Sci Rep. 2025 Jul 19;15(1):26295. doi: 10.1038/s41598-025-12180-7.

ABSTRACT

Bronchoalveolar lavage (BAL) is crucial for the diagnosis of interstitial lung disease (ILD). Although BAL lymphocytosis is found in patients with connective tissue disease (CTD)-related ILD, the effects of CTD-associated features on BAL lymphocytosis have not been elucidated. To identify CTD-associated features that affect BAL lymphocyte fraction in patients with idiopathic interstitial pneumonia (IIP). This post hoc analysis of a prospective, multicentre cohort study was conducted between 2015 and 2020. Overall, 222 patients newly diagnosed with IIP were consecutively enrolled, and 74 autoimmune features were comprehensively analysed during IIP diagnosis. The median age was 71 years, and the median observation period was 36 months. The clinical characteristics related to a significant increase in BAL lymphocyte fraction were consolidation opacity on high-resolution computed tomography (HRCT), morphologic domain of interstitial pneumonia with autoimmune features (IPAF), serum CXCL10 concentration, and acute/subacute onset (all p < 0.05). In contrast, presence of joint lesion/mucocutaneous lesion/dry symptoms, autoantibodies, or other CTD-like features on HRCT and surgical lung biopsy did not affect the BAL lymphocyte fraction (all p ≥ 0.05). Furthermore, a high BAL lymphocyte fraction (≥ 8.5%) was related to a low proportion of progressive pulmonary fibrosis (p < 0.001) and favourable survival (log-rank, p = 0.020) in patients with non-idiopathic pulmonary fibrosis (IPF). IPAF morphologic domain especially with consolidation opacity on HRCT and high CXCL10 concentration, but not CTD-like symptoms, autoantibodies, or CTD-like features on lung biopsy, were related to a high BAL lymphocyte fraction with favourable survival in patients with non-IPF.

PMID:40683979 | DOI:10.1038/s41598-025-12180-7

Bioorg Chem. 2025 Jul 12;163:108731. doi: 10.1016/j.bioorg.2025.108731. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a common mesenchymal lung disease. Inhibiting of the PIM-1 protein has been identified as a promising therapeutic strategy for IPF. Previous studies have shown that paeonol has certain activity against IPF. To identify more potent compound, a total of 41 novel paeonol-based derivatives were designed, synthesized, and their activity was evaluated by inducing fibrotic phenotypes in NIH-3T3 cells in vitro. Among them, compound B6 demonstrated potent activity (inhibitory rates = 91.2 ± 1.7 %) with low toxicity (viability rate = 99.7 ± 0.42 %). CETSA analysis revealed that it could bind to PIM-1. Further studies indicated that it effectively regulated the production of IPF markers, including collagen I and α-SMA. In bleomycin (BLM)-induced IPF mice model, it also significantly inhibited the phosphorylation of p65 in lung tissues and influenced the production of SASP factors, including IL-6, IL-1β, and IL-10. These results suggest that compound B6 may serve as a promising lead compound for alleviating the clinical symptoms of IPF.

PMID:40682967 | DOI:10.1016/j.bioorg.2025.108731

Mol Ther. 2025 Jul 16:S1525-0016(25)00539-8. doi: 10.1016/j.ymthe.2025.07.003. Online ahead of print.

ABSTRACT

Here, we present a combination of cell and gene therapy that harnesses the regenerative properties of GDF11 in age-related pulmonary fibrosis. Our genome-edited SafeCell-GDF11 mouse embryonic stem cell line provides controlled proliferation and efficient derivation to lung progenitors while inducibly expressing GDF11. When these cells were transplanted into bleomycin-injured aged mice, they acted as a source of reparative cells, restoring the damaged alveolar epithelium. Furthermore, the transplanted cells acted as an "in situ factory," enabling the production of GDF11 in response to the inducer drug. This approach attenuated age-associated senescence and led to the successful resolution of fibrosis. Our study presents a GDF11-expressing cell-based strategy that demonstrates the feasibility of promoting alveolar regeneration in a mouse model of age-related pulmonary fibrosis. Additionally, this approach offers a versatile tool that can be expanded to incorporate other regenerative and anti-aging factors. This helps overcome limitations such as high production costs and a short half-life of therapeutic factors. One of the strengths of our system is its ability to allow precise regulation of factor expression when needed to address specific aging phenotypes.

