scholarly journals COVID-19 lung disease shares driver AT2 cytopathic features with Idiopathic pulmonary fibrosis

2021 ◽  
Author(s):  
Saptarshi Sinha ◽  
Vanessa Castillo ◽  
Celia R. Espinoza ◽  
Courtney Tindle ◽  
Ayden G. Fonseca ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Er Stress ◽  
Lung Disease ◽  
Disease Models ◽  
Specific Gene ◽  
Alveolar Type ◽  
Ppi Network ◽  
Gene Signatures ◽  
Network Analyses

Background: In the aftermath of Covid-19, a long-haul form of mysterious and progressive fibrotic lung disease has emerged, i.e., post-COVID-19 lung disease (PCLD), for which we currently lack insights into pathogenesis, disease models, or treatment options. Method: Using an AI-guided approach, we analyzed > 1000 human lung transcriptomic datasets associated with various lung conditions using two viral pandemic (ViP and sViP) and one covid lung gene signatures. Upon identifying similarities between COVID-19 and idiopathic pulmonary fibrosis (IPF), we subsequently dissected the basis for such similarity from molecular, cytopathic, and immunologic perspectives using a panel of IPF-specific gene signatures, alongside signatures of alveolar type II (AT2) cytopathies and of prognostic monocyte-driven processes that are known drivers of IPF. To pinpoint the AT2 processes that are shared points of convergence between COVID-19 and IPF, transcriptome-derived findings were used to construct protein-protein interaction (PPI) network. Key findings were validated in hamster and human adult lung organoid (ALO) pre-clinical models of COVID-19 using immunohistochemistry and qPCR. Findings: We found that COVID-19 resembles IPF at a fundamental level; it recapitulates the gene expression patterns (ViP and IPF signatures), cytokine storm (IL15-centric) and the AT2 cytopathic changes, e.g., injury, DNA damage, arrest in a transient, damage-induced progenitor state, and senescence-associated secretory phenotype (SASP). These immunocytopathic features were induced in pre-clinical COVID models (ALO and hamster) and reversed with effective anti-CoV-2 therapeutics in hamsters. PPI-network analyses pinpointed ER stress as one of the shared early triggers of both diseases, and IHC studies validated the same in the lungs of deceased subjects with COVID-19 and SARS-CoV-2-challenged hamster lungs. Lungs from tg-mice, in which ER stress is induced specifically in the AT2 cells, faithfully recapitulate the host immune response and alveolar cytopathic changes that are induced by SARS-CoV-2. Interpretation: Like IPF, COVID-19 may be driven by injury-induced ER stress that culminates into progenitor state arrest and SASP in AT2 cells. The ViP signatures in monocytes may be key determinants of prognosis. The insights, signatures, disease models identified here are likely to spur the development of therapies for patients with IPF and other fibrotic interstitial lung disease.

scholarly journals Disparate Interferon Signaling and Shared Aberrant Basaloid Cells in Single-Cell Profiling of Idiopathic Pulmonary Fibrosis and Systemic Sclerosis-Associated Interstitial Lung Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Eleanor Valenzi ◽  
Tracy Tabib ◽  
Anna Papazoglou ◽  
John Sembrat ◽  
Humberto E. Trejo Bittar ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Interstitial Lung Disease ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Lung Disease ◽  
Single Cell ◽  
Alveolar Type ◽  
Type I ◽  
Interferon Signaling ◽  
Mesenchymal Transition

Idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD) differ in the predominant demographics and identified genetic risk alleles of effected patients, however both diseases frequently progress to respiratory failure and death. Contrasting advanced SSc-ILD to IPF provides insight to the role dysregulated immunity may play in pulmonary fibrosis. To analyze cell-type specific transcriptome commonalities and differences between IPF and SSc-ILD, we compared single-cell RNA-sequencing (scRNA-seq) of 21 explanted lung tissue specimens from patients with advanced IPF, SSc-ILD, and organ donor controls. Comparison of IPF and SSc-ILD tissue identified divergent patterns of interferon signaling, with interferon-gamma signaling upregulated in the SPP1hi and FABP4hi macrophages, cytotoxic T cells, and natural kill cells of IPF, while type I interferon signaling and production was upregulated in the corresponding SSc-ILD populations. Plasmacytoid dendritic cells were found in diseased lungs only, and exhibited upregulated cellular stress pathways in SSc-ILD compared to IPF. Alveolar type I cells were dramatically decreased in both IPF and SSc-ILD, with a distinct transcriptome signature separating these cells by disease. KRT5-/KRT17+ aberrant basaloid cells exhibiting markers of cellular senescence and epithelial-mesenchymal transition were identified in SSc-ILD for the first time. In summary, our study utilizes the enriched capabilities of scRNA-seq to identify key divergent cell types and pathways between IPF and SSc-ILD, providing new insights into the shared and distinct mechanisms between idiopathic and autoimmune interstitial lung diseases.

