Eur J Med Chem. 2023 May 3;256:115442. doi: 10.1016/j.ejmech.2023.115442. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a severe and progressive lung disease with poor prognosis and limited treatment options. The c-Jun N-Terminal Kinase 1 (JNK1), a key component of the MAPK pathway, has been implicated in the pathogenesis of IPF and represents a potential therapeutic target. However, the development of JNK1 inhibitors has been slowed, partly due to synthetic complexity in medicinal chemistry modification. Here, we report a synthesis-accessibility-oriented strategy for designing JNK1 inhibitors based on computational prediction of synthetic feasibility and fragment-based molecule generation. This strategy led to the discovery of several potent JNK1 inhibitors, such as compound C6 (IC50 = 33.5 nM), which exhibited comparable activity to the clinical candidate CC-90001 (IC50 = 24.4 nM). The anti-fibrotic effect of C6 was further confirmed in animal model of pulmonary fibrosis. Moreover, compound C6 could be synthesized in only two steps, compared to nine steps for CC-90001. Our findings suggest that compound C6 is a promising lead for further optimization and development as a novel anti-fibrotic agent targeting JNK1. In addition, the discovery of C6 also demonstrates the feasibility of synthesis-accessibility-oriented strategy in lead discovery.

PMID:37156184 | DOI:10.1016/j.ejmech.2023.115442

Pharmacol Ther. 2023 May 5:108436. doi: 10.1016/j.pharmthera.2023.108436. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disorder of unknown origin and the most common interstitial lung disease. It progresses with the recruitment of fibroblasts and myofibroblasts that contribute to the accumulation of extracellular matrix (ECM) proteins, leading to the loss of compliance and alveolar integrity, compromising the gas exchange capacity of the lung. Moreover, while there are therapeutics available, they do not offer a cure. Thus, there is a pressing need to identify better therapeutic targets. With the advent of transcriptomics, proteomics, and metabolomics, the cellular mechanisms underlying disease progression are better understood. Metabolic homeostasis is one such factor and its dysregulation has been shown to impact the outcome of IPF. Several metabolic pathways involved in the metabolism of lipids, protein and carbohydrates have been implicated in IPF. While metabolites are crucial for the generation of energy, it is now appreciated that metabolites have several non-metabolic roles in regulating cellular processes such as proliferation, signaling, and death among several other functions. Through this review, we succinctly elucidate the role of several metabolic pathways in IPF. Moreover, we also discuss potential therapeutics which target metabolism or metabolic pathways.

PMID:37150402 | DOI:10.1016/j.pharmthera.2023.108436

Eur Respir J. 2023 May 5;61(5):2300346. doi: 10.1183/13993003.00346-2023. Print 2023 May.

NO ABSTRACT

PMID:37147007 | DOI:10.1183/13993003.00346-2023

Thorax. 2023 May 5:thorax-2023-220229. doi: 10.1136/thorax-2023-220229. Online ahead of print.

NO ABSTRACT

PMID:37147125 | DOI:10.1136/thorax-2023-220229

Eur Respir J. 2023 May 5;61(5):2300459. doi: 10.1183/13993003.00459-2023. Print 2023 May.

NO ABSTRACT

PMID:37147006 | DOI:10.1183/13993003.00459-2023

Int J Tuberc Lung Dis. 2023 May 1;27(5):395-400. doi: 10.5588/ijtld.22.0604.

ABSTRACT

OBJECTIVE: To determine whether mediastinal lymph node enlargement (MLNE) predicts progressive pulmonary fibrosis (PPF).METHODS: A total of 800 patients hospitalised for interstitial lung diseases (ILDs) were included in our study. The clinical presentations, radiographic features and laboratory findings of the patients were reviewed.RESULTS: MLNE was present in 313 (39.1%) ILD patients and were associated with higher total fibrosis score and risk of death than ILD patients without MLNE. The risk factors for PPF were age (OR 1.044, 95% CI 1.020-1.069; P < 0.001), the total extent of fibrosis (OR 1.396, 95% CI 1.116-1.746; P = 0.003) and MLNE (OR 2.130, 95% CI 1.362-3.332; P = 0.001) compared to non-PPF. Multivariable analysis showed that age, the lactate dehydrogenase level, MLNE, the total fibrosis score and pulmonary arterial systolic pressure were risk/prognostic factors for ILD patients. The model was robust in patients with idiopathic pulmonary fibrosis. However, the only risk/prognostic factor common to other ILD subgroups was the total fibrosis score.CONCLUSIONS: MLNE is associated with higher total fibrosis score and worse prognosis in ILD patients and could predict the occurrence of PPF. The only risk/prognostic factor applicable to all subgroups of ILDs is the total pulmonary fibrosis score.

