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1.
preprints.org; 2024.
Preprint in English | PREPRINT-PREPRINTS.ORG | ID: ppzbmed-10.20944.preprints202402.0739.v1

ABSTRACT

Given the various clinical manifestations that characterize COVID-19, the scientific community is constantly searching for biomarkers with prognostic value. SP-A and SP-D collectins play a crucial role in ensuring proper alveolar function and an alteration of their serum levels have been reported in several pulmonary diseases characterized by ARDS and pulmonary fibrosis. Considering that such clinical manifestations can also occur during SARS-CoV-2 infection, we wondered if these collectins could act as prognostic markers. In this regard, serum levels of SP-A and SP-D were measured by enzyme immunoassay in patients with SARS-CoV-2 infection (n=51) at admission (T0) and after 7 days (T1) and compared with healthy donors (n=11). SP-D increased in COVID-19 patients compared to healthy controls during the early phases of infection, while a significant reduction was observed at T1. Stratifying SARS-CoV-2 patients according to disease severity, increased serum SP-D levels were observed in severe compared to mild patients. In the light of these results SP-D, but not SP-A, seems to be an eligible marker of COVID-19 pneumonia and the early detection of SP-D serum levels could be crucial for a preventive clinical management


Subject(s)
Respiratory Distress Syndrome , Pneumonia , Adenocarcinoma, Bronchiolo-Alveolar , Lung Diseases , Pulmonary Fibrosis , COVID-19
2.
researchsquare; 2024.
Preprint in English | PREPRINT-RESEARCHSQUARE | ID: ppzbmed-10.21203.rs.3.rs-3919495.v1

ABSTRACT

Background Radiation-induced pulmonary fibrosis (RIPF) is a late-stage complication of therapeutic radiation, associated with poor prognosis and limited therapeutic options. Radiation-induced lung injury (RILI) is an early manifestation of RIPF, and intervention of RILI is an effective method for preventing long-term RIPF. Mesenchymal stem cell (MSC)-derived exosomes exhibit regenerative activity in injured lungs and are effective drug-delivery nanoparticles. SARS-CoV-2-S-RBD enables ACE2+ cell targeting of MSC extracellular vesicles. miR-486-5p is a multifunctional miRNA with angiogenic and anti-fibrotic activities and is enriched in MSC-derived exosomes. In this study, we investigated the therapeutic effects of miR-486-5p and SARS-COV-2-S-RBD-engineered MSC exosomes on RIPF in vitro and in vivo.Results Adenovirus-mediated gene modification led to the overexpression of miR-486-5p in umbilical cord MSCs (UC-MSCs), which further enriched miR-486-5p in UC-MSCs-derived exosomes. MiR-486-5p-engineered MSC exosomes (miR-486-MSC-Exo) promoted the proliferation and migration of irradiated MLE-12 cells in vitro and inhibited RILI in vivo. An in vitro assay revealed the occurrence of ferroptosis, a major form of cell death during radiation injury, indicated by the upregulated expression of fibrosis-related genes. miR-486-MSC-Exo effectively reversed these changes. MiR-486-MSC-Exo strongly reversed the upregulated expression of MLE-12 fibrosis-related genes induced by TGF in vitro and improved pathological fibrosis in the RIPF model in vivo. The distribution of RBD-VSVG-MSC exosomes labeled with DiR dye in hACE2CKI/CKI Sftpc-Cre+ mice demonstrated that the fluorescence of RBD-VSVG exosomes remained in the lungs for a long time. miR-486-RBD-MSC-exosomes significantly improved the survival rate and pathological changes in hACE2CKI/CKI Sftpc-Cre+ RIPF mice. Furthermore, miR-486-MSC-Exo exerted anti-fibrotic effects through targeted inhibition of SMAD2 and activation of Akt phosphorylation.Conclusions Here, miR-486-MSC-Exo inhibited lung injury and alleviated fibrosis in vivo and in vitro. Surface modification with COVID-S-RBD conferred engineered exosomes with the ability to target the lungs of animal models. The therapeutic effects of miR-486-5p and COVID-S-RBD-engineered MSC exosomes on RIPF were significantly enhanced. MSC-derived exosomes modified with recombinant COVID-S-RBD enabled targeted delivery of miR-486-5p, which is an effective approach for the treatment of RIPF.


