Idiopathic Pulmonary Fibrosis Group Research Articles

Regenerative capacity of alveolar type 2 cells is proportionally reduced following disease progression in idiopathic pulmonary fibrosis-derived organoid cultures.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease that leads to respiratory failure and death due to irreversible scarring of the distal lung. While historically considered a chronic inflammatory disorder, the aberrant function of the alveolar epithelium is now recognized to play a central role in IPF pathophysiology. This study aimed to investigate the regenerative capacity of AT2 cells using IPF-derived alveolar organoids and to examine the effects of disease progression on this capacity. Lung tissues from 3 pneumothorax patients and 6 IPF patients (early and advanced stages) were obtained by VATS and lung transplantation. HTII-280+ cells were isolated from CD31-CD45-EpCAM+ cells in the distal lungs of IPF and pneumothorax patients using fluorescence-activated cell sorting (FACS) and resuspended in 48-well plates to establish IPF-derived alveolar organoids. Immuno-staining was used to confirm the presence of AT2 cells. FACS sorting yielded approximately 1% AT2 cells of the total cells in early IPF tissue, and the number decreased as the disease progressed, compared with 2.7% in pneumothorax. Additionally, the cultured organoids in the IPF groups were smaller in size and fewer in number compared to those from pneumothorax patients. The colony-forming efficiency decreased as the disease progressed. In immuno-staining results, the IPF organoids showed lower expression of SFTPC compared to the pneumothorax group and contained KRT5+ cells. This study confirmed that the regenerative capacity of AT2 cells in IPF decreases as the disease progresses, and IPF AT2 cells inherently exhibit functional abnormalities and altered differentiation plasticity.

The potential role of lung microbiota and lauroylcarnitine in T-cell activation associated with checkpoint inhibitor pneumonitis

Checkpoint inhibitor pneumonitis (CIP) is a potentially fatal adverse event characterized by new pulmonary infiltrates in cancer patients receiving immune checkpoint inhibitor therapy. This study aims to explore the interplay between lung microbiota, dysregulated metabolites, and host immunity in CIP. We recruited thirteen hospitalized CIP patients, eleven idiopathic pulmonary fibrosis (IPF) patients, and ten new-onset non-small cell lung cancer patients. Bronchoalveolar lavage fluid samples were collected for 16S rRNA gene sequencing. The percentages of immune cells were determined using manual counting and flow cytometry. Interactions among microbiota, metabolites, and lymphocytes were analyzed using cultured mouse splenocytes and human T cells. Proteobacteria emerged as the dominant phylum, notably abundant in both the CIP and IPF groups. Vibrio, Halomonas, Mangrovibacter, and Salinivibrio were the predominant microbiota because of their discriminative abundance patterns. Vibrio (r=0.72, P-adj=0.007) and Halomonas (r=0.65, P-adj=0.023) demonstrated strong correlations with lymphocytes. Vibrio metschnikovii and Mangrovibacter plantisponsors were more abundant in the CIP group than in the IPF group. Lauroylcarnitine, a key intermediary metabolite co-occurring with the predominant microbiota, exhibited a potent effect on cytokine secretion by mouse and human T cells, notably enhancing IFN-γ and TNF-α production from CD4 and CD8 cells invitro. Lauroylcarnitine, co-occurring with the predominant lung microbiota in CIP, could activate T cells invitro. These findings suggest potential involvement of lung microbiota and acylcarnitine metabolism dysregulation in the pathogenesis of CIP. This work was supported by Peking University People's Hospital Scientific Research Development Funds (RDJ2022-15) and Provincial Key Clinical Specialty Capacity Building Project 2020 (Department of the Respiratory Medicine).

Single-cell RNA sequencing reveals special basal cells and fibroblasts in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is the most predominant type of idiopathic interstitial pneumonia and has an increasing incidence, poor prognosis, and unclear pathogenesis. In order to investigate the molecular mechanisms underlying IPF further, we performed single-cell RNA sequencing analysis on three healthy controls and five IPF lung tissue samples. The results revealed a significant shift in epithelial cells (ECs) phenotypes in IPF, which may be attributed to the differentiation of alveolar type 2 cells to basal cells. In addition, several previously unrecognized basal cell subtypes were preliminarily identified, including extracellular matrix basal cells, which were increased in the IPF group. We identified a special population of fibroblasts that highly expressed extracellular matrix-related genes, POSTN, CTHRC1, COL3A1, COL5A2, and COL12A1. We propose that the close interaction between ECs and fibroblasts through ligand–receptor pairs may have a critical function in IPF development. Collectively, these outcomes provide innovative perspectives on the complexity and diversity of basal cells and fibroblasts in IPF and contribute to the understanding of possible mechanisms in pathological lung fibrosis.