PMID:37143232 | DOI:10.5588/ijtld.22.0604

Eur Respir J. 2023 May 4:2200474. doi: 10.1183/13993003.00474-2022. Online ahead of print.

ABSTRACT

BACKGROUND: In idiopathic pulmonary fibrosis (IPF) myofibroblasts are key effectors of fibrosis and architectural distortion by excessive deposition of extracellular matrix and their acquired contractile capacity. Single-cell RNA-sequencing (scRNA-seq) has precisely defined the IPF myofibroblast transcriptome, but identifying critical transcription factor (TF) activity by this approach is imprecise.

METHODS: We performed single-nucleus ATAC sequencing (snATAC-seq) on explanted lungs from patients with IPF (n=3) and donor controls (n=2) and integrated this with a larger scRNA-seq dataset (n=10 IPF, 8 control) to identify differentially accessible chromatin regions and enriched TF motifs within lung cell populations. We performed RNA-sequencing on pulmonary fibroblasts of bleomycin-injured Twist1-overexpressing COL1A2 Cre-ER mice to examine alterations in fibrosis-relevant pathways following Twist1 overexpression in collagen-producing cells.

RESULTS: TWIST1, and other E-box TF motifs, were significantly enriched in open chromatin of IPF myofibroblasts compared to both IPF non-myogenic (Log2FC=8.909, adj p-value=1.82E-35) and control fibroblasts (Log2FC=8.975, adj p-value=3.72E-28). TWIST1 expression was selectively upregulated in IPF myofibroblasts (Log2FC=3.136, adj p-value= 1.41E-24), with two regions of TWIST1 having significantly increased accessibility in IPF myofibroblasts. Overexpression of Twist1 in COL1A2-expressing fibroblasts of bleomycin-injured mice resulted in increased collagen synthesis and upregulation of genes with enriched chromatin accessibility in IPF myofibroblasts.

CONCLUSIONS: Our studies utilizing human multiomic single-cell analyses combined with in vivo murine disease models confirm a critical regulatory function for TWIST1 in IPF myofibroblast activity in the fibrotic lung. Understanding the global process of opening TWIST1 and other E-box TF motifs that govern myofibroblast differentiation may identify new therapeutic interventions for fibrotic pulmonary diseases.

PMID:37142338 | DOI:10.1183/13993003.00474-2022

Clin Pharmacokinet. 2023 May 4. doi: 10.1007/s40262-023-01250-6. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Pirfenidone is an antifibrotic agent that has been proven to slow down the progression of idiopathic pulmonary fibrosis (IPF). This study aimed to characterize the population pharmacokinetics (PK) and exposure-efficacy analysis of pirfenidone in patients with IPF.

METHODS: Data from 10 hospitals with 106 patients were used to develop a population PK model. The annual decline in forced vital capacity (FVC) over 52 weeks was integrated with pirfenidone plasma concentration to characterize the exposure-efficacy relationship.

RESULTS: A linear one-compartment model with first-order absorption and elimination processes and lag time best described the pirfenidone PK. The population estimates of clearance and central volume of distribution at steady-state were 13.37 L/h and 53.62 L, respectively. Bodyweight and food were statistically correlated with PK variability but had no significant influence on pirfenidone exposure. Annual decline in FVC with pirfenidone plasma concentration was described by a maximum drug effect (Emax) model. The typical EC50 was 1.73 mg/L (1.18-2.31 mg/L) and the corresponding EC80 was 2.18 mg/L (1.49-2.87 mg/L). Simulations showed that two dosing regimens of 500 and 600 mg three times daily were predicted to generate 80% of the Emax.

CONCLUSIONS: In patients with IPF, covariates such as bodyweight and food might not be sufficient for dose adjustment, and a low dose of 1500 mg/day could also provide 80% of the Emax, as the standard dose (1800 mg/day).