scholarly journals Complications in Idiopathic Pulmonary Fibrosis: Focus on Their Clinical and Radiological Features

Diagnostics ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 450
Author(s):  
Federica Galioto ◽  
Stefano Palmucci ◽  
Giovanna M. Astuti ◽  
Ada Vancheri ◽  
Giulio Distefano ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Lung Disease ◽  
Integrated Approach ◽  
Correct Treatment ◽  
Radiological Features ◽  
Palliative Care Services ◽  
Pictorial Essay ◽  
Personalized Approach ◽  
Fibrotic Lung Disease

Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease with uncertain origins and pathogenesis; it represents the most common interstitial lung disease (ILD), associated with a pathological pattern of usual interstitial pneumonitis (UIP). This disease has a poor prognosis, having the most lethal prognosis among ILDs. In fact, the progressive fibrosis related to IPF could lead to the development of complications, such as acute exacerbation, lung cancer, infections, pneumothorax and pulmonary hypertension. Pneumologists, radiologists and pathologists play a key role in the identification of IPF disease, and in the characterization of its complications—which unfortunately increase disease mortality and reduce overall survival. The early identification of these complications is very important, and requires an integrated approach among specialists, in order to plane the correct treatment. In some cases, the degree of severity of patients having IPF complications may require a personalized approach, based on palliative care services. Therefore, in this paper, we have focused on clinical and radiological features of the complications that occurred in our IPF patients, providing a comprehensive and accurate pictorial essay for clinicians, radiologists and surgeons involved in their management.

scholarly journals Antifibrotic Therapies and Progressive Fibrosing Interstitial Lung Disease (PF-ILD): Building on INBUILD

2021 ◽  
Vol 10 (11) ◽  
pp. 2285
Author(s):  
John N. Shumar ◽  
Abhimanyu Chandel ◽  
Christopher S. King
Keyword(s):  
Interstitial Lung Disease ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Lung Disease ◽  
Lung Diseases ◽  
Interstitial Lung Diseases ◽  
Treatment Pathway ◽  
Antifibrotic Therapy ◽  
New Treatment ◽  
Fibrotic Lung Diseases

Progressive fibrosing interstitial lung disease (PF-ILD) describes a phenotypic subset of interstitial lung diseases characterized by progressive, intractable lung fibrosis. PF-ILD is separate from, but has radiographic, histopathologic, and clinical similarities to idiopathic pulmonary fibrosis. Two antifibrotic medications, nintedanib and pirfenidone, have been approved for use in patients with idiopathic pulmonary fibrosis. Recently completed randomized controlled trials have demonstrated the clinical efficacy of antifibrotic therapy in patients with PF-ILD. The validation of efficacy of antifibrotic therapy in PF-ILD has changed the treatment landscape for all of the fibrotic lung diseases, providing a new treatment pathway and opening the door for combined antifibrotic and immunosuppressant drug therapy to address both the fibrotic and inflammatory components of ILD characterized by mixed pathophysiologic pathways.

scholarly journals SAT0098 TREATMENT OF A COHORT OF PATIENTS WITH INTERSTITIAL LUNG DISEASE AND RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 982.2-982
Author(s):  
C. Aguilera Cros ◽  
M. Gomez Vargas ◽  
R. J. Gil Velez ◽  
J. A. Rodriguez Portal
Keyword(s):  
Rheumatoid Arthritis ◽  
Interstitial Lung Disease ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Lung Disease ◽  
Latin American ◽  
Usual Interstitial Pneumonia ◽  
Specific Treatment ◽  
American Thoracic Society ◽  
Rapid Progression