Demographic and Clinical Factors Associated With Diagnostic Confidence in Interstitial Lung Disease: Findings From the Pulmonary Fibrosis Foundation Patient Registry

BACKGROUNDAccurate diagnosis of interstitial lung disease (ILD) can be challenging. Accordingly, clinicians may attribute a diagnostic certainty based on guideline criteria and clinical judgment. However, further research is needed to refine this approach and improve diagnostic clarity. RESEARCH QUESTIONWhat are the real-world factors associated with diagnostic confidence in fibrotic ILD? STUDY DESIGN AND METHODSData were included from all patients enrolled in the Pulmonary Fibrosis Foundation Patient Registry from March 2016 to August 2018. Baseline demographic and clinical characteristics were collected at enrollment, or at the test date closest to the date of consent for longitudinal measures. Descriptive analyses were performed separately for all participants, as well as for subgroup participants with idiopathic pulmonary fibrosis (IPF) and participants with non-IPF ILD, stratified by the level of investigator diagnostic confidence (High vs Medium/Low) assigned at registry enrollment. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable logistic regression, with the aforementioned characteristics as predictors. RESULTSData up to April 2022 from 1,992 participants were included. In adjusted logistic regression analyses among all participants, antifibrotic use (OR [95% CI], 1.51 [1.09-2.07]), longer time since diagnosis (0.94 [0.89-0.98]) at the research unit of 365 days, and diabetes (2.56 [1.01-6.44]) were significantly associated with higher diagnostic confidence, and non-IPF idiopathic interstitial pneumonia (vs IPF; 0.36 [0.24-0.55]), insurance - others (0.65 [0.43-0.97]), and Hispanic ethnicity (0.54 [0.31-0.94]) were significantly associated with lower diagnostic confidence. Factors associated with diagnostic confidence in the IPF and/or non-IPF ILD groups included age, male sex, region, immunomodulatory medication, multidisciplinary team discussion, surgical lung biopsy, and definite high-resolution computed tomography pattern. INTERPRETATIONThese findings suggest that certain demographic and clinical factors may influence physicians’ confidence in diagnosis of IPF and non-IPF ILD. Tailored physician education may help to reduce biases and improve consistency in diagnosis.

A prognostic model of idiopathic pulmonary fibrosis constructed based on macrophage and mitochondria-related genes

BackgroundStudies have shown that mitochondrial function and macrophages may play a role in the development of idiopathic pulmonary fibrosis (IPF). However, the understanding of the interactions and specific mechanisms between mitochondrial function and macrophages in pulmonary fibrosis is still very limited.MethodsTo construct a prognostic model for IPF based on Macrophage- related genes (MaRGs) and Mitochondria-related genes (MitoRGs), differential analysis was performed to achieve differentially expressed genes (DEGs) between IPF and Control groups in the GSE28042 dataset. Then, MitoRGs, MaRGs and DEGs were overlapped to screen out the signature genes. The univariate Cox analysis and the least absolute shrinkage and selection operator (LASSO) algorithm were implemented to achieve key genes. Furthermore, the independent prognostic analysis was employed. The ingenuity pathway analysis (IPA) was employed to further understand the molecular mechanisms of key genes.Next, the immune infiltration analysis was implemented to identify differential immune cells between two risk subgroups.ResultsThere were 4791 DEGs between IPF and Control groups. Furthermore, 26 signature genes were achieved by the intersection processing. Three key genes including ALDH2, MCL1, and BCL2A1 were achieved, and the risk model based on the key genes was created. In addition, a nomogram for survival forecasting of IPF patients was created based on riskScore, Age, and Gender, and we found that key genes were associated with classical pathways including ‘Apoptosis Signaling’, ‘PI3K/AKT Signaling’, and so on. Next, two differential immune cells including Monocytes and CD8 T cells were identified between two risk subgroups. Moreover, we found that MIR29B2CHG and hsa-mir-1-3p could regulate the expression of ALDH2.ConclusionWe achieved 3 key genes including ALDH2, MCL1,, and BCL2A1 associated with IPF, providing a new theoretical basis for clinical treatment of IPF.