PMID:37142851 | DOI:10.1007/s40262-023-01250-6

Front Genet. 2023 Apr 17;14:1129247. doi: 10.3389/fgene.2023.1129247. eCollection 2023.

ABSTRACT

Objective: To elucidate the potential causality of leukocyte telomere length (LTL) with immune-mediated inflammatory diseases (IMIDs), we conducted a Mendelian randomization (MR) study. Methods: The genetically predicted causation between LTL and IMIDs was evaluated using a two-sample MR method. We analyzed 16 major IMIDs, which included systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), ankylosing spondylitis (AS), sicca syndrome (SS), rheumatoid arthritis (RA), type 1 diabetes (T1D), primary sclerosing cholangitis (PSC), idiopathic pulmonary fibrosis (IPF), atopic dermatitis (AD), sarcoidosis, hypothyroidism, hyperthyroidism, psoriasis, and childhood asthma. The random-effects inverse-variance weighted (IVW) method was performed as the main analytical approach in MR. Various sensitivity analyses, including MR-Egger, MR robust adjusted profile score (MR-RAPS), weighted median, MR pleiotropy residual sum and outlier (MR-PRESSO) methods, weighted mode, radial plot, and radial regression, were used to guarantee the robustness of the results and detect horizontal pleiotropy. Cochran's Q value was calculated to check for heterogeneity, and the MR Steiger approach was used to test the causal direction. Results: The MR results indicated significant inverse associations of LTL with risks of psoriasis (OR: 0.77, 95% CI: 0.66-0.89, and p = 3.66 × 10-4), SS (OR: 0.75, CI: 0.58-0.98, and p = 0.03), RA (OR: 0.77, 95% CI: 0.68-0.88, and p = 9.85 × 10-5), hypothyroidism (OR: 0.84, 95% CI: 0.78-0.91, and p = 7,08 × 10-6), hyperthyroidism (OR: 0.60, 95% CI: 0.44-0.83, and p = 1.90 × 10-3), sarcoidosis (OR: 0.67, 95% CI: 0.54-0.83, and p = 2.60 × 10-4), and IPF (OR: 0.41, 95% CI: 0.29-0.58, and p = 4.11 × 10-7) in the FinnGen study. We observed that longer LTL was associated with an increased risk of AS susceptibility (OR: 1.51, 95% CI: 1.18-1.94, and p = 9.66 × 10-4). The results of the IVW method showed no causal relationship between TL and SLE (OR: 0.92, 95% CI: 0.62-1.38, and p = 0.69) in the FinnGen study; however, a significantly positive correlation was shown between LTL and SLE in another larger GWAS (OR: 1.87, 95% CI: 1.37-2.54, and p = 8.01 × 10-5). Conclusion: Our findings reveal that abnormal LTL has the potential to increase the risk of IMIDs. Therefore, it could be treated as a predictor and may provide new potential treatment targets for IMIDs. However, the change of LTL may not be the direct cause of IMIDs. Further studies should aim at the pathogenic mechanism or potential protective effects of LTL in IMIDs.

PMID:37139230 | PMC:PMC10150136 | DOI:10.3389/fgene.2023.1129247

Drug Des Devel Ther. 2023 Apr 27;17:1289-1302. doi: 10.2147/DDDT.S404710. eCollection 2023.

ABSTRACT

PURPOSE: Our study aims to reveal the pharmacological mechanism of Astragaloside IV in the treatment of pulmonary fibrosis(PF) through network pharmacology and experimental validation.

METHODS: We first determined the in vivo anti-pulmonary fibrosis effect of Astragaloside IV by HE, MASSON staining, and lung coefficients, then used network pharmacology to predict the signaling pathways and molecularly docked key pathway proteins, and finally validated the results by in vivo and in vitro experiments.