Subject(s)
Fibrosis , Pulmonary Fibrosis , Lung Diseases , Radiation Injuries
3.
authorea preprints; 2024.
Preprint in English | PREPRINT-AUTHOREA PREPRINTS | ID: ppzbmed-10.22541.au.170667437.73023879.v1

ABSTRACT

COVID-19 has caused global pandemics since the emergent outbreak and resulted in a large number of deaths. IL-6, as an important autoimmune cytokine, had been suggested for the treatment of acute respiratory distress syndrome (ARDS) patients in COVID-19. A review of the relevant literature revealed more than one role for IL-6 in the lung infection because of its diverse biological effects. It may have a variety of different physiological functions in the development of lung infection. We have summarized its role in different progress of COVID-19, including lung infection, pneumonia, ALI, pulmonary fibrosis, and lung translation and even lung cancer. This will facilitate a deeper understanding of the role of IL-6 in the treatment of COVID-19.


Subject(s)
Respiratory Distress Syndrome , Pneumonia , Lung Diseases , Lung Neoplasms , Pulmonary Fibrosis , COVID-19
4.
biorxiv; 2024.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2024.01.21.576509

ABSTRACT

Pulmonary fibrosis is an increasing and major cause of death worldwide. Understanding the cellular and molecular mechanisms underlying the pathophysiology of lung fibrosis may lead to urgently needed diagnostic and prognostic strategies for the disease. SOX9 is a core transcription factor that has been associated with fibrotic disease, however its role and regulation in acute lung injury and/or fibrosis have not been fully defined. In this study we apply a hypothesis based approach to uncover unique SOX9-protein signatures associated with both acute lung injury and fibrotic progression. Using in vivo models of lung injury in the presence or absence of SOX9, our study shows SOX9 is essential to the damage associated response of alveolar epithelial cells from an early time-point in lung injury. In parallel, as disease progresses, SOX9 is responsible for regulating tissue damaging ECM production from pro-fibrotic fibroblasts. In determining the in vivo role of SOX9 we identified secreted ECM components downstream of SOX9 as markers of acute lung injury and fibrosis. To underscore the translational potential of our SOX9-regulated markers, we analysed serum samples from acute COVID19, post COVID19 and idiopathic pulmonary fibrosis (IPF) patient cohorts. Our hypothesis driven SOX9-panels showed significant capability in all cohorts at identifying patients who had poor disease outcomes. This study shows that SOX9 is functionally critical to disease in acute lung injury and pulmonary fibrosis and its regulated pathways have diagnostic, prognostic and therapeutic potential in both COVID19 and IPF disease.


Subject(s)
Fibrosis , Idiopathic Pulmonary Fibrosis , Adenocarcinoma, Bronchiolo-Alveolar , Lung Diseases , Disease , Pulmonary Fibrosis , COVID-19 , Acute Lung Injury
5.
researchsquare; 2024.
Preprint in English | PREPRINT-RESEARCHSQUARE | ID: ppzbmed-10.21203.rs.3.rs-3868352.v1

ABSTRACT

Backgrounds : The management of lung complications, especially fibrosis, after coronavirus disease (COVID-19) pneumonia, is an important issue in the COVID-19 post-pandemic era. We aimed to investigate risk factors for pulmonary fibrosis development in patients with severe COVID-19 pneumonia.Methods Clinical and radiologic data were prospectively collected from 64 patients who required mechanical ventilation due to COVID-19 pneumonia and were enrolled from eight hospitals in South Korea. Fibrotic changes on chest computed tomography (CT) was evaluated by visual assessment, and extent of fibrosis (mixed disease score) was measured using automatic quantification system.Results Sixty-four patients were enrolled, and their mean age was 58.2 years (64.1% were males). On chest CT (median interval: 60 days [interquartile range, IQR; 41–78 days] from enrolment), 35 (54.7%) patients showed ≥ 3 fibrotic lesions. The most frequent fibrotic change was traction bronchiectasis (47 patients, 73.4%). Median extent of fibrosis measured by automatic quantification was 10.6% (IQR, 3.8–40.7%). In a multivariable Cox proportional hazard model, which included nine variables with a p-value of < 0.10 in an unadjusted analysis as well as age, sex, and body mass index, male sex (hazard ratio [HR], 3.01; 95% confidence interval [CI], 1.27–7.11) and higher initial sequential organ failure assessment (SOFA) score (HR, 1.18; 95% CI, 1.02–1.37) were independently associated with pulmonary fibrosis (≥ 3 fibrotic lesions).Conclusion Our data suggests that male gender and higher SOFA score at intensive care unit admission were associated with pulmonary fibrosis in patients with severe COVID-19 pneumonia requiring mechanical ventilation.