Background:There is no specific treatment for interstitial lung disease (ILD) secondary to Rheumatoid Arthritis (RA) other than the treatment of RA without extra-articular involvement. Current regimens usually include corticosteroid therapy with or without immunosuppressants (IS), there is no consensus for the treatment.Objectives:To analyze the different treatment regimens in a cohort of patients with ILD and RA in our clinical practice.Methods:Descriptive study of 57 patients treated in our Hospital (1/1/2018 until 12/31/2019) with a diagnosis of RA (ACR 2010 criteria) and secondary ILD.The most recent American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Society (ALAT) guidelines define three HRCT (High Resolution Computed Tomography) patterns of fibrosing lung disease in the setting of idiopathic pulmonary fibrosis (IPF): definite Usual Interstitial pneumonia (UIP) (traction bronchiectasis and honeycombing), possible UIP and inconsistent with UIP. The distinction between definite UIP and possible UIP in these to the presence or absence of honeycombing. Approved by the Ethics Committee.Quantitative variables are expressed as mean (SD) and dichotomous variables as percentages (%). Statistical analysis with SPSS version 21.Results:21 men and 36 women were included, with a mean age of 69 ± 10 years (mean ± SD), history of smoking (smokers 14%, non-smokers 43%, former smokers 42%). Clinical ILD at diagnosis (dyspnea 61%, dry cough 56%, crackling 70%, acropachy 7%). 84% were positive rheumatoid factor and 70% positive anticitrullinated protein antibody.Diagnosis of ILD by HRCT in 100% of patients with different patterns: defined UIP 26 (45%), probable UIP 2 (3%) and not UIP 29 (50%). The diagnosis of ILD was confirmed by biopsy in 12 patients.79% underwent (T) treatment prior to the diagnosis of ILD with glucocorticoids and disease-modifying drugs (DMARD). Among the traditional DMARDs used were: Methotrexate 68% (there were no cases of MTX pneumonitis), Leflunomide 47%, Hydroxychloroquine 26% and Sulfasalazine 21%. Biological therapy in 15 patients: Etanercept 19%, Adalimumab 5%, Infliximab 3% and Certolizumab 2%. Two patients presented an exacerbation and rapid progression of the ILD during the T with Etanercept with the final result of death.T with IS after the diagnosis of ILD in 80% of patients (Azathioprine 15, Rituximab 14, Abatacept 10, Tocilizumab 4, Sarilumab 1, Mofetil mycophenolate 1 and Cyclophosphamide 1).Two patients with defined UIP perform T with antifibrotic: 1st Nintedanib (INBUILD Trial, This article was published on September 29, 2019, at NEJM.org) 2nd Pirfenidone (initial diagnosis of IPF Idiopathic Pulmonary Fibrosis and subsequent of seropositive RA with UIP). Both improved greater than 10% in forced vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLCO) in the 6 months after onset of T.Conclusion:Our results, in general, agree with what is published in the literature. Prospective, multicentre and larger sample studies are necessary to better define which patients would benefit more from IS T or antifibrotic T (or if the antifibrotic should be added to the previous IS).Disclosure of Interests:None declared

scholarly journals Clinicoserological features of antisynthetase syndrome (ASyS)-associated interstitial lung disease presenting to respiratory services: comparison with idiopathic pulmonary fibrosis and ASyS diagnosed in rheumatology services

2021 ◽  
Vol 8 (1) ◽  
pp. e000829
Author(s):  
Shaney L Barratt ◽  
Havra H Adamali ◽  
Caroline Cotton ◽  
Ben Mulhearn ◽  
Hina Iftikhar ◽  
...  
Keyword(s):  
Interstitial Lung Disease ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Lung Disease ◽  
Trna Synthetase ◽  
Musculoskeletal Symptoms ◽  
Antisynthetase Syndrome ◽  
Cytoplasmic Staining ◽  
Phenotypic Differences ◽  
Lung Physiology

IntroductionAntisynthetase syndrome (ASyS) is a rare autoimmune connective tissue disease (CTD), associated with autoantibodies targeting tRNA synthetase enzymes, that can present to respiratory (interstitial lung disease (ILD)) or rheumatology (myositis, inflammatory arthritis and systemic features) services. The therapeutic management of CTD-associated ILD and idiopathic pulmonary fibrosis (IPF) differs widely, thus accurate diagnosis is essential.MethodsWe undertook a retrospective, multicentre observational cohort study designed to (1) evaluate differences between ASyS-associated ILD with IPF, (2) phenotypic differences in patients with ASyS-ILD presenting to respiratory versus rheumatology services, (3) differences in outcomes between ASySassociated with Jo-1 versus non-Jo-1 autoantibodies and (4) compare long-term outcomes between these groups.ResultsWe identified 76 patients with ASyS-ILD and 78 with IPF. Patients with ASyS were younger at presentation (57 vs 77 years, p<0.001) with a female predominance (57% vs 33%, p=0.006) compared with IPF. Cytoplasmic staining on indirect immunofluorescence was a differentiating factor between ASyS and IPF (71% vs 0%, p<0.0001). Patients with ASyS presenting initially to respiratory services (n=52) had a higher prevalence of ASyS non-Jo-1 antibodies and significantly fewer musculoskeletal symptoms/biochemical evidence of myositis, compared with those presenting to rheumatology services (p<0.05), although lung physiology was similar in both groups. There were no differences in high-resolution CT appearances or outcomes in those with Jo-1 versus non-Jo-1 ASyS-ILD.ConclusionsExtended autoimmune serology is needed to evaluate for ASyS autoantibodies in patients presenting with ILD, particularly in younger female patients. Musculoskeletal involvement is common in ASyS (typically Jo-1 autoantibodies) presenting to rheumatology but the burden of ILD is similar to those presenting to respiratory medicine.