RESULTS: In in vivo experiments, we found that Astragaloside IV improved body weight (P < 0.05), increased lung coefficients (P < 0.05), and reduced lung inflammation and collagen deposition in mice with pulmonary fibrosis. The network pharmacology results showed that Astragaloside IV had 104 cross-targets with idiopathic pulmonary fibrosis, and the results of KEGG enrichment analysis indicated that cellular senescence could be an important pathway for Astragaloside IV in the treatment of pulmonary fibrosis. Astragaloside IV also bound well to senescence-associated proteins, according to molecular docking results. The results of both in vivo and in vitro experiments showed that Astragaloside IV significantly inhibited senescence protein markers such as P53, P21, and P16 and delayed cellular senescence (P < 0.05). In in vivo experiments, we also found that Astragaloside IV reduced the production of SASPs (P < 0.05), and in in vitro experiments, Astragaloside IV also reduced the production of ROS. In addition, by detecting epithelial-mesenchymal transition(EMT)-related marker protein expression, we also found that Astragaloside IV significantly inhibited the development of EMT in both in vivo and in vitro experiments (P < 0.05).

CONCLUSION: Our research found that Astragaloside IV could alleviate bleomycin-induced PF by preventing cellular senescence and EMT.

PMID:37138582 | PMC:PMC10150770 | DOI:10.2147/DDDT.S404710

Curr Mol Med. 2023 May 1. doi: 10.2174/1566524023666230501205149. Online ahead of print.

ABSTRACT

BACKGROUND: Extensive deposition of extracellular matrix (ECM) in idiopathic pulmonary fibrosis (IPF) is due to hyperactivation and proliferation of pulmonary fibroblasts. However, the exact mechanism is not clear.

OBJECTIVE: This study focused on the role of CTBP1 in lung fibroblast function, elaborated its regulation mechanism, and analyzed the relationship between CTBP1 and ZEB1. Meanwhile, the anti-pulmonary fibrosis effect and its molecular mechanism of Toosendanin were studied.

METHODS: Human IPF fibroblast cell lines (LL-97A and LL-29) and normal fibroblast cell lines (LL-24) were cultured in vitro. The cells were stimulated with FCS, PDGF-BB, IGF-1, and TGF-β1, respectively. BrdU detected cell proliferation. The mRNA expression of CTBP1 and ZEB1 was detected by QRT-PCR. Western blotting was used to detect the expression of COL1A1, COL3A1, LN, FN, and α-SMA proteins. An animal model of pulmonary fibrosis was established to analyze the effects of CTBP1 silencing on pulmonary fibrosis and lung function in mice.

RESULTS: CTBP1 was up-regulated in IPF lung fibroblasts. Silencing CTBP1 inhibits growth factor-driven proliferation and activation of lung fibroblasts. Overexpression of CTBP1 promotes growth factor-driven proliferation and activation of lung fibroblasts. Silencing CTBP1 reduced the degree of pulmonary fibrosis in mice with pulmonary fibrosis. Western blot, CO-IP, and BrdU assays confirmed that CTBP1 interacts with ZEB1 and promotes the activation of lung fibroblasts. Toosendanin can inhibit the ZEB1/CTBP1protein interaction and further inhibit the progression of pulmonary fibrosis.

CONCLUSION: CTBP1 can promote the activation and proliferation of lung fibroblasts through ZEB1. CTBP1 promotes lung fibroblast activation through ZEB1, thereby increasing excessive deposition of ECM and aggravating IPF. Toosendanin may be a potential treatment for pulmonary fibrosis. The results of this study provide a new basis for clarifying the molecular mechanism of pulmonary fibrosis and developing new therapeutic targets.

PMID:37138491 | DOI:10.2174/1566524023666230501205149

BMC Pulm Med. 2023 May 3;23(1):154. doi: 10.1186/s12890-023-02450-3.

ABSTRACT

INTRODUCTION: The antifibrotic drug nintedanib is used for the treatment of idiopathic pulmonary fibrosis (IPF). We analysed the effect of nintedanib on antifibrotic treatment outcome in real-world cohorts of Czech EMPIRE registry.

PATIENTS/METHODS: Data of 611 Czech IPF subjects, 430 (70%) treated with nintedanib (NIN group), 181 (30%) with no-antifibrotic treatment (NAF group) were analysed. The influence of nintedanib on overall survival (OS), pulmonary function parameters as forced vital capacity (FVC) and diffusing lung capacity for carbon monoxide (DLCO), as well as GAP score (gender, age, physiology) and and CPI (composite physiological index) were investigated.

