Front Med (Lausanne). 2025 May 22;12:1584014. doi: 10.3389/fmed.2025.1584014. eCollection 2025.

ABSTRACT

BACKGROUND: Pulmonary fibrosis is a leading cause of death in patients with Systemic sclerosis (SSc). Single nucleotide polymorphisms (SNPs) within Toll interacting protein (TOLLIP) coding gene have been associated with progression and prognosis of Idiopathic Pulmonary Fibrosis (IPF). Aim of the present study was to investigate the association of TOLLIP SNPs with the presence, severity and outcome of interstitial lung disease (ILD) in patients with SSc.

PATIENTS AND METHODS: 106 consecutive SSc patients (77 female) with (N = 53) and without ILD (N = 53) and 212 healthy controls (HC) (154 female) were genotyped for two SNPs within TOLLIP (rs3750920, rs5743890) by using TaqMan™ SNP Genotyping Assay (Thermo Fischer Scientific, USA). Disease progression was defined as ≥ 10% relative decline in FVC% pred. or ≥ 5 to < 10% decline in relative FVC% pred. and 15% relative decline in DLCO% pred. From baseline.

RESULTS: The TOLLIP rs5743890 minor Allele (C) was more frequent in HC than in SSc patients (41% vs. 16%, p = 0.021). The homozygote alleles of rs5743890 were significantly overrepresented in SSc patients compared to HC (84% vs. 71%, p = 0.008). Among SSc patients with ILD, those carrying the rs5743890 T/C genotype had a tendentially worse survival (158 vs. 213 months, p = 0.162) and a significantly higher rate of disease progression (66% vs. 22%, p = 0.003) compared to homozygotes. The rs5743890 minor allele C was an independent predictor of progression after adjustment for a number of covariates (HR 4.29, 95% CI 1.48-12.48, p = 0.008). Moreover, the TC haplotype appeared to be an even stronger predictor of progression than rs5743890 alone (HR 7.71, 95% CI 1.79-33.12, p = 0.006).

CONCLUSION: TOLLIP SNP rs5743890 genotype distribution seems to differ in SSc patients compared to HC. The rs5743890 heterozygote genotype and the TC haplotype may be associated with an increased risk of progression in patients with SSc-ILD.

PMID:40475958 | PMC:PMC12137070 | DOI:10.3389/fmed.2025.1584014

bioRxiv [Preprint]. 2025 May 22:2025.05.17.654673. doi: 10.1101/2025.05.17.654673.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease characterized by impaired fibroblast clearance and excessive extracellular matrix (ECM) protein production. Wilms' Tumor 1 (WT1), a transcription factor, is selectively upregulated in IPF fibroblasts. However, the mechanisms by which WT1 contributes to fibroblast accumulation and ECM production remain unknown. Here, we investigated the heterogeneity of WT1-expressing mesenchymal cells using single-nucleus RNA sequencing of distal lung tissues from IPF patients and control donors. WT1 was selectively upregulated in a subset of IPF fibroblasts that co-expressed several pro- survival and ECM genes. The results of both loss-of-function and gain-of-function studies are consistent with a role for WT1 as a positive regulator of pro-survival genes to impair apoptotic clearance and promote ECM production. Fibroblast-specific overexpression of WT1 augmented fibroproliferation, myofibroblast accumulation, and ECM production during bleomycin-induced pulmonary fibrosis in young and aged mice. Together, these findings suggest that targeting WT1 is a promising strategy for attenuating fibroblast expansion and ECM production during fibrogenesis.

PMID:40475429 | PMC:PMC12139862 | DOI:10.1101/2025.05.17.654673

Open Respir Arch. 2025 Mar 19;7(2):100432. doi: 10.1016/j.opresp.2025.100432. eCollection 2025 Apr-Jun.

ABSTRACT

INTRODUCTION: This study aims to describe the clinical features, hospital management, and outcomes of patients with interstitial lung disease (ILD) and acute respiratory failure (ARF) admitted to the respiratory intermediate care units (RICUs).

MATERIAL AND METHODS: An observational study was conducted on ILD patients admitted to the RICU between June 1, 2021, and May 30, 2024. Main variables analysed included demographics, non-invasive respiratory support (NIRS) types, ILD-related variables, lung transplant outcomes, and survival rates.