PMID:40676836 | DOI:10.1016/j.ymthe.2025.07.003

Int Immunopharmacol. 2025 Jul 17;163:115244. doi: 10.1016/j.intimp.2025.115244. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a serious chronic lung disease characterized by progressive dyspnea and deterioration of lung function. According to existing observations, platelet activation and fibroblast-myofibroblast differentiation plays an important role in the development of IPF. This study aimed to investigate the role of podoplanin (PDPN) in this differentiation process during IPF progression. Specifically, the article explores PDPN expression in human IPF and bleomycin (BLM)-induced pulmonary fibrosis in mice, along with the effects and mechanisms of the PDPN monoclonal antibody SZ168 on pulmonary fibrosis both in vitro and in vivo.

METHODS: Data analysis of human IPF datasets to identify PDPN as a differentially expressed gene. Following this, in vivo and in vitro experiments were conducted to investigate the role and underlying mechanisms of PDPN in the progression of IPF. Additionally, we measured PDPN levels in the serum of IPF patients to validate its differential expression.

RESULTS: Our findings show that PDPN is highly expressed in IPF patients. Additionally, PDPN expression is elevated in TGF-β1-induced fibroblasts and in the lungs of bleomycin-induced mouse models. We particularly found that PDPN was expressed in WI-38 human pulmonary fibroblasts. Knockdown of PDPN in fibroblasts suppresses TGF-β-induced differentiation into myofibroblasts. Furthermore, the PDPN monoclonal antibody SZ168 inhibits platelet-induced fibroblast differentiation. Mechanistic analysis reveals that PDPN promotes bleomycin-induced pulmonary fibrosis via the activation of the RhoA/ROCK signaling pathway.

CONCLUSIONS: PDPN is significantly upregulated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), and closely associated with the differentiation of fibroblasts into myofibroblasts. The monoclonal antibody SZ168 effectively inhibits platelet activation, thereby inhibiting the differentiation of fibroblasts induced by PDPN and mitigating the progression of pulmonary fibrosis.

PMID:40680610 | DOI:10.1016/j.intimp.2025.115244

Am J Respir Crit Care Med. 2025 Jul 18. doi: 10.1164/rccm.202503-0591LE. Online ahead of print.

NO ABSTRACT

PMID:40680241 | DOI:10.1164/rccm.202503-0591LE

Am J Respir Crit Care Med. 2025 Jul 18. doi: 10.1164/rccm.202501-0208OC. Online ahead of print.

ABSTRACT

RATIONALE: Progressive pulmonary fibrosis (PPF) is common in patients with fibrotic interstitial lung disease (ILD) and leads to high mortality. While PPF guideline criteria include computed tomography (CT)-based progression, these measures are qualitative and prone to inter-reader variability. Quantitative CT (qCT) measurements have the potential to overcome this limitation.

OBJECTIVES: The objectives of this study were to determine whether changes in qCT measures of pulmonary fibrosis are associated with transplant-free survival (TFS) in a diverse ILD cohort and establish a quantitative CT measure of PPF (qctPPF).

METHODS: A retrospective cohort analysis was performed in individuals with fibrotic ILD including idiopathic pulmonary fibrosis (IPF) (n=350) who underwent serial chest CT for clinical indications. Commercially available software was used to generate qCT measures of pulmonary fibrosis, which were tested for association with two-year TFS using a multivariable Cox proportional hazard model. Iterative modeling was then performed to develop a composite qctPPF measure. Results were validated in an independent ILD cohort (n=92).