RESULTS: During 2 year follow-up we observed that nintedanib treated patients had longer OS, compared to those treated with no-antifibrotic drugs (p < 0.00001). Nintedanib reduces risk of mortality over no-antifibrotic treatment by 55% (p < 0.001). We have observed no significant difference in the rate of FVC and DLCO decline between the NIN and NAF group. Changes within 24 months from baseline in CPI were not significant between the groups (NAF and NIN).

CONCLUSION: Our real-practice study showed the benefit of nintedanib treatment on survival. There were no significant differences between NIN and NAF groups in changes from baseline in FVC %, DLCO % predicted and CPI.

PMID:37138274 | DOI:10.1186/s12890-023-02450-3

Nat Commun. 2023 May 4;14(1):2560. doi: 10.1038/s41467-023-38177-2.

ABSTRACT

Pulmonary fibrosis results from dysregulated lung repair and involves multiple cell types. The role of endothelial cells (EC) in lung fibrosis is poorly understood. Using single cell RNA-sequencing we identified endothelial transcription factors involved in lung fibrogenesis, including FOXF1, SMAD6, ETV6 and LEF1. Focusing on FOXF1, we found that FOXF1 is decreased in EC within human idiopathic pulmonary fibrosis (IPF) and mouse bleomycin-injured lungs. Endothelial-specific Foxf1 inhibition in mice increased collagen depositions, promoted lung inflammation, and impaired R-Ras signaling. In vitro, FOXF1-deficient EC increased proliferation, invasion and activation of human lung fibroblasts, and stimulated macrophage migration by secreting IL-6, TNFα, CCL2 and CXCL1. FOXF1 inhibited TNFα and CCL2 through direct transcriptional activation of Rras gene promoter. Transgenic overexpression or endothelial-specific nanoparticle delivery of Foxf1 cDNA decreased pulmonary fibrosis in bleomycin-injured mice. Nanoparticle delivery of FOXF1 cDNA can be considered for future therapies in IPF.

PMID:37137915 | DOI:10.1038/s41467-023-38177-2

Arch Med Res. 2023 May 1:S0188-4409(23)00058-9. doi: 10.1016/j.arcmed.2023.04.002. Online ahead of print.

ABSTRACT

BACKGROUND: A better capacity to identify patients with idiopathic pulmonary fibrosis (IPF) at risk of acute exacerbation (AEIPF) might improve outcomes and reduce healthcare costs.

AIMS: We critically appraised the available evidence of the differences in clinical, respiratory, and biochemical parameters between AEIPF and IPF patients with stable disease (SIPF) by conducting a systematic review and meta-analysis.

METHODS: PubMed, Web of Science and Scopus were reviewed up until August 1, 2022, for studies reporting differences in clinical, respiratory, and biochemical parameters (including investigational biomarkers) between AEIPF and SIPF patients. The Joanna Briggs Institute Critical Appraisal Checklist was used to assess the risk of bias.

RESULTS: Twenty-nine cross-sectional studies published between 2010 and 2022 were identified (all with a low risk of bias). Of the 32 meta-analysed parameters, significant differences were observed between groups, assessed through standard mean differences or relative ratios, with age, forced vital capacity, vital capacity, carbon monoxide diffusion capacity, total lung capacity, oxygen partial pressure, alveolar-arterial oxygen gradient, P/F ratio, 6 min walk test distance, C-reactive protein, lactate dehydrogenase, white blood cell count, albumin, Krebs von den Lungen 6, surfactant protein D, high mobility group box 1 protein, and interleukin-1β, 6, and 8.

CONCLUSIONS: We identified significant differences between AEIPF and SIPF patients in age and specific parameters of respiratory function, inflammation, and epithelial lung damage. Prospective studies are warranted to determine the capacity of these parameters to predict AEIPF more accurately (PROSPERO registration number: CRD42022356640).

PMID:37137756 | DOI:10.1016/j.arcmed.2023.04.002

BMJ Open. 2023 May 2;13(5):e070513. doi: 10.1136/bmjopen-2022-070513.

