Contemporary Concise Review 2022: Interstitial lung disease.

Novel genetic associations for idiopathic pulmonary fibrosis (IPF) risk have been identified. Common genetic variants associated with IPF are also associated with chronic hypersensitivity pneumonitis. The characterization of underlying mechanisms, such as pathways involved in myofibroblast differentiation, may reveal targets for future treatments. Newly identified circulating biomarkers are associated with disease progression and mortality. Deep learning and machine learning may increase accuracy in the interpretation of CT scans. Novel treatments have shown benefit in phase 2 clinical trials. Hospitalization with COVID-19 is associated with residual lung abnormalities in a substantial number of patients. Inequalities exist in delivering and accessing interstitial lung disease specialist care.

Systematic review of overlapping microRNA patterns in COVID-19 and idiopathic pulmonary fibrosis.

BACKGROUND: Pulmonary fibrosis is an emerging complication of SARS-CoV-2 infection. In this study, we speculate that patients with COVID-19 and idiopathic pulmonary fibrosis (IPF) may share aberrant expressed microRNAs (miRNAs) associated to the progression of lung fibrosis. OBJECTIVE: To identify miRNAs presenting similar alteration in COVID-19 and IPF, and describe their impact on fibrogenesis. METHODS: A systematic review of the literature published between 2010 and January 2022 (PROSPERO, CRD42022341016) was conducted using the key words (COVID-19 OR SARS-CoV-2) AND (microRNA OR miRNA) or (idiopathic pulmonary fibrosis OR IPF) AND (microRNA OR miRNA) in Title/Abstract. RESULTS: Of the 1988 references considered, 70 original articles were appropriate for data extraction: 27 studies focused on miRNAs in COVID-19, and 43 on miRNAs in IPF. 34 miRNAs were overlapping in COVID-19 and IPF, 7 miRNAs presenting an upregulation (miR-19a-3p, miR-200c-3p, miR-21-5p, miR-145-5p, miR-199a-5p, miR-23b and miR-424) and 9 miRNAs a downregulation (miR-17-5p, miR-20a-5p, miR-92a-3p, miR-141-3p, miR-16-5p, miR-142-5p, miR-486-5p, miR-708-3p and miR-150-5p). CONCLUSION: Several studies reported elevated levels of profibrotic miRNAs in COVID-19 context. In addition, the balance of antifibrotic miRNAs responsible of the modulation of fibrotic processes is impaired in COVID-19. This evidence suggests that the deregulation of fibrotic-related miRNAs participates in the development of fibrotic lesions in the lung of post-COVID-19 patients.

Bioinformatics-based investigation on the genetic influence between SARS-CoV-2 infections and idiopathic pulmonary fibrosis (IPF) diseases, and drug repurposing.

Some recent studies showed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and idiopathic pulmonary fibrosis (IPF) disease might stimulate each other through the shared genes. Therefore, in this study, an attempt was made to explore common genomic biomarkers for SARS-CoV-2 infections and IPF disease highlighting their functions, pathways, regulators and associated drug molecules. At first, we identified 32 statistically significant common differentially expressed genes (cDEGs) between disease (SARS-CoV-2 and IPF) and control samples of RNA-Seq profiles by using a statistical r-package (edgeR). Then we detected 10 cDEGs (CXCR4, TNFAIP3, VCAM1, NLRP3, TNFAIP6, SELE, MX2, IRF4, UBD and CH25H) out of 32 as the common hub genes (cHubGs) by the protein-protein interaction (PPI) network analysis. The cHubGs regulatory network analysis detected few key TFs-proteins and miRNAs as the transcriptional and post-transcriptional regulators of cHubGs. The cDEGs-set enrichment analysis identified some crucial SARS-CoV-2 and IPF causing common molecular mechanisms including biological processes, molecular functions, cellular components and signaling pathways. Then, we suggested the cHubGs-guided top-ranked 10 candidate drug molecules (Tegobuvir, Nilotinib, Digoxin, Proscillaridin, Simeprevir, Sorafenib, Torin 2, Rapamycin, Vancomycin and Hesperidin) for the treatment against SARS-CoV-2 infections with IFP diseases as comorbidity. Finally, we investigated the resistance performance of our proposed drug molecules compare to the already published molecules, against the state-of-the-art alternatives publicly available top-ranked independent receptors by molecular docking analysis. Molecular docking results suggested that our proposed drug molecules would be more effective compare to the already published drug molecules. Thus, the findings of this study might be played a vital role for diagnosis and therapies of SARS-CoV-2 infections with IPF disease as comorbidity risk.