Idiopathic pulmonary fibrosis essential biomarkers and immunological infiltration in lung tissue are identified by a bioinformatics analysis

OBJECTIVE: This research aims to pinpoint key biomarkers and immunological infiltration of idiopathic pulmonary fibrosis (IPF) through bioinformatics analysis. METHODS: From the GEO database, 12 gene expression profiles were obtained. The LIMMA tool in Bioconductor accustomed to identify the genes that are expressed differently (DEGs), and analyses of functional enrichment were performed. A protein-protein interaction network (PPI) was constructed using STRING and Cytoscape, and a modular analysis was performed. Analysis of the immunological infiltration of lung tissue between IPF and healthy groups was done using the CIBERSORTx method. RESULTS: 11,130 genes with differential expression (including 7,492 up-regulated and 3,638 down-regulated) were found. The selected up-regulated DEGs were mainly involved in the progression of pulmonary fibrosis and the selected down-regulated DEGs maintain the relative stability of intracellular microenvironment, according to functional enrichment analysis. KEGG enrichment analysis revealed that up-regulated DEGs were primarily abundant in the PI3K-Akt signaling mechanism, whereas down-regulated DEGs were associated with cancer pathways. The most significant modules involving 8 hub genes were found after the PPI network was analyzed. IPF lung tissue had a greater percentage of B memory cells, plasma cells, T cells follicular helper, T cells regulatory, T cells gamma delta, macrophages M0 and resting mast cells. while a relatively low proportion of T cells CD4 memory resting, NK cells resting and neutrophils. CONCLUSION: This research demonstrates the differences of hub genes and immunological infiltration in IPF.

Role of serum B-cell-activating factor and interleukin-17 as biomarkers in the classification of interstitial pneumonia with autoimmune features.

Interstitial pneumonia with autoimmune features (IPAF) is a type of interstitial lung disease (ILD) with immune features that do not meet the diagnostic criteria for specific connective tissue diseases (CTDs). This retrospective case-control study investigated the role of serum B-cell-activating factor of the tumor necrosis factor family (BAFF) and interleukin (IL)-17 as biomarkers for IPAF. The differences in serum BAFF, IL-17, and IL-10 were compared among patients with idiopathic pulmonary fibrosis (IPF), IPAF, ILD associated with CTD (CTD-ILD), and healthy controls. The patients were treatment naïve. The correlations of BAFF with IL-10, IL-17, and pulmonary function were analyzed. The classifiable value of BAFF for IPAF was examined. The results showed that the serum levels of BAFF and IL-17 in the IPAF and CTD-ILD groups were higher than in the IPF group. High BAFF levels and high predicted diffusion capacity of the lungs for carbon monoxide (DLCO) were independent predictive factors for IPAF vs IPF. In the IPAF and CTD-ILD groups, serum BAFF levels were negatively correlated with predicted values of forced vital capacity (FVC%) and diffusing capacity of the lungs for carbon monoxide (DLCO%) and positively correlated with serum IL-17 and IL-10 levels. The cutoff value of combined BAFF and IL-17 was 0.704, and the sensitivity and specificity for classifying IPAF were 78.9 and 95.7%, respectively. In conclusion, combining serum BAFF and IL-17 as a biomarker may have classifiable value in differentiating IPAF from other forms of ILD.

Safety and efficacy of CT-guided percutaneous microwave ablation for stage I non-small cell lung cancer in patients with comorbid idiopathic pulmonary fibrosis.

To evaluate the safety and efficacy of microwave ablation (MWA) for stage I non-small cell lung cancer (NSCLC) in patients with idiopathic pulmonary fibrosis (IPF). A retrospective single-center cohort study was conducted in patients with clinical stage I NSCLC who underwent CT-guided MWA from Nov 2016 to Oct 2021. The patients were divided into the IPF group and the non-IPF group. The primary endpoints were 90-day adverse events and hospital length of stay (HLOS). The secondary endpoints included overall survival (OS) and progression-free survival (PFS). A total of 107 patients (27 with IPF and 80 without IPF) were finally included for analysis. No procedure-related acute exacerbation of IPF or death occurred post-MWA. The rates of adverse events were similar between the groups (48.6% vs. 47.7%; p = 0.998). The incidence of grade 3 adverse events in the IPF group was higher than that in the non-IPF group without a significant difference (13.5% vs. 4.6%; p = 0.123). Median HLOS was 5days in both groups without a significant difference (p = 0.078). The 1-year and 3-year OS were 85.2%/51.6% in the IPF group, and 97.5%/86.4% in the non-IPF group. The survival of patients with IPF was significantly poorer than the survival of patients without IPF (p < 0.001). There was no significant difference for PFS (p = 0.271). MWA was feasible in the treatment of stage I NSCLC in patients with IPF. IPF had an adverse effect on the survival of stage I NSCLC treated with MWA. CT-guided microwave ablation is a well-tolerated and effective potential alternative treatment for stage I non-small cell lung cancer in patients with idiopathic pulmonary fibrosis. • Microwave ablation for stage I non-small cell lung cancer was well-tolerated without procedure-related acute exacerbation of idiopathic pulmonary fibrosis and death in patients with idiopathic pulmonary fibrosis. • No differences were observed in the incidence of adverse events between patients with idiopathic pulmonary fibrosis and those without idiopathic pulmonary fibrosis after microwave ablation (48.6% vs. 47.7%; p = 0.998). • The 1-year and 3-year overall survival rates (85.2%/51.6%) in the idiopathic pulmonary fibrosis group were worse than those in the non- idiopathic pulmonary fibrosis group (97.5%/86.4%) (p < 0.001).