MEASUREMENTS AND MAIN RESULTS: Increasing ground glass opacity and decreasing lung volume showed consistent association with decreased TFS across cohorts when modeled continuously and dichotomously. qctPPF classification was associated with >3-fold increased hazard of death or transplant in the test (HR 4.41; 95% CI 2.77-7.03) and validation (HR 3.54; 95% CI 1.62-7.71) cohorts. Agreement between qctPPF and radiologist-determined PPF was poor (=0.20), with qctPPF classification maintaining prognostic significance when discordant with radiologist interpretation.

CONCLUSIONS: Changes in qCT measures are associated with clinically relevant outcomes and could improve PPF classification.

PMID:40680162 | DOI:10.1164/rccm.202501-0208OC

JHLT Open. 2025 Jun 18;9:100323. doi: 10.1016/j.jhlto.2025.100323. eCollection 2025 Aug.

ABSTRACT

The year 2025 marks an important landmark: almost 40 years since the first pediatric lung transplant (LTX), over 3-5 years since the availability of elexacaftor/tezacaftor/ivacaftor in several countries, and 5-10 years since striking shifts were reported in the diagnoses that accounted for pediatric LTX. We review historic indications for pediatric LTX, highlighting shifts in these over time, and analyze data from the ISHLT International Thoracic Organ Transplant Registry, United Network of Organ Sharing, Canadian Cystic Fibrosis (CF) Registry, and other databases up to the present day. Currently, pediatric CF-related LTX cases are at record lows in many countries. Non-retransplant bronchiolitis obliterans seems to be on the rise as a transplant indication in pediatrics, which is particularly true in the younger age group per ISHLT data. Childhood interstitial lung disease is increasing as an indication, especially in North America. Idiopathic pulmonary arterial hypertension (IPAH) and pulmonary hypertension as a whole now account for record highs as indications for pediatric LTX around the world, with IPAH alone now accounting for nearly 20% of pediatric LTX in the United States, for instance. This information will help guide future international pediatric thoracic transplant consensus guidelines around candidate selection and optimization, placing more emphasis on non-CF considerations.

PMID:40678364 | PMC:PMC12270605 | DOI:10.1016/j.jhlto.2025.100323

Cell Biosci. 2025 Jul 17;15(1):103. doi: 10.1186/s13578-025-01428-4.

ABSTRACT

The architecture of the mammalian lung is both intricate and distinct. The respiratory system consists of a complex network of semirigid airway tubes, stretching from the trachea to the alveoli, highly vascularized sacs responsible for gas exchange. This system demands precise regulation. The mammalian target of rapamycin (mTOR) functions as a receptor and regulatory hub for various cellular processes, including metabolism, proliferation, and autophagy, and plays a pivotal role in lung development and regeneration, continuing to influence cellular processes into early childhood. Over the past decade, studies have identified abnormally elevated mTOR activity in adult lung diseases such as acute lung injury and idiopathic pulmonary fibrosis, leading to the approval of mTOR inhibitors for clinical use. However, during fetal lung development and the postnatal period, mTOR often exhibits a dual role. Its dynamic expression requires careful adaptation to temporal and spatial variations. The safety and efficacy of mTOR inhibitors during these developmental windows remain uncertain, as the role of mTOR becomes increasingly complex in response to the dramatic changes in lung tissue. This review aims to analyze the regulatory mechanisms and functional roles of the mTOR pathway throughout various stages of lung development and adult pulmonary diseases, highlighting the need for caution in using mTOR inhibitors during critical developmental phases. Careful evaluation is essential when considering pharmaceutical interventions for abnormal lung development and pediatric pulmonary disorders.

PMID:40676702 | PMC:PMC12273038 | DOI:10.1186/s13578-025-01428-4

Sci Rep. 2025 Jul 17;15(1):25926. doi: 10.1038/s41598-025-09318-y.