ABSTRACT

INTRODUCTION: Interstitial lung diseases consist of a range of lung disorders, the most prevalent being idiopathic pulmonary fibrosis (IPF). IPF is a chronic, progressive disease, resulting in loss of lung function and potentially significant impacts on quality of life. There is an increasing need to address unmet needs in this population as there is evidence that unmet needs may impact quality of life and health outcomes. The key objective of this scoping review is to define the unmet needs of patients living with a diagnosis of IPF and to identify gaps in the literature relating to unmet needs. Findings will inform the development of services and the introduction of patient-centred clinical care guidelines for IPF.

METHODS AND ANALYSIS: This scoping review is guided by the methodological framework for conducting scoping reviews developed by the Joanna Briggs Institute. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews checklist is used for guidance. The following databases will be searched: CINAHL, MEDLINE, PsycINFO, Web of Science, Embase and ASSIA and include a comprehensive grey literature search. The review will report on adult patients >18 with a diagnosis of IPF or pulmonary fibrosis and be limited to publications from 2011 onwards, with no language restrictions applied. Two independent reviewers will screen articles in consecutive stages for relevance against the inclusion and exclusion criteria. Data will be extracted using a predefined data extraction form and analysed using descriptive and thematic analysis. Findings will be presented in tabular form, coupled with a narrative summary of the evidence.

ETHICS AND DISSEMINATION: Ethics approval is not required for this scoping review protocol. We will disseminate our findings using traditional approaches that include open access peer-reviewed publications and scientific presentations.

PMID:37130693 | DOI:10.1136/bmjopen-2022-070513

Chin Med J (Engl). 2023 May 3. doi: 10.1097/CM9.0000000000002171. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterized by progressive lung fibrogenesis and histological features of usual interstitial pneumonia. IPF has a poor prognosis and presents a spectrum of disease courses ranging from slow evolving disease to rapid deterioration; thus, a differential diagnosis remains challenging. Several biomarkers have been identified to achieve a differential diagnosis; however, comprehensive reviews are lacking. This review summarizes over 100 biomarkers which can be divided into six categories according to their functions: differentially expressed biomarkers in the IPF compared to healthy controls; biomarkers distinguishing IPF from other types of interstitial lung disease; biomarkers differentiating acute exacerbation of IPF from stable disease; biomarkers predicting disease progression; biomarkers related to disease severity; and biomarkers related to treatment. Specimen used for the diagnosis of IPF included serum, bronchoalveolar lavage fluid, lung tissue, and sputum. IPF-specific biomarkers are of great clinical value for the differential diagnosis of IPF. Currently, the physiological measurements used to evaluate the occurrence of acute exacerbation, disease progression, and disease severity have limitations. Combining physiological measurements with biomarkers may increase the accuracy and sensitivity of diagnosis and disease evaluation of IPF. Most biomarkers described in this review are not routinely used in clinical practice. Future large-scale multicenter studies are required to design and validate suitable biomarker panels that have diagnostic utility for IPF.

PMID:37130223 | DOI:10.1097/CM9.0000000000002171

J Immunol Res. 2023 Apr 19;2023:4835710. doi: 10.1155/2023/4835710. eCollection 2023.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a disease with significant morbidity, progressive deterioration of lung function till death, and lack of effective treatment options. This study aims to explore the global research trends in IPF and immune response to predict the research hotspot in the future. Materials and methods. All related publications on IPF and immune response since the establishment of diagnostic criteria for IPF were retrieved using the Web of Science (WOS) database. VOSviewer, GraphPad Prism 6, CiteSpace version 5.6. R5 64-bit, and a bibliometrics online platform were used to extract and analyze the trends in relevant fields.

RESULTS: From March 1, 2000, to September 30, 2022, a total of 658 articles with 25,126 citations met the inclusion criteria. The United States ranked first in number of publications (n = 217), number of citations (n = 14,745), and H-index (62). China ranked second in publications (n = 124) and seventh and fifth for citation frequency and H-index, respectively. The American Journal of Respiratory and Critical Care Medicine (impact factor = 30.528) published the most articles in the field. The author Kaminski N. from the United States was the most influential author with 26 publications and an H-index of 24. Among the 52 keywords that co-occurred at least 20 times, the main keywords were concentrated in "Inflammation related" and "Biomarker related" clusters. "biomarker" (AAY 2018.64, 25 times) was a newly emerged keyword.