Plant miRNA osa-miR172d-5p suppressed lung fibrosis by targeting Tab1.

Lung fibrosis, including idiopathic pulmonary fibrosis, is an intractable disease accompanied by an irreversible dysfunction in the respiratory system. Its pathogenesis involves the transforming growth factorß (TGFß)-induced overproduction of the extracellular matrix from fibroblasts; however, limited countermeasures have been established. In this study, we identified osa-miR172d-5p, a plant-derived microRNA (miR), as a potent anti-fibrotic miR. In silico analysis followed by an in vitro assay based on human lung fibroblasts demonstrated that osa-miR172d-5p suppressed the gene expression of TGF-ß activated kinase 1 (MAP3K7) binding protein 1 (Tab1). It also suppressed the TGFß-induced fibrotic gene expression in human lung fibroblasts. To assess the anti-fibrotic effect of osa-miR172d-5p, we established bleomycin-induced lung fibrosis models to demonstrate that osa-miR172d-5p ameliorated lung fibrosis. Moreover, it suppressed Tab1 expression in the lung tissues of bleomycin-treated mice. In conclusion, osa-miR172d-5p could be a potent candidate for the treatment of lung fibrosis, including idiopathic pulmonary fibrosis.

A MUC5B Gene Polymorphism, rs35705950-T, Confers Protective Effects Against COVID-19 Hospitalization but Not Severe Disease or Mortality.

Rationale: A common MUC5B gene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis (IPF), but its role in severe acute respiratory syndrome coronavirus 2 infection and disease severity is unclear. Objectives: To assess whether rs35705950-T confers differential risk for clinical outcomes associated with coronavirus disease (COVID-19) infection among participants in the Million Veteran Program (MVP). Methods: The MUC5B rs35705950-T allele was directly genotyped among MVP participants; clinical events and comorbidities were extracted from the electronic health records. Associations between the incidence or severity of COVID-19 and rs35705950-T were analyzed within each ancestry group in the MVP followed by transancestry meta-analysis. Replication and joint meta-analysis were conducted using summary statistics from the COVID-19 Host Genetics Initiative (HGI). Sensitivity analyses with adjustment for additional covariates (body mass index, Charlson comorbidity index, smoking, asbestosis, rheumatoid arthritis with interstitial lung disease, and IPF) and associations with post-COVID-19 pneumonia were performed in MVP subjects. Measurements and Main Results: The rs35705950-T allele was associated with fewer COVID-19 hospitalizations in transancestry meta-analyses within the MVP (Ncases = 4,325; Ncontrols = 507,640; OR = 0.89 [0.82-0.97]; P = 6.86 × 10-3) and joint meta-analyses with the HGI (Ncases = 13,320; Ncontrols = 1,508,841; OR, 0.90 [0.86-0.95]; P = 8.99 × 10-5). The rs35705950-T allele was not associated with reduced COVID-19 positivity in transancestry meta-analysis within the MVP (Ncases = 19,168/Ncontrols = 492,854; OR, 0.98 [0.95-1.01]; P = 0.06) but was nominally significant (P < 0.05) in the joint meta-analysis with the HGI (Ncases = 44,820; Ncontrols = 1,775,827; OR, 0.97 [0.95-1.00]; P = 0.03). Associations were not observed with severe outcomes or mortality. Among individuals of European ancestry in the MVP, rs35705950-T was associated with fewer post-COVID-19 pneumonia events (OR, 0.82 [0.72-0.93]; P = 0.001). Conclusions: The MUC5B variant rs35705950-T may confer protection in COVID-19 hospitalizations.