ABSTRACT

The pathogenesis of pulmonary fibrosis involves structural remodeling and functional impairment of lung tissue, accompanied by increased secretion of pro-inflammatory mediators and abnormal synthesis of the extracellular matrix (ECM). Thrombospondin-2 (THBS2), an ECM glycoprotein encoding gene, has been extensively studied in liver and heart fibrosis. However, its role in idiopathic pulmonary fibrosis (IPF) in humans remains incompletely understood. Lung fibroblasts were obtained from normal individuals and IPF patients, and THBS2 expression was detected. Then, THBS2 overexpression and knockdown cell models as well as exogenous human THBS2 active protein administration cell models were established to explore the role of THBS2 in cell aggressive phenotype, collagen synthesis and proinflammatory mediator secretion. Furthermore, TGF-β1 inhibitor was used to investigate the underlying mechanism of THBS2 affecting collagen synthesis. Finally, in the bleomycin (BLM) -induced pulmonary fibrosis model, the severity of pulmonary fibrosis in mice was evaluated by administering exogenous mouse THBS2 active protein. THBS2 expression was significantly up-regulated in lung tissues of IPF patients and in IPF lung fibroblasts. THBS2 Overexpression and exogenous human THBS2 active protein markedly enhanced the proliferation and migration of fibroblasts and increased the levels of COL1A1, COL1A2, COL3A1, LOX and LOXL2. These effects were attenuated after knockdown of THBS2 in IPF fibroblasts. Animal models also confirmed that exogenous mouse THBS2 protein could aggravate bleomycin-induced pathological changes and collagen deposition in lung tissues of mice. Using TGF-β1 inhibitor SB525334 reduced the protein expression of downstream molecules (TGFBR1, TGFBR2, P-Smad2/3) and collagen synthesis but did not inhibit the upregulation of post-translational modification enzymes LOX and LOXL2 involved in collagen synthesis. Meanwhile, we observed that THBS2 overexpression significantly promoted inflammatory secretome (IL-1β, IL-6 and IL-8). THBS2 is overexpressed in IPF. Functionally, THBS2 promotes the invasive phenotype (proliferation and migration), collagen synthesis and inflammation secretome in fibroblasts. Mechanistically, THBS2 promotes collagen synthesis through the TGF-β1/Smad2/3 signaling pathway.

PMID:40676074 | DOI:10.1038/s41598-025-09318-y

Eur Respir J. 2025 Jul 17:2500022. doi: 10.1183/13993003.00022-2025. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by progressive fibrosis of lung parenchyma. The histopathology of IPF exhibits temporal and spatial heterogeneity, including immature fibroblastic foci (FF) and densely collagenized fibrosis. FF serve as dynamic niches of profibrotic fibroblasts and play a pivotal role in fibrosis progression and transition into dense fibrosis (DF). Here, we integrated single-cell RNA sequencing (scRNA-seq) with spatial transcriptomics to elucidate cellular heterogeneity and the novel cell type involved not only in FF formation but also in DF development. We identified a novel myofibroblast population, WNT5A+ CTHRC1+ myofibroblasts, enriched in both FF and DF regions, underscoring their pivotal role in fibrosis progression. Differential gene expression analysis revealed the activation of p21-activated kinase 2 (PAK2) in these fibrotic areas, including WNT5A+ CTHRC1+ myofibroblasts. PAK inhibition significantly suppressed TGF-β-induced myofibroblast differentiation and collagen production in IPF-derived fibroblasts. Furthermore, in a bleomycin-induced lung fibrosis mouse model, intraperitoneal administration of the PAK inhibitor significantly attenuated fibrotic progression. This study highlights the therapeutic potential of PAK inhibition for IPF, particularly targeting pathogenic fibroblasts within both FF and DF regions. By leveraging spatial transcriptomics and scRNA-seq, we provide a comprehensive molecular and cellular atlas of FF and DF in IPF lung tissue, offering new insights into fibrosis progression and therapeutic intervention.

PMID:40675771 | DOI:10.1183/13993003.00022-2025

Front Immunol. 2025 Jul 2;16:1541645. doi: 10.3389/fimmu.2025.1541645. eCollection 2025.