Subject(s)
Fibrosis , Pneumonia , Kidney Diseases , Lung Diseases , Coronavirus Infections , Pulmonary Fibrosis , COVID-19
6.
arxiv; 2023.
Preprint in English | PREPRINT-ARXIV | ID: ppzbmed-2312.13752v1

ABSTRACT

Airway-related quantitative imaging biomarkers are crucial for examination, diagnosis, and prognosis in pulmonary diseases. However, the manual delineation of airway trees remains prohibitively time-consuming. While significant efforts have been made towards enhancing airway modelling, current public-available datasets concentrate on lung diseases with moderate morphological variations. The intricate honeycombing patterns present in the lung tissues of fibrotic lung disease patients exacerbate the challenges, often leading to various prediction errors. To address this issue, the 'Airway-Informed Quantitative CT Imaging Biomarker for Fibrotic Lung Disease 2023' (AIIB23) competition was organized in conjunction with the official 2023 International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI). The airway structures were meticulously annotated by three experienced radiologists. Competitors were encouraged to develop automatic airway segmentation models with high robustness and generalization abilities, followed by exploring the most correlated QIB of mortality prediction. A training set of 120 high-resolution computerised tomography (HRCT) scans were publicly released with expert annotations and mortality status. The online validation set incorporated 52 HRCT scans from patients with fibrotic lung disease and the offline test set included 140 cases from fibrosis and COVID-19 patients. The results have shown that the capacity of extracting airway trees from patients with fibrotic lung disease could be enhanced by introducing voxel-wise weighted general union loss and continuity loss. In addition to the competitive image biomarkers for prognosis, a strong airway-derived biomarker (Hazard ratio>1.5, p<0.0001) was revealed for survival prognostication compared with existing clinical measurements, clinician assessment and AI-based biomarkers.


Subject(s)
Fibrosis , Pulmonary Fibrosis , Lung Diseases , COVID-19
7.
biorxiv; 2023.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2023.09.13.557622

ABSTRACT

The long-term health effects of SARS-CoV-2, termed Post-Acute Sequelae of COVID-19 (PASC), are quickly evolving into a major public health concern, but the underlying cellular and molecular etiology remain poorly defined. There is growing evidence that PASC is linked to abnormal immune responses and/or poor organ recovery post-infection. However, the exact processes linking non-resolving inflammation, impaired tissue repair, and PASC are still unclear. In this report, we utilized a cohort of respiratory PASC patients with viral infection-mediated pulmonary fibrosis and a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. Using a combination of imaging and spatial transcriptomics, we identified dysregulated proximal interactions between immune cells and epithelial progenitors unique to respiratory PASC but not acute COVID-19 or idiopathic pulmonary fibrosis (IPF). Specifically, we found a central role for lung-resident CD8+ T cell-macrophage interactions in maintaining Krt8hi transitional and ectopic Krt5+ basal cell progenitors, and the development of fibrotic sequelae after acute viral pneumonia. Mechanistically, CD8+ T cell derived IFN-{gamma} and TNF stimulated lung macrophages to chronically release IL-1{beta}, resulting in the abnormal accumulation of dysplastic epithelial progenitors in fibrotic areas. Notably, therapeutic neutralization of IFN-{gamma} and TNF, or IL-1{beta} after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function. Together, our findings implicate a dysregulated immune-epithelial progenitor niche in driving respiratory PASC and identify potential therapeutic targets to dampen chronic pulmonary sequelae post respiratory viral infections including SARS-CoV-2.


