plant/chemistry , Drugs, Chinese Herbal/pharmacology , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/metabolism , Acute Lung Injury , Animals , Arenaria Plant/physiology , COVID-19/complications , COVID-19/drug therapy , COVID-19/pathology , Cytokines/metabolism , Disease Models, Animal , Drugs, Chinese Herbal/therapeutic use , Ethanol/chemistry , Female , Male , Mice , Mice, Inbred C57BL , NF-E2-Related Factor 2/metabolism , NF-kappa B/metabolism , Oxidative Stress/drug effects , Paraquat , Phytotherapy , Pulmonary Edema/drug therapy , Pulmonary Edema/pathology , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/pathology , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Signal Transduction/drug effects , Smad2 Protein/metabolism , Smad3 Protein/metabolism , Survival Rate , Transforming Growth Factor beta1/metabolism
19.
Int J Mol Sci ; 21(15)2020 Jul 27.
Article in English | MEDLINE | ID: covidwho-680190

ABSTRACT

In March 2020, the World Health Organization declared the severe acute respiratory syndrome corona virus 2 (SARS-CoV2) infection to be a pandemic disease. SARS-CoV2 was first identified in China and, despite the restrictive measures adopted, the epidemic has spread globally, becoming a pandemic in a very short time. Though there is growing knowledge of the SARS-CoV2 infection and its clinical manifestations, an effective cure to limit its acute symptoms and its severe complications has not yet been found. Given the worldwide health and economic emergency issues accompanying this pandemic, there is an absolute urgency to identify effective treatments and reduce the post infection outcomes. In this context, phosphodiesterases (PDEs), evolutionarily conserved cyclic nucleotide (cAMP/cGMP) hydrolyzing enzymes, could emerge as new potential targets. Given their extended distribution and modulating role in nearly all organs and cellular environments, a large number of drugs (PDE inhibitors) have been developed to control the specific functions of each PDE family. These PDE inhibitors have already been used in the treatment of pathologies that show clinical signs and symptoms completely or partially overlapping with post-COVID-19 conditions (e.g., thrombosis, inflammation, fibrosis), while new PDE-selective or pan-selective inhibitors are currently under study. This review discusses the state of the art of the different pathologies currently treated with phosphodiesterase inhibitors, highlighting the numerous similarities with the disorders linked to SARS-CoV2 infection, to support the hypothesis that PDE inhibitors, alone or in combination with other drugs, could be beneficial for the treatment of COVID-19.


Subject(s)
Coronavirus Infections/drug therapy , Phosphodiesterase Inhibitors/therapeutic use , Pneumonia, Viral/drug therapy , Pulmonary Fibrosis/prevention & control , Betacoronavirus/drug effects , COVID-19 , Clinical Trials as Topic , Coronavirus Infections/complications , Coronavirus Infections/metabolism , Disease Progression , Humans , Pandemics , Phosphodiesterase Inhibitors/pharmacology , Pneumonia, Viral/complications , Pneumonia, Viral/metabolism , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/metabolism , SARS-CoV-2 , Signal Transduction/drug effects , Treatment Outcome
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