ABSTRACT

Extracellular Vesicles (EVs), released by all cell types and detectable in biological samples, carry a variety of biological molecules. These molecules mediate communication and signaling with both local and distant cells, potentially playing a role in the pathogenesis of diseases, including Interstitial Lung Diseases and, more specifically, Idiopathic Pulmonary Fibrosis. To better understand the role of EVs in IPF, a systematic search was performed in PubMed, Scopus, and Ovid databases. These searches were conducted from January 1st, 2019, the period during which the MISEV 2018 guidelines were published, to August 31st, 2024. The SANRA scale was used for quality assessment. A total of 691 papers were screened, and 16, in the end, were definitively enrolled for our evaluation. The studies were reviewed in the following steps: 1) the nomenclature used to define EVs; 2) conformity with the MISEV 2018 guidelines; 3) the biological samples used to isolate EVs; 4) the main conclusion of each manuscript. There was significant heterogeneity among the publications in all the aforementioned steps, such as the type and source of EVs and the analysis of EVs content, primarily a wide array of different miRNAs in the various publications. Despite these differences, the emerging role of EVs and their potential usefulness both in therapies and clinical practice is of growing interest.

PMID:40672958 | PMC:PMC12263404 | DOI:10.3389/fimmu.2025.1541645

Sci Rep. 2025 Jul 17;15(1):25896. doi: 10.1038/s41598-025-12046-y.

ABSTRACT

Previous studies have suggested a potential correlation between obesity and idiopathic pulmonary fibrosis (IPF). This study aimed to elucidate pathogenic pathways connecting obesity and IPF and identify diagnostic biomarkers for obesity-related pulmonary fibrosis. Obesity and IPF datasets were obtained through the Gene Expression Omnibus (GEO) database. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were used to identify shared genes for obesity and IPF. Functional enrichment (GO/KEGG), protein-protein interaction (PPI) networks, and machine learning algorithms were applied to screen hub genes, validated by ROC curves. High-fat diet (HFD)-induced obese mice with bleomycin-induced pulmonary fibrosis underwent histological assessment and qRT-PCR validation. Molecular docking evaluated flavonoid binding to hub genes. We identified 128 shared genes between obesity and IPF, predominantly enriched in immune and inflammatory pathways. Machine learning prioritized three hub genes (NLRC4, SPI1, and NCF2), validated by ROC analysis (AUC > 0.7). In animal model, these genes exhibited significant upregulation, correlating with exacerbated fibrosis. Molecular docking highlighted strong binding affinities (-6.3 to -9.6 kcal/mol) between dietary flavonoids and hub targets. Immune-inflammatory dysregulation links obesity and IPF via NLRC4, SPI1, and NCF2. These genes serve as diagnostic biomarkers and therapeutic targets, with flavonoids showing intervention potential. Our findings advance mechanistic insights into obesity-related pulmonary fibrosis.

PMID:40670650 | DOI:10.1038/s41598-025-12046-y

Rev Med Chil. 2025 Jul;153(7):527-538. doi: 10.4067/s0034-98872025000700527.

ABSTRACT

Interstitial lung diseases are a heterogeneous group of disorders characterized by inflammation and/or fibrosis of the lung parenchyma, leading to a progressive loss of lung function. Idiopathic pulmonary fibrosis (IPF) is a representative model with a pathophysiology common to other types of pulmonary fibrosis.

AIM: This review presents the pathophysiological mechanisms and existing and developing antifibrotic therapies of IPF.

METHOD: Qualitative study through a narrative review of the pathophysiological phenomena of IPF and advances in antifibrotic therapy.

RESULTS: The role of the alveolar epithelium, fibroblast/myofibroblast activity, cellular senescence and aging, immune system activity, oxidation-reduction mechanisms and genetic characteristics have been identified, which reveal the complex pathophysiology of this disease. Currently, there are only two therapies available to mitigate the effects of pulmonary fibrosis, Pirfenidone and Nintedanib, and the development and research of other antifibrotic drugs is still pending.

CONCLUSIONS: There are multiple pathophysiological phenomena in IPF. Understanding them is the basis for the development and evolution of antifibrotic therapies.

PMID:40668019 | DOI:10.4067/s0034-98872025000700527

bioRxiv [Preprint]. 2025 Jun 21:2025.06.10.658504. doi: 10.1101/2025.06.10.658504.