Subject(s)
Neoplasms, Glandular and Epithelial , Respiratory Tract Infections , COVID-19 , Acute Disease , Idiopathic Pulmonary Fibrosis , Adenocarcinoma, Bronchiolo-Alveolar , Inflammation , Pulmonary Fibrosis , Pneumonia, Viral
8.
biorxiv; 2023.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2023.07.14.548971

ABSTRACT

The lung, as a primary target of SARS-CoV-2, exhibits heterogeneous microenvironment accompanied by various histopathological changes following virus infection. However, comprehensive insight into the protein basis of COVID-19-related pulmonary injury with spatial resolution is currently deficient. Here, we generated a region-resolved quantitative proteomic atlas of seven major pathological structures within the lungs of COVID-19 victims by integrating histological examination, laser microdissection, and ultrasensitive proteomic technologies. Over 10,000 proteins were quantified across 71 dissected FFPE post-mortem specimens. By comparison with control samples, we identified a spectrum of COVID-19-induced protein and pathway dysregulations in alveolar epithelium, bronchial epithelium, and pulmonary blood vessels, providing evidence for the proliferation of transitional-state pneumocytes. Additionally, we profiled the region-specific proteomes of hallmark COVID-19 pulmonary injuries, including bronchiole mucus plug, pulmonary fibrosis, airspace inflammation, and hyperplastic alveolar type 2 cells. Bioinformatic analysis revealed the enrichment of cell-type and functional markers in these regions (e.g. enriched TGFBI in fibrotic region). Furthermore, we identified the up-regulation of proteins associated with viral entry, host restriction, and inflammatory response in COVID-19 lungs, such as FURIN and HGF. Collectively, this study provides spatial proteomic insights for understanding COVID-19-caused pulmonary injury, and may serve as a valuable reference for improving therapeutic intervention for severe pneumonia.


Subject(s)
Pneumonia , Adenocarcinoma, Bronchiolo-Alveolar , Inflammation , Pulmonary Fibrosis , COVID-19 , Pulmonary Embolism
9.
Ter Arkh ; 94(11): 1333-1339, 2022 Dec 26.
Article in Russian | MEDLINE | ID: covidwho-20234221

ABSTRACT

The viral infectious disease pandemic caused by SARS-CoV-2 has affected over 500 million people and killed over 6 million. This is the official data provided by the WHO as of the end of May 2022. Among people who have recovered from COVID-19, post-COVID syndrome is quite common. Scattered epidemiological studies on post-COVID syndrome, however, indicate its high relevance. One of the manifestations of post-COVID syndrome is the development of pulmonary fibrosis (PF). This article is devoted to the analysis of literature data on epidemiology, immunomorphology, as well as X-ray morphological and functional characteristics of PF in patients with post-COVID syndrome. Attention is drawn to the various phenotypes of the post-COVID syndrome and the incidence of PF, which, as clinical practice shows, is most common in people who have had severe COVID-19. This article discusses in detail the molecular biological and immunological mechanisms of PF development. The fibrotic process of the lung parenchyma is not an early manifestation of the disease; as a rule, radiomorphological signs of this pathological process develop after four weeks from the onset of acute manifestations of a viral infection. The characteristic signs of PF include those that indicate the process of remodulation of the lung tissue: volumetric decrease in the lungs, "cellular" degeneration of the lung parenchyma, bronchiectasis and traction bronchiolectasis. The process of remodulating the lung tissue, in the process of fibrosis, is accompanied by a violation of the lung function; a particularly sensitive test of functional disorders is a decrease in the diffusion capacity of the lung tissue. Therefore, in the process of monitoring patients with post-COVID syndrome, a dynamic study of the ventilation function of the lungs is recommended. The main clinical manifestation of PF is dyspnea that occurs with minimal exertion. Shortness of breath also reflects another important aspect of fibrous remodulation of the lung parenchyma - oxygen dissociation is disturbed, which reflects a violation of the gas exchange function of the lungs. There are no generally accepted treatments for PF in post-COVID syndrome. The literature considers such approaches as the possibility of prescribing antifibrotic therapy, hyaluronidase, and medical gases: thermal helium, nitric oxide, and atomic hydrogen. The article draws attention to the unresolved issues of post-covid PF in people who have had COVID-19.


Subject(s)
COVID-19 , Pulmonary Fibrosis , Humans , COVID-19/complications , Pulmonary Fibrosis/diagnosis , Pulmonary Fibrosis/epidemiology , Pulmonary Fibrosis/etiology , SARS-CoV-2 , Lung/diagnostic imaging , Lung/pathology , Dyspnea
11.
Nat Med ; 29(6): 1563-1577, 2023 Jun.
Article in English | MEDLINE | ID: covidwho-20242944

ABSTRACT

Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1+ profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas.