The mechanism of Shenlong Jianji treatment of idiopathic pulmonary fibrosis inhibits fibroblast-to-myofibroblast transformation via the TGF-β1/smads signaling pathway

Ethnopharmacological relevanceShenlong Jianji (SLJJ) is a Chinese herbal compound composed of traditional medicines for supplementing Qi, nourishing Yin, promoting blood circulation, and removing obstruction in channels. It is widely used to treat idiopathic pulmonary fibrosis (IPF) in China. However, the underlying mechanism of SLJJ remains unclear. Aim of this studyTo elucidate the efficacy and mechanisms of SLJJ in the treatment of IPF through in vivo and in vitro experiments. Material and methods84 Wistar rats were randomly and equally divided into 7 groups: the control group (CTRL), the SHAM operation group (SHAM), the model group (IPF), the low dose of SLJJ group (L-SLJJ), the middle dose of SLJJ group (M-SLJJ), the high dose of SLJJ group (H-SLJJ), and the pirfenidone group (PFD). The rats in the CTRL, SHAM, and IPF groups were given normal saline each time for 28 days; the SLJJ groups were given Shenlong Jianji (9 g kg-1·d-1, 18 g kg-1·d-1, 36 g kg-1·d-1), and pirfenidone was administered as a sequential dose. After 28 days, the general condition of the rats was evaluated, and samples were collected. The lung coefficient was measured. The pathological changes of lung in each group were observed by H&E staining and Masson staining. α-SMA, collagen 1, and E-cadherin proteins were detected by immunohistochemistry. α-SMA, collagen 1, vimentin, E-cadherin, N-cadherin, TGF-β1, smad2, and smad3 proteins were detected by WB in vivo.In vitro, A scratch test was used to assess the ratio of cell migration. α-SMA, vimentin, E-cadherin, and N-cadherin protein levels were evaluated by a cellular immunofluorescence assay. TGF-β1/smads signaling pathway was detected by WB. HPLC-Q-TOF/MS analysis was used to identify the active compounds in the SLJJ. Molecular docking determined the free binding energy of the compound with the TGF-β1 protein. ResultsSLJJ significantly improved the respiratory symptoms, heart rate, mental state, and food intake of IPF group rats and decreased the lung coefficient. In the IPF group, inflammatory cells were infiltrated, and the thickened alveoli wall and alveoli collapse were shown, while significantly alleviating pathological changes in the SLJJ and PFD groups. Masson staining showed that SLJJ and PFD decreased the collagen expression. Immunohistochemical results showed that the expressions of α-SMA, collagen 1, and N-cadherin decreased in the SLJJ and PFD groups, while E-cadherin increased significantly compared with the IPF group. SLJJ regulates TGF-β1/smads signaling pathway proteins in vivo. SLJJ decreased the ratio of migration in HFL-1 cells; SLJJ reduced the fluorescence intensity of α-SMA, vimentin, and N-cadherin and increased the fluorescence intensity of E-cadherin in primary rat lung (PRL) fibroblast cells and HFL-1 cells. WB results showed that SLJJ significantly down-regulated α-SMA, Vimentin, N-cadherin, TGF-β1, smad2, and p-smad2/3 proteins expression and up-regulated E-cadherin protein expression in vitro, whereas SRI-011381 (a TGF-β1 agonist) antagonized the effects of SLJJ. ConclusionSLJJ inhibits idiopathic pulmonary fibrosis. The TGF- β1/Smads signaling pathway can be the target of SLJJ, which inhibits fibroblast-to-myofibroblast transformation and is expected to be a new drug for the treatment of IPF.