RESULTS: Of the 401 patients admitted, 51 (13%) had ILD, of whom 34 (67%) were male. Idiopathic pulmonary fibrosis (IPF) was the most common condition (33%), and high-flow oxygen therapy (HFOT) was the primary treatment (94%). Infection (29%) and disease progression (36%) were the main hospitalization causes. Of the 27 patients (53%) evaluated for transplantation, 18 (36%) underwent a lung transplant, with 5 (28%) directly transplanted from the RICU and 55% (N = 15) were added to the emergency-driven list. Overall survival rates for ICU-eligible patients were 89% at one month, 77% at six months, and 72% at one year, while non-ICU eligible had lower survival probabilities of 31%, 13%, and 13%, respectively.

CONCLUSIONS: The RICU should be considered a bridge therapy for patients who are ICU candidates and eligible for lung transplant during ILD exacerbations, potentially reducing ICU admissions. However, patients who are not ICU candidates face high short- and medium-term mortality risks. The significance of this study highlights the need to establish a specific RICU admission protocol for patients experiencing ILD exacerbations.

PMID:40475088 | PMC:PMC12139016 | DOI:10.1016/j.opresp.2025.100432

Front Pharmacol. 2025 May 22;16:1534989. doi: 10.3389/fphar.2025.1534989. eCollection 2025.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic lung disease with high mortality. Current therapies are very limited, with nintedanib and pirfenidone being the only non-invasive but non-curative interventions, ultimately bridging to lung transplantation.

METHODS: In silico modeling of dysregulated pathways in IPF and screening for putative interfering small molecules identified carvedilol as a promising anti-fibrotic agent. We validated drug-mediated effects on key features of fibroblast activation in functional assays and gene expression analyses in human embryonic lung fibroblasts (MRC-5). Precision-cut lung slices (PCLSs) generated from human lung tissue were assessed for secreted fibrotic markers' expression.

RESULTS: Treatment with carvedilol reduced metabolic activity, inhibited cell proliferation, and led to decreased migratory activity, as observed in scratch wound assays, in human lung fibroblasts. The functional profile was reflected at the transcriptional level as commonly known fibrotic marker genes, e.g., alpha smooth muscle actin and collagen 1, were robustly repressed. Proteomic profiling underlined a strong extracellular matrix interference with elevated syntheses of several collagen types and various integrins, which play a critical role in pro-fibrotic downstream signaling. Comparison of healthy and fibrotic lung tissue validated an upregulation of pro-fibrotic miR-21 secretion in the ex vivo PCLS model, which remained unchanged upon carvedilol therapy.

CONCLUSION: Herein, carvedilol demonstrated significant anti-fibrotic effects on human lung fibroblasts in vitro, thus presenting great potential as an anti-IPF treatment. In addition, miR-21 was validated as a secreted pro-fibrotic biomarker in the ex vivo PCLS model.

PMID:40474967 | PMC:PMC12137325 | DOI:10.3389/fphar.2025.1534989

Eur Respir J. 2025 Jun 5:2401667. doi: 10.1183/13993003.01667-2024. Online ahead of print.

ABSTRACT

The formation of myofibroblast foci constitutes a hallmark pathological feature of idiopathic pulmonary fibrosis (IPF), yet the mechanism remains elusive. RNA binding motif single-stranded interacting protein 1 (RBMS1), is known to be essential for proliferation and cell cycle progression; however, its role in pulmonary fibrosis remains to be clarified.This study aimed to systematically elucidate the role and underlying mechanism of RBMS1 in pulmonary fibrosis utilising mouse primary lung fibroblasts (mPLFs), fibroblast-specific Rbms1 deletion and overexpression mice models, and lung samples from IPF patients.RBMS1 was highly expressed in both IPF patient lungs and murine bleomycin (BLM)-induced fibrotic lesions. Notably, elevated RBMS1 expression was observed in the cytoplasm of mPLFs following TGF-β1 stimulation. Rbms1 promoted lung fibroblast activation, while knockdown of Rbms1 mitigated TGF-β1-induced fibrogenesis. In vivo, overexpression impaired lung function and exacerbated pulmonary fibrosis, whereas fibroblast-specific Rbms1 deletion exhibited a significant reduction in fibrosis post-BLM treatment. Mechanistically, Rbms1 binds to Sumo2 3'UTR, enhancing the mRNA stability. Furthermore, Rbms1 induced the SUMOylation of Smad4, with lysine 158 identified as a critical SUMOylation site. Meanwhile, Sumo2 knockdown alleviated the Rbms1-driven exacerbation of pulmonary fibrosis. Importantly, the nortriptyline pharmacologically inhibited RBMS1 to ameliorate pulmonary fibrosis in mice.Collectively, our study sheds light on the regulatory role of RBMS1 in pulmonary fibrosis, highlighting its therapeutic potential for targeted antifibrotic strategies.