Subject(s)
COVID-19 , Lung Neoplasms , Pulmonary Fibrosis , Humans , Lung , Lung Neoplasms/genetics , Macrophages
12.
Aging (Albany NY) ; 15(11): 4625-4641, 2023 06 07.
Article in English | MEDLINE | ID: covidwho-20239369

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) pandemic. The severity of COVID-19 increases with each decade of life, a phenomenon that suggest that organismal aging contributes to the fatality of the disease. In this regard, we and others have previously shown that COVID-19 severity correlates with shorter telomeres, a molecular determinant of aging, in patient's leukocytes. Lung injury is a predominant feature of acute SARS-CoV-2 infection that can further progress to lung fibrosis in post-COVID-19 patients. Short or dysfunctional telomeres in Alveolar type II (ATII) cells are sufficient to induce pulmonary fibrosis in mouse and humans. Here, we analyze telomere length and the histopathology of lung biopsies from a cohort of alive post-COVID-19 patients and a cohort of age-matched controls with lung cancer. We found loss of ATII cellularity and shorter telomeres in ATII cells concomitant with a marked increase in fibrotic lung parenchyma remodeling in post- COVID-19 patients compared to controls. These findings reveal a link between presence of short telomeres in ATII cells and long-term lung fibrosis sequel in Post-COVID-19 patients.


Subject(s)
COVID-19 , Neoplasms , Pulmonary Fibrosis , Humans , Mice , Animals , Pulmonary Fibrosis/pathology , COVID-19/pathology , SARS-CoV-2 , Alveolar Epithelial Cells , Lung/pathology , Neoplasms/pathology , Telomere/pathology
14.
Sci Rep ; 13(1): 6554, 2023 04 21.
Article in English | MEDLINE | ID: covidwho-2311154

ABSTRACT

The purpose was to examine patient-centered outcomes and the occurrence of lung fibrotic changes on Chest computed tomography (CT) imaging following pneumonia-related acute respiratory distress syndrome (ARDS). We sought to investigate outpatient clinic chest CT imaging in survivors of COVID19-related ARDS and non-COVID-related ARDS, to determine group differences and explore relationships between lung fibrotic changes and functional outcomes. A retrospective practice analysis of electronic health records at an ICU Recovery Clinic in a tertiary academic medical center was performed in adult patients surviving ARDS due to COVID-19 and non-COVID etiologies. Ninety-four patients with mean age 53 ± 13 and 51% male were included (n = 64 COVID-19 and n = 30 non-COVID groups). There were no differences for age, sex, hospital length of stay, ICU length of stay, mechanical ventilation duration, or sequential organ failure assessment (SOFA) scores between the two groups. Fibrotic changes visualized on CT imaging occurred in a higher proportion of COVID-19 survivors (70%) compared to the non-COVID group (43%, p < 0.001). Across both groups, patients with fibrotic changes (n = 58) were older, had a lower BMI, longer hospital and ICU LOS, lower mean RASS scores, longer total duration of supplemental oxygen. While not statistically different, patients with fibrotic changes did have reduced respiratory function, worse performance on the six-minute walk test, and had high occurrences of anxiety, depression, emotional distress, and mild cognitive impairment regardless of initial presenting diagnosis. Patients surviving pneumonia-ARDS are at high risk of impairments in physical, emotional, and cognitive health related to Post-Intensive Care Syndrome. Of clinical importance, pulmonary fibrotic changes on chest CT occurred in a higher proportion in COVID-ARDS group; however, no functional differences were measured in spirometry or physical assessments at ICU follow-up. Whether COVID infection imparts a unique recovery is not evident from these data but suggest that long-term follow up is necessary for all survivors of ARDS.


Subject(s)
COVID-19 , Pneumonia , Pulmonary Fibrosis , Respiratory Distress Syndrome , Adult , Humans , Male , Middle Aged , Aged , Female , COVID-19/complications , Pulmonary Fibrosis/complications , Pulmonary Fibrosis/diagnostic imaging , Retrospective Studies , Pneumonia/complications , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/epidemiology
15.
J Appl Microbiol ; 134(1)2023 Jan 23.
Article in English | MEDLINE | ID: covidwho-2308562