Study on Potential Differentially Expressed Genes in Idiopathic Pulmonary Fibrosis by Bioinformatics and Next-Generation Sequencing Data Analysis.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with reduced quality of life and earlier mortality, but its pathogenesis and key genes are still unclear. In this investigation, bioinformatics was used to deeply analyze the pathogenesis of IPF and related key genes, so as to investigate the potential molecular pathogenesis of IPF and provide guidance for clinical treatment. Next-generation sequencing dataset GSE213001 was obtained from Gene Expression Omnibus (GEO), and the differentially expressed genes (DEGs) were identified between IPF and normal control group. The DEGs between IPF and normal control group were screened with the DESeq2 package of R language. The Gene Ontology (GO) and REACTOME pathway enrichment analyses of the DEGs were performed. Using the g:Profiler, the function and pathway enrichment analyses of DEGs were performed. Then, a protein-protein interaction (PPI) network was constructed via the Integrated Interactions Database (IID) database. Cytoscape with Network Analyzer was used to identify the hub genes. miRNet and NetworkAnalyst databaseswereused to construct the targeted microRNAs (miRNAs), transcription factors (TFs), and small drug molecules. Finally, receiver operating characteristic (ROC) curve analysis was used to validate the hub genes. A total of 958 DEGs were screened out in this study, including 479 up regulated genes and 479 down regulated genes. Most of the DEGs were significantly enriched in response to stimulus, GPCR ligand binding, microtubule-based process, and defective GALNT3 causes HFTC. In combination with the results of the PPI network, miRNA-hub gene regulatory network and TF-hub gene regulatory network, hub genes including LRRK2, BMI1, EBP, MNDA, KBTBD7, KRT15, OTX1, TEKT4, SPAG8, and EFHC2 were selected. Cyclothiazide and rotigotinethe are predicted small drug molecules for IPF treatment. Our findings will contribute to identification of potential biomarkers and novel strategies for the treatment of IPF, and provide a novel strategy for clinical therapy.

Survival and acute exacerbation for patients with idiopathic pulmonary fibrosis (IPF) or non-IPF idiopathic interstitial pneumonias: 5-year follow-up analysis of a prospective multi-institutional patient registry

ObjectiveFew prospective cohort studies with relatively large numbers of patients with non-idiopathic pulmonary fibrosis (non-IPF) of idiopathic interstitial pneumonia (IIP) have been described. We aimed to assess disease progression and...

Plasma LTBP2 as a potential biomarker in differential diagnosis of connective tissue disease-associated interstitial lung disease and idiopathic pulmonary fibrosis: a pilot study.

Few biomarkers distinguish connective tissue disease-associated interstitial lung disease (CTD-ILD) from idiopathic pulmonary fibrosis (IPF). Latent transforming growth factor-β binding protein-2 (LTBP2), a secreted extracellular matrix protein, is involved in pulmonary fibrosis. However, the role of LTBP2 in differentially diagnosing CTD-ILD and IPF is unclear. In this study, enzyme-linked immunosorbent assays quantified plasma LTBP2 concentrations in 200 individuals (35 healthy controls, 42 CTD patients without ILD, 89 CTD-ILD patients, and 34 IPF patients). CTD-ILD and IPF were further classified based on chest imaging pattern and pulmonary function test results. Plasma LTBP2 levels were significantly elevated in the IPF group compared with the CTD-ILD group. ROC analysis further suggested the possible value of LTBP2 in differentially diagnosing CTD-ILD and IPF. Additionally, CTD-ILD patients with progressive lung fibrosis had higher plasma LTBP2 concentrations than those who did not. Similarly, patients with IPF developing acute exacerbation showed higher plasma LTBP2 levels than those with stable IPF. This is the first study showing that LTBP2 was closely associated with the usual interstitial pneumonia (UIP) pattern in rheumatoid arthritis-associated ILD (RA-ILD). Moreover, the optimal cutoff values of LTBP2 for distinguishing IPF from CTD-UIP/RA-UIP were 33.75 and 38.33ng/mL with an AUC of 0.682 and 0.681, respectively. Our findings suggest that plasma LTBP2 levels may differentially diagnose CTD-ILD and IPF, and assess their fibrotic activity. Additionally, clinical LTBP2 evaluation may be a great aid to identifying the presence of the UIP pattern in RA-ILD and to discriminating IPF from CTD-UIP, particularly RA-UIP.