ABSTRACT

Acute and repetitive lung epithelial injury can lead to irreversible and even progressive pulmonary fibrosis; Idiopathic pulmonary fibrosis (IPF) is a fatal disease and quintessential example of this phenomenon. The composition of epithelial cells in human pulmonary fibrosis - irrespective of disease etiology - is marked by the presence of Aberrant Basaloid cells: an abnormal cell phenotype with pro-fibrotic and senescent features, localized to the surface of fibrotic lesions. Despite their relevance to human pulmonary fibrosis, the exotic molecular profile of Aberrant Basaloid cells has obscured their etiology, preventing insights into how or why these cells emerge with fibrosis. Here we identify cellular intermediaries between Aberrant Basaloid and normal alveolar epithelial cells in human IPF tissue. We track the emergence of Aberrant Basaloid cells from alveolar epithelial cells ex vivo and uncover a role for similar cells in epithelial regeneration under normal conditions. Lastly, we characterize the epigenetic changes that distinguish Aberrant Basaloid cells from their progenitors and identify hallmarks of AP-1 injury memory retention. This study elucidates the phenomenon of maladaptive epithelial plasticity and regeneration in pulmonary fibrosis and re-contextualizes therapeutic strategies for epithelial dysfunction.

PMID:40667263 | PMC:PMC12262340 | DOI:10.1101/2025.06.10.658504

bioRxiv [Preprint]. 2025 Jun 21:2025.06.16.659944. doi: 10.1101/2025.06.16.659944.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic pulmonary disease with unknown etiology. Since approved idiopathic pulmonary fibrosis (IPF) drugs only slow disease progression, novel therapeutics are required that improve clinical outcomes. Here, we report a single cell RNA-Seq and regulatory network analysis of the largest IPF cohort assembled to date. Segregating this cohort based on status of treatment with approved antifibrotics (untreated, nintedanib- and pirfenidone-treated), we describe for the first time the transcriptional landscape of untreated IPF across 40 lung cell types, and the elements of this program that are impacted by approved antifibrotics. On average, 60% of the untreated IPF-dysregulated transcriptome is refractory to treatment with these drugs, a transcriptional deficit we refer to as the IPF therapeutic gap. Regulatory network analysis indicated a dominant functional footprint for the transcription factor STAT3 in both untreated IPF and in the IPF therapeutic gap. Validating our analysis in a translational precision cut lung slice platform that recapitulates IPF explants, treatment with a STAT3 inhibitor reduced the IPF therapeutic gap in numerous lung cell types. Finally, we implicated STAT3 as a master transcription factor that regulates a network comprising numerous profibrotic transcription factors in IPF alveolar fibroblasts, a critical fibrotic cell lineage. Our study represents a comprehensive resource for translational lung fibrosis research and establishes a novel strategy for drug discovery in human disease more broadly.

PMID:40666833 | PMC:PMC12262394 | DOI:10.1101/2025.06.16.659944

Biol Direct. 2025 Jul 15;20(1):83. doi: 10.1186/s13062-025-00658-3.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive pulmonary disease characterized by alveolar structural destruction and fibrosis. In recent years, efferocytosis has been recognized as playing a crucial role in the occurrence and progression of IPF. This study aimed to identify and regulate key efferocytosis-related genes to elucidate their potential roles and clinical significance in IPF.

METHODS: IPF-related datasets (GSE32537) were obtained from the Gene Expression Omnibus (GEO) database. Differential gene expression analysis and weighted gene coexpression network analysis (WGCNA) were applied to identify key genes associated with IPF, intersecting them with efferocytosis-related genes (ERGs) to obtain IPF-ERGs. Protein‒protein interaction (PPI) network construction and enrichment analysis were performed to elucidate the potential functions of these genes in IPF. Seven machine learning algorithms were employed to screen for hub genes with high diagnostic value. The GSE70866 dataset was used for validation, and a nomogram was constructed. Additionally, the CIBERSORT algorithm was used to analyze immune infiltration levels, and transcriptomic validation of the hub genes was conducted in animal experiments.