Role of Mesenchymal Stem Cells and Extracellular Vesicles in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial fibrotic disease that leads to disability and death within 5 years of diagnosis. Pulmonary fibrosis is a disease with a multifactorial etiology. The concept of aberrant regeneration of the pulmonary epithelium reveals the pathogenesis of IPF, according to which repeated damage and death of alveolar epithelial cells is the main mechanism leading to the development of progressive IPF. Cell death provokes the migration, proliferation and activation of fibroblasts, which overproduce extracellular matrix, resulting in fibrotic deformity of the lung tissue. Mesenchymal stem cells (MSCs) and extracellular vesicles (EVs) are promising therapies for pulmonary fibrosis. MSCs, and EVs derived from MSCs, modulate the activity of immune cells, inhibit the expression of profibrotic genes, reduce collagen deposition and promote the repair of damaged lung tissue. This review considers the molecular mechanisms of the development of IPF and the multifaceted role of MSCs in the therapy of IPF. Currently, EVs-MSCs are regarded as a promising cell-free therapy tool, so in this review we discuss the results available to date of the use of EVs-MSCs for lung tissue repair.

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

BACKGROUND: In the aftermath of Covid-19, some patients develop a fibrotic lung disease, i.e., post-COVID-19 lung disease (PCLD), for which we currently lack insights into pathogenesis, disease models, or treatment options. METHODS: Using an AI-guided approach, we analyzed > 1000 human lung transcriptomic datasets associated with various lung conditions using two viral pandemic signatures (ViP and sViP) and one covid lung-derived signature. 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. Transcriptome-derived findings were used to construct protein-protein interaction (PPI) network to identify the major triggers of AT2 dysfunction. Key findings were validated in hamster and human adult lung organoid (ALO) pre-clinical models of COVID-19 using immunohistochemistry and qPCR. FINDINGS: 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 diseases. FUNDING: This work was supported by the National Institutes for Health grants R01- GM138385 and AI155696 and funding from the Tobacco-Related disease Research Program (R01RG3780).

Epigenetic Changes and Functions in Pneumoconiosis.

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

Identification of hub genes associated with COVID-19 and idiopathic pulmonary fibrosis by integrated bioinformatics analysis.

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

SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis.

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

Chronic lung diseases are associated with gene expression programs favoring SARS-CoV-2 entry and severity.

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

The networks of m6A-SARS-CoV-2 related genes and immune infiltration patterns in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with a poor prognosis. The current coronavirus disease 2019 (COVID-19) shares some similarities with IPF. SARS-CoV-2 related genes have been reported to be broadly regulated by N6-methyladenosine (m6A) RNA modification. Here, we identified the association between m6A methylation regulators, COVID-19 infection pathways, and immune responses in IPF. The characteristic gene expression networks and immune infiltration patterns of m6A-SARS-CoV-2 related genes in different tissues of IPF were revealed. We subsequently evaluated the influence of these related gene expression patterns and immune infiltration patterns on the prognosis/lung function of IPF patients. The IPF cohort was obtained from the Gene Expression Omnibus dataset. Pearson correlation analysis was performed to identify the correlations among genes or cells. The CIBERSORT algorithm was used to assess the infiltration of 22 types of immune cells. The least absolute shrinkage and selection operator (LASSO) and proportional hazards model (Cox model) were used to develop the prognosis prediction model. Our research is pivotal for further understanding of the cellular and genetic links between IPF and SARS-CoV-2 infection in the context of the COVID-19 pandemic, which may contribute to providing new ideas for prognosis assessment and treatment of both diseases.

Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity.

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

Alveolar cells under mechanical stressed niche: critical contributors to pulmonary fibrosis.

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