Risk factor analysis of the development of severe radiation pneumonitis in patients with non-small cell lung cancer treated with curative radiotherapy, with focus on underlying pulmonary disease

BackgroundWe aim to identify the multifaceted risk factors that can affect the development of severe radiation pneumonitis (RP) in patients with non-small cell lung cancer (NSCLC) treated with curative high-dose radiotherapy with or without concurrent chemotherapy.MethodsWe retrospectively reviewed the medical records of 175 patients with stage-I-III NSCLC treated with curative thoracic X-ray radiotherapy at the Korea University Guro Hospital between June 2019 and June 2022. Treatment-related complications were evaluated using the Common Terminology Criteria for Adverse Events (version 4.03).ResultsThe median follow-up duration was 15 months (range: 3–47 months). Idiopathic pulmonary fibrosis (IPF) as an underlying lung disease (P < 0.001) and clinical stage, regarded as the concurrent use of chemotherapy (P = 0.009), were associated with a high rate of severe RP. In multivariate analyses adjusting confounding variables, the presence of IPF as an underlying disease was significantly associated with severe RP (odds ratio [95% confidence interval] = 48.4 [9.09–347]; P < 0.001). In a subgroup analysis of stage-I-II NSCLC, the incidence of severe RP in the control, chronic obstructive pulmonary disease (COPD), and IPF groups was 3.2%, 4.3%, and 42.9%, respectively (P < 0.001). The incidence of severe RP was 15.2%, 10.7%, and 75.0% in the control, COPD, and IPF groups, respectively (P < 0.001) in the stage-III NSCLC group.ConclusionsThis study revealed that IPF as an underlying lung disease and the concurrent use of chemotherapy are associated with a high rate of severe RP. In contrast, COPD did not increase the risk of pulmonary toxicity after receiving curative high-dose radiotherapy.

Genetic Programs Between Steroid-Sensitive and Steroid-Insensitive Interstitial Lung Disease

The effectiveness of corticosteroids (GCs) varies greatly in interstitial lung diseases (ILDs). In this study, we aimed to compare the gene expression profiles of patients with cryptogenic organizing pneumonia (COP), idiopathic pulmonary fibrosis (IPF), and non-specific interstitial pneumonia (NSIP) and identify the molecules and pathways responsible for GCs sensitivity in ILDs. Three datasets (GSE21411, GSE47460, and GSE32537) were selected. Differentially expressed genes (DEGs) among COP, IPF, NSIP, and healthy control (CTRL) groups were identified. Functional enrichment analysis and protein–protein interaction network analysis were performed to examine the potential functions of DEGs. There were 128 DEGs when COP versus CTRL, 257 DEGs when IPF versus CTRL, 205 DEGs when NSIP versus CTRL, and 270 DEGs when COP versus IPF. The DEGs in different ILDs groups were mainly enriched in the inflammatory response. Further pathway analysis showed that “interleukin (IL)-17 signaling pathway” (hsa04657) and “tumor necrosis factor (TNF) signaling pathway” were associated with different types of ILDs. A total of 10 genes associated with inflammatory response were identified as hub genes and their expression levels in the IPF group were higher than those in the COP group. Finally, we identified two GCs’ response-related differently expressed genes (FOSL1 and DDIT4). Our bioinformatics analysis demonstrated that the inflammatory response played a pathogenic role in the progression of ILDs. We also illustrated that the inflammatory reaction was more severe in the IPF group compared to the COP group and identified two GCs’ response-related differently expressed genes (FOSL1 and DDIT4) in ILDs.

Dysregulated cross-talk between alveolar epithelial cells and stromal cells in idiopathic pulmonary fibrosis reduces epithelial regenerative capacity.

In idiopathic pulmonary fibrosis (IPF) constant epithelial micro-injury and aberrant interactions within the stromal micro-environment lead to abnormal alveolar repair and fibrosis. We hypothesized that alveolar epithelial regenerative responses in IPF are impaired due to disturbed crosstalk between epithelial cells and their stromal niche. We established organoid cultures from unfractionated suspensions and isolated EpCAM+ cells from distal lung tissue of patients with and without IPF. We observed significantly more organoids being formed from unfractionated suspensions compared to isolated EpCAM+ cell cultures, indicating the presence of supportive cells in the unfractionated suspensions. Importantly, lower organoid numbers were observed in unfractionated cultures from IPF lungs compared to non-IPF lungs. This difference was not found when comparing organoid formation from isolated EpCAM+ cells alone between IPF and non-IPF groups, suggesting that crosstalk between the supportive population and epithelial cells is impaired in lungs from IPF patients. Additionally, organoids grown from IPF lung-derived cells were larger in size compared to those from non-IPF lungs in both unfractionated and EpCAM+ cultures, indicating an intrinsic abnormality in epithelial progenitors from IPF lungs. Together, our observations suggest that dysregulated crosstalk between alveolar progenitor cells and the stromal niche affects the regenerative capacity, potentially contributing to alveolar impairment in IPF.