PMID:40473311 | DOI:10.1183/13993003.01667-2024

Eur Respir J. 2025 Jun 5;65(6):2500036. doi: 10.1183/13993003.00036-2025. Print 2025 Jun.

NO ABSTRACT

PMID:40473306 | DOI:10.1183/13993003.00036-2025

Eur Respir J. 2025 Jun 5;65(6):2500938. doi: 10.1183/13993003.00938-2025. Print 2025 Jun.

NO ABSTRACT

PMID:40473296 | DOI:10.1183/13993003.00938-2025

Naunyn Schmiedebergs Arch Pharmacol. 2025 Jun 5. doi: 10.1007/s00210-025-04305-6. Online ahead of print.

ABSTRACT

Chronic respiratory diseases represent a growing global health challenge, marked by rising prevalence and mortality rates. Inflammatory lung conditions including asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome, and idiopathic pulmonary fibrosis are major contributors to this burden. These disorders are typically associated with persistent inflammation in the airways or lung tissue, resulting in obstructive or restrictive patterns of respiratory dysfunction. Many of these diseases involve both acute exacerbations and chronic progression, making diagnosis and management particularly complex. Conventional treatments often rely on systemic drug administration, which can be limited by suboptimal therapeutic efficacy and undesirable effects on non-target organs. In contrast, inhalation-based drug delivery offers a more direct and efficient route to the lungs, enabling localized drug action, reduced systemic toxicity, and faster therapeutic onset. Among the various inhalation approaches, dry powder inhalers (DPIs) have gained increasing attention for their user-friendly design, dose consistency, and breath-actuated delivery mechanisms. This review explores recent advances in pulmonary drug delivery, with a particular focus on the design, development, and clinical potential of DPIs. By enhancing site-specific drug delivery and supporting the move toward personalized respiratory therapies, DPIs are poised to play a pivotal role in the future of respiratory disease management.

PMID:40471243 | DOI:10.1007/s00210-025-04305-6

SA J Radiol. 2025 May 9;29(1):3098. doi: 10.4102/sajr.v29i1.3098. eCollection 2025.

ABSTRACT

BACKGROUND: Evaluation of diffuse interstitial lung disease (ILD) in thoracic imaging is complicated. Radiologists often use a pattern approach to interpretation; however, they are rarely aware of the statistical frequency of disease presentation.

OBJECTIVES: To evaluate the relative frequency of causes of fibrotic ILD as a function of imaging patterns.

METHOD: A CT database of 396 cases of fibrotic ILD was amassed from an institutional diffuse lung disease registry and retrospective search of medical records. Three radiologists and one pulmonologist independently and blindly reviewed the CT scans for the distribution of fibrosis, predominant feature and non-pulmonary findings.

RESULTS: Peripheral fibrosis was most common (291/396, 73.5%), usually caused by idiopathic pulmonary fibrosis (IPF) and connective tissue diseases-related interstitial lung disease (CTD-ILD) but occasionally by hypersensitivity pneumonitis (HP), idiopathic nonspecific interstitial pneumonia (iNSIP) and asbestosis. Peripheral fibrosis with honeycombing was usually IPF and without honeycombing, was usually CTD-ILD. Peripheral fibrosis with pleural plaques was always asbestosis. Peripheral fibrosis with oesophageal dilatation was usually connective tissue diseases. Consolidative-like peripheral fibrosis was CTD-ILD. Axial fibrosis (61/396, 15.4%) was usually sarcoidosis, HP, CTD-ILD or silicosis. Axial fibrosis with predominantly consolidative-like fibrosis, honeycombing, or reticulation was usually sarcoidosis. Axial fibrosis predominated by ground glass opacity was usually HP or CTD-ILD. Lymph node calcification or short axis > 17 mm increased the probability that axial fibrosis was due to sarcoidosis. The non-specific fibrosis phenotype was uncommon (44/396, 11.1%), usually CTD-ILD (25/44, 57%) but also HP, IPF, iNSIP or asbestosis.