ABSTRACT

AIMS: To evaluate the effects of the Qingwen Gupi decoction (QGT) in a rat model of bleomycin-induced pulmonary fibrosis (PF), and explore the underlying mechanisms by integrating UPLC-Q-TOF/MS metabolomics and 16S rDNA sequencing of gut microbiota. METHODS AND RESULTS: The animals were randomly divided into the control, PF model, pirfenidone-treated, and low-, medium-, and high-dose QGT groups. The lung tissues were examined and the expression of TGF-ß, SMAD-3, and SMAD-7 mRNAs in the lung tissues were analyzed. Metabolomic profiles were analyzed by UPLC-QTOF/MS, and the intestinal flora were examined by prokaryotic 16 rDNA sequencing. Pathological examination and biochemical indices revealed that QGT treatment improved the symptoms of PF by varying degrees. Furthermore, QGT significantly downregulated TGF-ß1 and Smad-3 mRNAs and increased the expression levels of Smad-7. QGT-L in particular increased the levels of 18 key metabolic biomarkers that were associated with nine gut microbial species and may exert antifibrosis effects through arachidonic acid metabolism, glycerophospholipid metabolism, and phenylalanine metabolism. CONCLUSIONS: QGT alleviated PF in a rat model through its anti-inflammatory, antioxidant, and anti-fibrotic effects, and by reversing bleomycin-induced gut dysbiosis.This study lays the foundation for further research on the pathological mechanisms of PF and the development of new drug candidates.


Subject(s)
Gastrointestinal Microbiome , Pulmonary Fibrosis , Rats , Animals , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/pathology , Lung , Bleomycin/adverse effects , Transforming Growth Factor beta/metabolism , Metabolomics
16.
Bioorg Chem ; 138: 106592, 2023 Sep.
Article in English | MEDLINE | ID: covidwho-2311750

ABSTRACT

Pulmonary fibrosis is the end-stage change of a large class of lung diseases characterized by the proliferation of fibroblasts and the accumulation of a large amount of extracellular matrix, accompanied by inflammatory damage and tissue structure destruction, which also shows the normal alveolar tissue is damaged and then abnormally repaired resulting in structural abnormalities (scarring). Pulmonary fibrosis has a serious impact on the respiratory function of the human body, and the clinical manifestation is progressive dyspnea. The incidence of pulmonary fibrosis-related diseases is increasing year by year, and no curative drugs have appeared so far. Nevertheless, research on pulmonary fibrosis have also increased in recent years, but there are no breakthrough results. Pathological changes of pulmonary fibrosis appear in the lungs of patients with coronavirus disease 2019 (COVID-19) that have not yet ended, and whether to improve the condition of patients with COVID-19 by means of the anti-fibrosis therapy, which are the questions we need to address now. This review systematically sheds light on the current state of research on fibrosis from multiple perspectives, hoping to provide some references for design and optimization of subsequent drugs and the selection of anti-fibrosis treatment plans and strategies.


Subject(s)
COVID-19 , Pulmonary Fibrosis , Humans , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/pathology , COVID-19/pathology , Lung , Fibrosis , Fibroblasts
17.
preprints.org; 2023.
Preprint in English | PREPRINT-PREPRINTS.ORG | ID: ppzbmed-10.20944.preprints202305.0181.v1

ABSTRACT

This review brings together the current knowledge regarding the risk factors, and the clinical, radiologic and histological features of both post-COVID-19 interstitial pul-monary fibrosis (PCPF) and Idiopathic Pulmonary Fibrosis (IPF) with a particular fo-cus on describing the similarities and the disparities between the fibrotic changes in these two diseases. It is important to highlight the common points of PCPF and IPF to observe if they are some targetable changes to improve patient outcomes. The litera-ture review was performed using numerous databases to identify relevant articles published in English through October 2022. This review would help clinicians, pathologists and researchers to make an accurate diagnosis, which can be useful in identifying the group of patients who can be selected for antifibrotic therapies, and future therapeutic perspectives.