Prevalence of diaphragm dysfunction in patients with interstitial lung disease (ILD): The role of diaphragmatic ultrasound

BackgroundDiaphragm ultrasound (DUS) has been extensively used in critically ill patients while data on outpatients with interstitial lung disease (ILD) are limited. We hypothesized that diaphragm function, assessed by ultrasound, could be impaired in patients with ILD, considering both Idiopathic Pulmonary Fibrosis (IPF) and Connective Tissue Disease (CTD-ILD), compared to healthy subjects. Moreover, this impairment could impact clinical and functional parameters. MethodsAll consecutive CTD-ILD and IPF patients followed in our center (March–October 2020) were screened. Diaphragm displacement (DD), inspiratory thickness (Ti), expiratory thickness (Te), thickening fraction (TF), and respiratory functional parameters were collected. The prevalence of diaphragmatic dysfunction (TF <30%) was then recorded. ResultsEighty-two consecutive patients (41 CTD-ILD, 41 IPF) and 15 age- and sex-matched controls were enrolled. In the overall population, 24 out of 82 (29%) presented diaphragmatic dysfunction. In CTD-ILD, DD and Ti were lower as compared to IPF (p = 0.021 and p = 0.036, respectively); while diaphragmatic dysfunction was more prevalent compared to controls (37% vs 7%, p = 0.043). TF positively correlated to patients’ functional parameters in the CTD-ILD group (FVC%pred: p = 0.003; r = 0.45), while not in the IPF group. Diaphragmatic dysfunction was associated with moderate/severe dyspnea in both CTD-ILD and IPF (p = 0.021). ConclusionThe prevalence of diaphragmatic dysfunction was 29% in patients with ILD and was associated with moderate/severe dyspnea. CTD-ILD presented lower DD compared with IPF and a higher prevalence of diaphragmatic dysfunction (TF<30%) compared with controls. TF was associated with lung function only in CTD-ILD patients, suggesting its potential role in the comprehensive patient assessment.

Plasma Wnt7b protein in rheumatoid arthritis: Detection of interstitial lung disease

ObjectiveTo determine the plasma level of Wingless-related integration site 7b (Wnt7b) protein in rheumatoid arthritis (RA) patients (with and without interstitial lung disease (ILD)) and in idiopathic pulmonary fibrosis (IPF) patients and its relationship with RA disease activity and/or severity of pulmonary fibrosis. To assess the validity of plasma Wnt7b for the detection of ILD among RA patients. MethodThis case-control study included 128 subjects (32 RA-ILD, 32 RA, 32 IPF, and 32 healthy controls). RA and RA-ILD Patients were evaluated for disease activity by DAS28 and disease activity grades were recorded according to DAS28 grades. Laboratory parameters as Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Rheumatoid Factor (RF), Anti-citrullinated peptide (Anti-CCP) were recorded. Plasma Wnt7b levels were measured by ELISA. Diagnosis of pulmonary fibrosis (for RA-ILD and IPF patients) was done by high resolution computed tomography (HRCT) and its severity was assessed mainly by pulmonary function test using forced vital capacity (FVC) grading. ResultsComparison of Wnt7b plasma levels showed a significant difference between the studied groups with the P-value < 0.018 (RA-ILD had the highest levels). Post hoc analysis revealed a significant difference in Wnt7b plasma levels between RA-ILD and IPF groups (P = 0.008). Also, RA-ILD and control groups had a significant difference (P = 0.039). However, there was a non-significant relationship between Wnt7b plasma levels and RA disease activity as well as the severity of pulmonary fibrosis. ROC curve analysis for the plasma Wnt7b levels revealed that a level ≥285.1 pg/ml had a sensitivity of 87.5% and a specificity of 43.8% for the detection of ILD in RA patients with positive likelihood ratio of 1.56 and negative likelihood ratio of 0.29. ConclusionRA-ILD patients had significantly higher plasma Wnt7b levels than the controls and IPF patients. These data suggest that the Wnt7b secretion is augmented by the concomitant presence of RA with pulmonary fibrosis. In addition, plasma Wnt7b may be used as a highly sensitive test for the detection of immunologically induced fibrotic changes in lung tissue among RA patients.

Exertional Desaturation Is More Severe in Idiopathic Pulmonary Fibrosis Than in Other Interstitial Lung Diseases.