CONCLUSION: Patterns of lung fibrosis provide guidelines to identify the cause.

CONTRIBUTION: A flow diagram that predicts the relative frequency of the causes of 10 patterns of ILD.

PMID:40470268 | PMC:PMC12135718 | DOI:10.4102/sajr.v29i1.3098

Front Med (Lausanne). 2025 May 21;12:1567232. doi: 10.3389/fmed.2025.1567232. eCollection 2025.

ABSTRACT

INTRODUCTION: Our retrospective study aimed to evaluate the impact of idiopathic pulmonary fibrosis (IPF) on the clinical outcomes of COVID-19 admissions using data from the 2020 nationwide inpatient sample (NIS).

METHODS: We performed multivariate adjustment for baseline comorbidities and demographics after univariate screening.

RESULTS: Among the 1,018,915 adults hospitalized with COVID-19 in 2020, 910 were also diagnosed with IPF. Patients admitted with both COVID-19 and IPF had a higher risk of mortality compared to those without IPF [adjusted OR 1.87 (95% CI 1.13-2.70), p < 0.01]. Additionally, patients with both conditions had higher odds of requiring mechanical ventilation [adjusted OR 1.66 (95 % CI 1.13-2.42) p = 0.01] and needing mechanical ventilation within the first 24 h of admission [adjusted OR 1.87 (95% CI 1.013-3.39) p = 0.04]. IPF patients incurred higher mean total hospitalization charges [$140,790 vs. $79,045, adjusted difference + $60,577 (SD ± 52,460)] and had a longer mean length of stay [11.2 vs. 7.5 days, adjusted difference 3.3 days longer (SD ± 2.0)] compared to the non-IPF cohort (p = 0.02).

DISCUSSION: Our findings suggest that IPF significantly worsens the clinical outcomes of COVID-19 hospitalizations, leading to increased healthcare utilization and costs. Further studies are needed to study this subpopulation during the postvaccination era to understand the effects on patient outcomes and to explore potential targeted interventions for improving prognosis in patients with both COVID-19 and IPF.

PMID:40470037 | PMC:PMC12133541 | DOI:10.3389/fmed.2025.1567232

Genet Res (Camb). 2025 May 28;2025:7575005. doi: 10.1155/genr/7575005. eCollection 2025.

ABSTRACT

Background: This study aims to investigate the causal relationships between 12 micronutrients and common chronic respiratory diseases, revealing whether these nutrients play a causative role in either preventing or exacerbating these conditions. Methods: We employed a bidirectional two-sample Mendelian randomization (MR) approach to explore the causal relationships between micronutrients and chronic respiratory diseases. Data were sourced from the IEU GWAS database, with micronutrients serving as exposure variables and chronic respiratory diseases as outcome variables for causal assessment. This was followed by reverse MR analysis, where the steps were reversed. Analytical methods included inverse-variance weighting (IVW), MR-Egger regression, and the weighted median method to correct for potential pleiotropy and reverse causality. Cochran's Q test and the MR-PRESSO method were used for pleiotropy tests to ensure robustness and reliability of the results. Results: The MR analysis revealed that the genetically predicted calcium is a protective factor for asthma (OR = 0.99, 95% CI 0.984-0.995, p < 0.01), vitamin B12 is a risk factor for asthma (OR = 1.015, 95% CI 1.005-1.024, p < 0.01), and vitamin E is a protective factor for idiopathic pulmonary fibrosis (IPF) (OR = 0.952, 95% CI 0.916-0.989, p=0.012). In the reverse MR analysis, asthma showed a potential causal relationship with calcium levels (OR = 0.829, 95% CI 0.704-0.976, p=0.025), while pneumoconiosis showed a potential risk causal relationship with calcium levels (OR = 1.003, 95% CI 1.002-1.004, p < 0.010). Additionally, pneumoconiosis was found to have a potential protective causal relationship with vitamin E levels (OR = 0.999, 95% CI 0.999-1.000, p=0.034), and sarcoidosis was found to have a potential protective causal relationship with vitamin B12 levels (OR = 0.989, 95% CI 0.979-1.000, p=0.044). Conclusion: This study shows significant causal associations among calcium, vitamin B12, and vitamin E with chronic respiratory diseases. There is a bidirectional protective causal relationship between calcium and asthma, suggesting that increasing calcium intake may reduce the risk of asthma. However, the causal relationships among other vitamins, minerals, and chronic respiratory diseases remain inconclusive, necessitating further research to validate these findings' robustness and generalizability.