Subject(s)
Fibrosis , Pulmonary Fibrosis , COVID-19 , Idiopathic Pulmonary Fibrosis
18.
ssrn; 2023.
Preprint in English | PREPRINT-SSRN | ID: ppzbmed-10.2139.ssrn.4431410

ABSTRACT

Pulmonary fibrosis is an interstitial lung disease caused by various factors such as exposure to workplace environmental contaminants, drugs, or X-rays. Epithelial cells are among the driving factors of pulmonary fibrosis. Immunoglobulin A (IgA), traditionally thought to be secreted by B cells, is an important immune factor involved in COVID-19 infection and vaccination. In current study, we found lung epithelial cells were involved in IgA secretion which, in turn, promoted pulmonary fibrosis. The spatial transcriptomics and single-cell sequencing suggests that Igha transcripts were highly expressed in the fibrotic lesion areas of lungs from silica-treated mice. Reconstruction of B-cell receptor (BCR) sequences revealed a new cluster of AT2-like epithelial cells with a shared BCR and high expression of genes related to IgA production. Furthermore, the secretion of IgA by AT2-like cells were trapped by extracellular matrix and aggravated pulmonary fibrosis by activating fibroblasts. Targeted blockade of IgA secretion by pulmonary epithelial cells may be a potential strategy for treating pulmonary fibrosis.


Subject(s)
Pulmonary Fibrosis , Lung Diseases, Interstitial , COVID-19
19.
Cell Chem Biol ; 30(3): 261-277.e8, 2023 03 16.
Article in English | MEDLINE | ID: covidwho-2288731

ABSTRACT

Pulmonary fibrosis is a typical sequela of coronavirus disease 2019 (COVID-19), which is linked with a poor prognosis for COVID-19 patients. However, the underlying mechanism of pulmonary fibrosis induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. Here, we demonstrated that the nucleocapsid (N) protein of SARS-CoV-2 induced pulmonary fibrosis by activating pulmonary fibroblasts. N protein interacted with the transforming growth factor ß receptor I (TßRI), to disrupt the interaction of TßRI-FK506 Binding Protein12 (FKBP12), which led to activation of TßRI to phosphorylate Smad3 and boost expression of pro-fibrotic genes and secretion of cytokines to promote pulmonary fibrosis. Furthermore, we identified a compound, RMY-205, that bound to Smad3 to disrupt TßRI-induced Smad3 activation. The therapeutic potential of RMY-205 was strengthened in mouse models of N protein-induced pulmonary fibrosis. This study highlights a signaling pathway of pulmonary fibrosis induced by N protein and demonstrates a novel therapeutic strategy for treating pulmonary fibrosis by a compound targeting Smad3.


Subject(s)
COVID-19 , Pulmonary Fibrosis , Animals , Mice , COVID-19/complications , Fibrosis , Nucleocapsid Proteins/therapeutic use , Pulmonary Fibrosis/complications , Pulmonary Fibrosis/drug therapy , SARS-CoV-2
20.
J Nanobiotechnology ; 21(1): 69, 2023 Feb 28.
Article in English | MEDLINE | ID: covidwho-2288660

ABSTRACT

BACKGROUND: The rapid increase in production and application of carbon nanotubes (CNTs) has led to wide public concerns in their potential risks to human health. Single-walled CNTs (SWCNTs), as an extensively applied type of CNTs, have shown strong capacity to induce pulmonary fibrosis in animal models, however, the intrinsic mechanisms remain uncertain. RESULTS: In vivo experiments, we showed that accelerated senescence of alveolar type II epithelial cells (AECIIs) was associated with pulmonary fibrosis in SWCNTs-exposed mice, as well as SWCNTs-induced fibrotic lungs exhibited impaired autophagic flux in AECIIs in a time dependent manner. In vitro, SWCNTs exposure resulted in profound dysfunctions of MLE-12 cells, characterized by impaired autophagic flux and accelerated cellular senescence. Furthermore, the conditioned medium from SWCNTs-exposed MLE-12 cells promoted fibroblast-myofibroblast transdifferentiation (FMT). Additionally, restoration of autophagy flux with rapamycin significantly alleviated SWCNTs-triggered senescence and subsequent FMT whereas inhibiting autophagy using 3-MA aggravated SWCNTs-triggered senescence in MLE-12 cells and FMT. CONCLUSION: SWCNTs trigger senescence of AECIIs by impairing autophagic flux mediated pulmonary fibrosis. The findings raise the possibility of senescence-related cytokines as potential biomarkers for the hazard of CNTs exposure and regulating autophagy as an appealing target to halt CNTs-induced development of pulmonary fibrosis.


Subject(s)
Nanotubes, Carbon , Pulmonary Fibrosis , Humans , Animals , Mice , Nanotubes, Carbon/toxicity , Pulmonary Fibrosis/chemically induced , Alveolar Epithelial Cells , Autophagy , Fibroblasts
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