Interstitial lung disease (ILD) is classified into several disease groups. Among them, idiopathic pulmonary fibrosis (IPF) has higher incidence and poor prognosis; therefore, it is important to characterize specific IPF symptoms. Exercise desaturation is a strong factor related to mortality in patients with ILD. Thus, the purpose of this study was to compare the degree of oxygen desaturation between IPF and other ILD (non-IPF ILD) patients during exercise, using the 6-minute walk test (6MWT). This retrospective study included 126 stable patients with ILD who underwent 6MWT in our outpatient department. The 6MWT was used to assess desaturation during exercise, 6-minute walk distance (6MWD), and dyspnea at the end of exercise. In addition, patient characteristics and pulmonary function test results were recorded. Study subjects were divided into 51 IPF patients and 75 non-IPF ILD patients. The IPF group had significantly lower nadir oxygen saturation determined by pulse oximetry (SpO2) during 6MWT than the non-IPF ILD group (IPF, 86.5 ± 4.6%; non-IPF ILD, 88.7 ± 5.3%; p = 0.02). The significant association between the nadir SpO2 and IPF or non-IPF ILD grouping remained even after adjusting for gender, age, body mass index, lung function, 6MWD, and dyspnea (β = -1.62; p <0.05). Even after adjusting for confounding factors, IPF patients had lower nadir SpO2 during 6MWT. Early assessment of exercise desaturation using the 6MWT may be more important in patients with IPF compared with patients with other ILDs.

Pulmonary vessel volume can help to differentiate fibrotic lung diseases

Objectives: Idiopathic pulmonary fibrosis (IPF), non-specific interstitial pneumonia (NSIP), and chronic hypersensitivity pneumonitis (CHP) are diffuse fibrosing lung diseases that are sometimes difficult to differentiate by only visual evaluation of CT images. We aimed to find if pulmonary vessel volume (PVV), a new quantitative CT measure, can help to differentiate these diseases at the time of diagnosis. Methods: We retrospectively measured PVV values of IPF, NSIP, and CHP patients diagnosed within the last five years in our institution, by using their CT images at the time of diagnosis. We used CALIPER-technology (Computer-Aided Lung Informatics for Pathology Evaluation and Rating) for the quantification of CT images. We compared the PVV values of disease groups by the Kruskal-Wallis test and performed ROC curve analysis to evaluate the ability of PVV to differentiate these diseases. Results: We measured the PVV values of 152 patients, 113 of them were diagnosed with IPF, 16 with NSIP, and 23 with CHP. The PVV value of the NSIP group was significantly lower than that of both IPF (p = 0.028) and CHP (p = 0.013) groups. However, there was no significant difference between IPF and CHP groups (p = 0.924). Selected cut-off values of PVV were found to differentiate NSIP from IPF with a specificity of 88%, and NSIP from CHP with a specificity of 91%. Conclusions: PVV measured by CALIPER at the time of diagnosis can help to differentiate NSIP from both IPF and CHP.

Identification of immune biomarkers associated with basement membranes in idiopathic pulmonary fibrosis and their pan-cancer analysis.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease of unknown etiology, characterized by diffuse alveolitis and alveolar structural damage. Due to the short median survival time and poor prognosis of IPF, it is particularly urgent to find new IPF biomarkers. Previous studies have shown that basement membranes (BMs) are associated with the development of IPF and tumor metastasis. However, there is still a lack of research on BMs-related genes in IPF. Therefore, we investigated the expression level of BMs genes in IPF and control groups, and explored their potential as biomarkers for IPF diagnosis. In this study, the GSE32537 and GSE53845 datasets were used as training sets, while the GSE24206, GSE10667 and GSE101286 datasets were used as validation sets. In the training set, seven immune biomarkers related to BMs were selected by differential expression analysis, machine learning algorithm (LASSO, SVM-RFE, Randomforest) and ssGSEA analysis. Further ROC analysis confirmed that seven BMs-related genes played an important role in IPF. Finally, four immune-related Hub genes (COL14A1, COL17A1, ITGA10, MMP7) were screened out. Then we created a logistic regression model of immune-related hub genes (IHGs) and used a nomogram to predict IPF risk. The nomogram model was evaluated to have good reliability and validity, and ROC analysis showed that the AUC value of IHGs was 0.941 in the training set and 0.917 in the validation set. Pan-cancer analysis showed that IHGs were associated with prognosis, immune cell infiltration, TME, and drug sensitivity in 33 cancers, suggesting that IHGs may be potential targets for intervention in human diseases including IPF and cancer.