PMID:40469921 | PMC:PMC12136874 | DOI:10.1155/genr/7575005

Cytojournal. 2025 Apr 1;22:37. doi: 10.25259/Cytojournal_223_2024. eCollection 2025.

ABSTRACT

OBJECTIVE: Idiopathic pulmonary fibrosis (PF) is a chronic and life-threatening lung disease. This study aimed to investigate the role of zinc finger and BTB domain containing 16 (Zbtb16), a transcription factor, in the progression of PF by analyzing its expression and regulatory effects in mouse and cell models.

MATERIAL AND METHODS: The gene expression profiles in bleomycin-induced (BL-I) PF lung tissues of mice were analyzed using the gene expression omnibus database. The mouse model of BL-I PF and cell model of transforming growth factor-β1 (TGF-β1)-induced mice lung epithelial cell (LEC) fibrosis was constructed. Zbtb16 expression was evaluated by reverse transcription quantitative polymerase chain reaction, Western blot, or immunohistochemistry. Tissue sections were assessed by hematoxylin and eosin, Masson, and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. The levels of protein, inflammation factors, and albumin were measured through Western blot or enzyme-linked immunosorbent assay.

RESULTS: Bioinformatics analysis found that Zbtb16 was the highest differentially expressed marker in BL-I PF mice. Zbtb16 was highly expressed in the mice and cell model. Zbtb16 silencing could reduce lung tissues' collagen deposition, pulmonary edema, and pulmonary apoptotic cells; improve vascular permeability; and decrease fibrosis markers and inflammation factors expressed in model mice. Zbtb16 silencing could reduce fibrosis markers and inflammation factor levels in the cell model (P < 0.05). Kyoto encyclopedia of genes and genomes and gene set enrichment analyses suggested that Zbtb16 might regulate BL-I PF in mice through the phosphoinositide 3-kinases (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway (PAmT-P). Co-immunoprecipitation showed the combination of AKT and Zbtb16. PAmT-P in the mice model and cell model was visibly activated (P < 0.05), and Zbtb16 silencing could inhibit it (P < 0.05). Moreover, the rescue experiments showed that the AKT activator SC79 could reverse the effect of TGF-β1 + small interfere RNA-Zbtb16 on LECs.

CONCLUSION: This study identified Zbtb16 as a key regulator of PF progression, mediating its effects through the PAmT-P. Zbtb16 silencing alleviated fibrosis and inflammation in vivo and in vitro, providing a promising target for therapeutic intervention in PF.

PMID:40469708 | PMC:PMC12134818 | DOI:10.25259/Cytojournal_223_2024

Front Immunol. 2025 May 21;16:1567994. doi: 10.3389/fimmu.2025.1567994. eCollection 2025.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by progressive scarring, alveolar destruction, and limited therapeutic options. Although the exact etiology of IPF remains unclear, emerging evidence suggests that ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation and oxidative stress, plays a significant role in its pathogenesis. Ferroptotic stress not only compromises alveolar epithelial cell integrity, but also triggers inflammatory responses and profibrotic signaling cascades that activate and sustain fibroblast dysfunction. This review delineates the core regulatory pathways of ferroptosis, iron metabolism, lipid peroxidation, antioxidant defenses, mitochondrial remodeling, and RNA editing, with an emphasis on their relevance in IPF. We explore how epithelial injury and macrophage-derived signals initiate ferroptosis, and how fibroblast subsets, shaped by scRNA-seq-defined heterogeneity and plasticity, respond to these cues by reinforcing ECM deposition and oxidative stress. Therapeutic avenues targeting ferroptosis, including antioxidant supplementation, iron chelation, and modulation of lipid metabolism, are discussed alongside cell-specific interventions and nanodelivery strategies. By integrating recent advances in molecular profiling and ferroptosis biology, this review provides a framework for leveraging ferroptosis as a tractable target in IPF and identifies novel directions for precision antifibrotic therapy.