CONCLUSIONS: The United States has an unequivocal advantage in IPF and immunization, but China shows a faster developing trend. The American Journal of Respiratory and Critical Care Medicine should be prioritized for leading articles. This study indicates that exploration of ideal immune-related biomarkers to provide evidence for the clinical work of IPF might be a hotspot in the near future.

PMID:37124548 | PMC:PMC10132898 | DOI:10.1155/2023/4835710

Front Immunol. 2023 Apr 14;14:1159856. doi: 10.3389/fimmu.2023.1159856. eCollection 2023.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease with limited therapeutic options. Recent studies have demonstrated that chemokines play a vital role in IPF pathogenesis. In the present study, we explored whether the gene signature associated with chemokines could be used as a reliable biological marker for patients with IPF.

METHODS: Chemokine-related differentially expressed genes (CR-DEGs) in IPF and control lung tissue samples were identified using data from the Gene Expression Omnibus database. A chemokine-related signature of the diagnostic model was established using the LASSO-Cox regression. In addition, unsupervised cluster analysis was conducted using consensus-clustering algorithms. The CIBERSORT algorithm was used to calculate immune cell infiltration across patient subgroups. Finally, we established a mouse model of bleomycin-induced pulmonary fibrosis and a model of fibroblasts treated with TGFβ1. Expression levels of chemokine-related signature genes were determined using real-time quantitative polymerase chain reaction (RT-qPCR).

RESULTS: We established a chemokine-related eleven-gene signature of a diagnostic model consisting of CXCL2, CCRL2, ARRB1, XCL1, GRK5, PPBP, CCL19, CCL13, CCL11, CXCL6, and CXCL13, which could easily distinguish between IPF patients and controls. Additionally, we identified two subtypes of IPF samples based on chemokine-related gene expression. Pulmonary function parameters and stromal scores were significantly higher in subtype 1 than in subtype 2. Several immune cell types, especially plasma cells and macrophages, differ significantly between the two subtypes. RT-qPCR results showed that the expression levels of Cxcl2 and Ccl2 increased considerably in bleomycin-induced mice. Meanwhile, Arrb1, Ccrl2, Grk5, and Ppbp expression was significantly reduced. Furthermore, multiple chemokine-related genes were altered in TGFβ1 or TNFα-induced fibroblast cells.

CONCLUSIONS: A novel chemokine-related eleven-signature of diagnostic model was developed. These genes are potential biomarkers of IPF and may play essential roles in its pathogenesis.

PMID:37122736 | PMC:PMC10140527 | DOI:10.3389/fimmu.2023.1159856

Am J Physiol Lung Cell Mol Physiol. 2023 Apr 25. doi: 10.1152/ajplung.00028.2023. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease. We discovered fibrogenic mesenchymal progenitor cells (MPCs) in the lungs of IPF patients that display cell autonomous fibrogenicity and drive fibrotic progression. In a study of the IPF MPC nuclear proteome, we identified DNA damage as one of the most altered functions in IPF MPCs. In prior work we found that IL-8 drives IPF MPC self-renewal. IL-8 can promote replicative stress and DNA damage and induce senescence through the CXCR2 receptor. We hypothesized that IL-8 promotes DNA damage-mediated senescence in IPF MPCs. We show that IL-8 induces DNA damage and promotes IPF MPC senescence. We discovered that IL-8 concurrently promotes senescence and upregulation of the programmed death ligand 1 (PD-L1) in a CXCR2-dependent manner. Disruption of PD-1/PD-L1 interaction promotes NK cell killing of IPF MPCs in vitro and arrests IPF MPC-mediated experimental lung fibrosis in vivo. IHC analysis of IPF lung tissue identifies PD-L1 expressing IPF MPCs co-distributing with NK cells and b-galactosidase positive cells. Our data indicate that IL-8 simultaneously promotes IPF MPC DNA damage-induced senescence and high PDL1 expression enabling IPF MPCs to elude immune cell targeted removal. Disruption of PD1/PDL1 interaction may limit IPF MPC mediated fibrotic progression.

PMID:37121574 | DOI:10.1152/ajplung.00028.2023

Respirology. 2023 Apr 30. doi: 10.1111/resp.14511. Online ahead of print.

ABSTRACT

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.

PMID:37121779 | DOI:10.1111/resp.14511