scholarly journals A Soft Voting Ensemble-Based Model for the Early Prediction of Idiopathic Pulmonary Fibrosis (IPF) Disease Severity in Lungs Disease Patients

Life ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1092
Author(s):  
Sikandar Ali ◽  
Ali Hussain ◽  
Satyabrata Aich ◽  
Moo Suk Park ◽  
Man Pyo Chung ◽  
...  
Keyword(s):  
Machine Learning ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Lung Disease ◽  
Lung Diseases ◽  
Early Stage ◽  
Confusion Matrix ◽  
Machine Learning Techniques ◽  
Training Dataset ◽  
Proposed Model

Idiopathic pulmonary fibrosis, which is one of the lung diseases, is quite rare but fatal in nature. The disease is progressive, and detection of severity takes a long time as well as being quite tedious. With the advent of intelligent machine learning techniques, and also the effectiveness of these techniques, it was possible to detect many lung diseases. So, in this paper, we have proposed a model that could be able to detect the severity of IPF at the early stage so that fatal situations can be controlled. For the development of this model, we used the IPF dataset of the Korean interstitial lung disease cohort data. First, we preprocessed the data while applying different preprocessing techniques and selected 26 highly relevant features from a total of 502 features for 2424 subjects. Second, we split the data into 80% training and 20% testing sets and applied oversampling on the training dataset. Third, we trained three state-of-the-art machine learning models and combined the results to develop a new soft voting ensemble-based model for the prediction of severity of IPF disease in patients with this chronic lung disease. Hyperparameter tuning was also performed to get the optimal performance of the model. Fourth, the performance of the proposed model was evaluated by calculating the accuracy, AUC, confusion matrix, precision, recall, and F1-score. Lastly, our proposed soft voting ensemble-based model achieved the accuracy of 0.7100, precision 0.6400, recall 0.7100, and F1-scores 0.6600. This proposed model will help the doctors, IPF patients, and physicians to diagnose the severity of the IPF disease in its early stages and assist them to take proactive measures to overcome this disease by enabling the doctors to take necessary decisions pertaining to the treatment of IPF disease.

scholarly journals Overlapping effects of miR-21 inhibition and drugs for idiopathic pulmonary fibrosis in the post-myocardial infarction setting

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
A Aimo ◽  
O Iborra Egea ◽  
C Passino ◽  
M Emdin
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Protein Interactions ◽  
Target Genes ◽  
Cardiac Fibrosis ◽  
Biological Significance ◽  
Oral Drugs ◽  
Network Analyses ◽  
Funding Sources ◽  
And Migration

Abstract Background Intracoronary infusion of a specific miR-21 inhibitor after reperfused MI has been reported to reduce cardiac fibrosis and hypertrophy and improve cardiac function in pigs. Possible drawbacks of anti-miR-21 therapy are the high costs of this therapy, and the need for intracoronary administration, preferably some days after reperfusion. Oral drugs with anti-fibrotic actions could have similar effects than anti-miR-21, while overcoming the limitations of anti-miR-21. We tested this hypothesis by examining the two oral drugs approved for idiopathic pulmonary fibrosis (nintedanib and pirfenidone). Methods We identified the regulatory profile of miR-21, which included 588 target genes. Only 99 of these interactions were supported by information from reporter gene assays. The biological significance of these 99 targets was evaluated through over-representation analysis, and 13 genes were identified as potentially related to cardiovascular diseases. We retrieved all known targets and main downstream interactions of nintedanib and pirfenidone from Drugbank. Finally, we cross-validated these datasets by using neural network analyses to search for protein-protein interactions, focusing on those shared by miR-21 inhibition, nintedanib and pirfenidone. Results Nintedanib and anti-miR21 had many targets in common, which could indicate an overlap in their corresponding mechanisms of action. The proto-oncogene SRC, which participates in gene transcription, immune response, apoptosis and migration, emerged as the leading signaling effector. By blocking SRC expression and many downstream effectors of SRC, as well as platelet-derived growth factor, nintedanib could decreased miR-21 expression. The molecular effects of nintedanib include inhibition of inflammation, fibrosis and angiogenesis, and then ultimately a relief from I/R injury, in a similar fashion than anti-miR-21. Contrary to nintedanib, no overlap between the effects of pirfenidone and anti-miR-21 was found. Conclusion Because of the remarkably strong overlapping with the targets of miR-21, there is a stronger rationale to assess nintedanib than pirfenidone as a cardioprotective therapy. If confirmed by experimental evidence, nintedanib could enter the stage of clinical trials to assess its efficacy in human patients with STEMI. Funding Acknowledgement Type of funding sources: None.

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