RESULTS: A total of 21 IPF-ERGs were identified, and machine learning further identified TLR2, ATG7, SPHK1, and ICAM1 as hub genes, which were significantly upregulated in the IPF group. Immune infiltration analysis revealed a significant increase in the infiltration levels of immune cell subsets, including memory B cells, CD8 + T cells, and resting dendritic cells, in the IPF group. Further clinical correlation analysis revealed a strong association between the expression levels of the hub genes and pulmonary function. A nomogram was constructed on the basis of the hub genes and validated for its potential clinical application. Consensus clustering classified IPF patients into two subtypes: C1, which was primarily by metabolic pathway activation, and C2, which was enriched in inflammatory and immune pathways. Transcriptomic analysis of animal experiments also confirmed the upregulation of hub gene expression in IPF.

CONCLUSION: This study identified TLR2, ATG7, SPHK1, and ICAM1 as four key hub genes, revealing their potential diagnostic value and biological functions in IPF. These genes may serve as potential diagnostic biomarkers and therapeutic targets, providing new insights for precision treatment.

CLINICAL TRIAL NUMBER: Not applicable.

PMID:40665394 | DOI:10.1186/s13062-025-00658-3

EJNMMI Radiopharm Chem. 2025 Jul 15;10(1):44. doi: 10.1186/s41181-025-00366-3.

ABSTRACT

BACKGROUND: Lung diseases such as idiopathic pulmonary fibrosis and acute respiratory distress syndrome (ARDS) are associated with significant morbidity and mortality, with limited treatment options. Platelet-derived growth factor receptor beta (PDGFRβ) signaling pathway is a key driver of fibrogenesis in different organs. In the lungs, pericytes have a high PDGFRβ expression, and their role as immune regulators and progenitors of myofibroblasts is increasingly recognized. Non-invasive techniques to assess active lung tissue remodeling are needed to improve disease monitoring and treatment evaluation. This study aimed to evaluate [18F]TZ-Z09591, targeting PDGFRβ, for imaging pulmonary injuries in human biopsies, and in vivo in animal models of lung injury.

RESULTS: [18F]TZ-Z09591 demonstrated high and specific binding to PDGFRβ-expressing cells. Autoradiography confirmed tracer uptake in lung injuries, including fibrotic foci, from human, rat, and pig lung tissues. In vivo positron emission tomography (PET) imaging of bleomycin-induced lung fibrosis in rats and an ARDS pig model showed significantly increased uptake in diseased lung segments compared to controls, especially in pulmonary injuries with collagen deposition, despite moderate background uptake.

CONCLUSIONS: This study demonstrated that [18F]TZ-Z09591 can assess PDGFRβ expression in pulmonary injuries, supporting its potential for non-invasive assessment of lung tissue remodeling. PET imaging targeting PDGFRβ could improve disease monitoring, and provide new insights into pulmonary fibrosis progression.

PMID:40664934 | DOI:10.1186/s41181-025-00366-3

Front Aging. 2025 Jun 30;6:1604051. doi: 10.3389/fragi.2025.1604051. eCollection 2025.

ABSTRACT

INTRODUCTION: The receptor for hyaluronan-mediated motility (RHAMM), a centrosomal protein expressing in multiple isoforms, is implicated in telomerase-independent aging. However, its involvement in telomerase regulation is unproven. This study aims to investigate whether RHAMM correlates with telomerase activity in mammalian cells.

METHODS: Mouse embryonic fibroblasts expressing or lacking full-length RHAMM (RHAMMFL, amino acids 1-794) and the shorter isoform RHAMMΔ163 (amino acids 164-794), were explored to examine the effect of RHAMM isoforms on mRNA expression of telomerase reverse transcriptase (TERT) and selective shelterin proteins regulating telomere maintenance.

RESULTS: The preliminary findings revealed that RHAMM regulated Tert expression based on its isoforms. RHAMMΔ163 enhanced Tert mRNA expression and promoted telomerase activity by stimulating sirtuin 1 (Sirt1), shelterin proteins Tpp1, and Pot1a and repressing the telomerase inhibitor Pinx1 levels. In contrast, RHAMMFL did not have significant effect on TERT expression and telomerase activity. Increasing Tert mRNA expression by blocking leucine zipper sequence with function-blocking RHAMM peptide NP-110 in a TERT-deficient mouse model of idiopathic pulmonary fibrosis, alongside suppressing Tpp1 and Pot1a expression in mouse embryonic fibroblasts using ERK1 inhibitor PD98059, highlights the importance of the HATABD domain (amino acids 718-751), which includes leucine zipper and ERK-binding sequences at the C-terminus of mouse RHAMM in regulating telomerase function. Increased telomerase activity raised Hmmr expression, suggesting a potential feedback loop between RHAMM and TERT expression.

DISCUSSION: Taken together, this report provides the first evidence that RHAMMΔ163 regulates TERT and shelterin expression and telomerase activity in mammalian cells.

PMID:40661163 | PMC:PMC12256479 | DOI:10.3389/fragi.2025.1604051

Medicine (Baltimore). 2025 Jul 11;104(28):e43102. doi: 10.1097/MD.0000000000043102.

ABSTRACT

Recent studies have suggested an increased incidence of various lung diseases following COVID-19 vaccination. However, causal relationships have not been definitively established. We conducted a two-sample Mendelian randomization (MR) study using publicly available genome-wide association study data to investigate potential causal relationships between COVID-19 vaccination status as the exposure and 14 different lung diseases as outcomes. The analytical methods included random-effects inverse-variance weighting, MR Egger, and weighted median, with additional heterogeneity and sensitivity analyses. Seven instrumental variables for exposure were selected (P < 5 × 10-8). MR analyses revealed that COVID-19 vaccination status was not associated with an increased risk of developing overall lung cancer (P = .78), lung adenocarcinoma (P = .557), squamous cell lung cancer (P = .557), non-small cell lung cancer (P = .173), asthma (P = .905), chronic obstructive pulmonary disease, bronchiectasis (P = .669), forced vital capacity (FVC), forced expiratory volume in 1 second/FVC (P = .794), pneumonia (P = .282), idiopathic pulmonary fibrosis (P = .486), pulmonary embolism (P = .267), pneumothorax (P = .73), or sarcoidosis (P = .732). Evidence of heterogeneity was observed in the inverse-variance weighting model for overall lung cancer, chronic obstructive pulmonary disease, and FVC, whereas no indications of horizontal pleiotropy or significant heterogeneity were noted for other lung diseases. COVID-19 vaccination does not appear to increase the risk of developing various lung diseases. These findings support the safety of COVID-19 vaccines in terms of respiratory health, reinforcing their role in public health interventions and vaccination policies.

PMID:40660535 | DOI:10.1097/MD.0000000000043102

Nano Lett. 2025 Jul 14. doi: 10.1021/acs.nanolett.5c02481. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a life-threatening interstitial lung disease and is one of the complications observed in individuals following COVID-19 infection. Although inhalable nanomedicines hold promise, nebulization-induced shear stress, dense airway mucus barrier, and inefficient in vivo clearance substantially compromise nanomedicine delivery efficiency and biosafety, thereby limiting their therapeutic efficacies. Herein, an inhalable microenvironment-responsive hybrid nanomedicine (PFD@FPNs-CAT) encapsulated with pirfenidone (PFD) and modified with catalase (CAT) is developed, which is able to overcome the supramolecular interactions owing to the small particle size, electronegativity, and PEGylated surface, thus enhancing the accumulation of PFD@FPNs-CAT in the lesions. Moreover, the surface-anchored CAT is demonstrated to relieve hypoxia, thus reversing the immunosuppressive microenvironment and further enhancing the therapeutic efficacy against IPF. Notably, due to the relatively low quantity of silica doping, PFD@FPNs-CAT demonstrates high stability and excellent biocompatibility. This inhalable mucus-penetrating nanomedicine remarkably inhibits the progression of IPF, illuminating the bright prospects for IPF therapy.

PMID:40657744 | DOI:10.1021/acs.nanolett.5c02481