PMID:40469306 | PMC:PMC12133551 | DOI:10.3389/fimmu.2025.1567994

Int Immunopharmacol. 2025 Jun 3;161:114962. doi: 10.1016/j.intimp.2025.114962. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a rare, chronic, and progressive interstitial lung disease characterized by an unclear etiology and pathogenesis. Current anti-fibrotic therapies frequently fall short in effectively halting disease progression. A critical aspect of IPF involves the role of macrophages, which exhibit distinct polarized phenotypes that significantly influence the initiation and progression of fibrosis within the lung immune microenvironment. Recent evidence highlights the importance of the JAK-STAT signaling pathway in regulating macrophage polarization, suggesting that its inhibition may offer a promising therapeutic strategy for IPF. In this study, Ruxolitinib, a JAK1/2 inhibitor that is approved for the treatment of myelofibrosis, was investigated for its effects on pulmonary fibrosis for the first time. The in vivo studies were conducted utilizing a bleomycin-induced pulmonary fibrosis model, and in vitro experiments were induced pro-inflammatory and pro-fibrotic macrophage polarization using LPS/IFN-γ and IL-4/13, respectively. Notably, our findings reveal that Ruxolitinib diminishes pro-inflammatory polarization, thereby promoting a more favorable pulmonary inflammatory microenvironment. Furthermore, Ruxolitinib inhibits fibrotic macrophage polarization, effectively curtailing myofibroblast activation and displaying clear anti-fibrotic effects. The underlying regulatory mechanism of Ruxolitinib is through inhibition of JAK1/2-mediated STAT signaling, which interrupts the pathways leading to the polarization of fibrotic macrophages and the activation of pro-inflammatory macrophages. Collectively, these results underline the potential of Ruxolitinib as a therapeutic option for IPF treatment, representing a pivotal advance in addressing a disease that has previously evaded effective pharmacological intervention.

PMID:40466612 | DOI:10.1016/j.intimp.2025.114962

J Cell Mol Med. 2025 Jun;29(11):e70639. doi: 10.1111/jcmm.70639.

ABSTRACT

A cellular characteristic of IPF is the transformation of fibrosis into myofibroblasts. This study identifies several transcription factors-STAT3, FOXP1, JUNB, ATF3, FosL2, BATF, Fra2 and AP-1-that play crucial roles in promoting pulmonary fibrogenesis. They achieve this by facilitating the differentiation of fibroblasts into myofibroblasts, as analysed through ATAC-seq and RNA-seq. Additionally, STAT3 ChIP-seq showed that STAT3 is significantly concentrated in accessible chromatin regions, including introns and intergenic areas. H3K27ac ChIP-seq and Co-IP demonstrated that STAT3 plays a role in the formation of super enhancer (SE), which promotes gene expression. CUT&RUN-qPCR and the pGL3-SE dual-luciferase reporter system assays proved that STAT3 enhanced pGL3-SE activities by facilitating H3K27ac modification, leading to promoting the transcription of target genes including RUNX1, JUNB, JUN, SMAD6, COL3A1 and PTPN1. In summary, this study shows that STAT3 contributes to the formation of SEs that accelerate the differentiation of fibroblasts into myofibroblasts, leading to IPF. This insight enhances our understanding of STAT3-related SEs and offers potential therapeutic strategies for fibrotic diseases.

PMID:40464702 | DOI:10.1111/jcmm.70639

Pulm Circ. 2025 Jun 3;15(2):e70102. doi: 10.1002/pul2.70102. eCollection 2025 Apr.

ABSTRACT

Lung vasculature arises from both pulmonary and systemic (bronchial) circulations. Remodeling and structural changes in lung vasculature have been recognized in end-stage fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF) but have not been well characterized. The vasculature that expands and supplies lung cancers is better described, with the recent recognition that systemic bronchial circulation expands to be the main blood supply to primary lung tumors. Here, we use publicly available single-cell RNA-sequencing (scRNA-seq) data to compare vascular endothelial cell (EC) populations in multiple progressive interstitial lung diseases (ILD) and non-small cell lung cancer (NSCLC) to identify common and distinct features. Lung tissue specimens were collected from healthy lung tissue (n = 59), ILD (n = 97), chronic obstructive pulmonary disease (n = 22), and NSCLC (n = 8). We identify two subtypes of expanded EC populations in both ILD and NSCLC, "Bronch-1" and "Bronch-2", expressing transcripts associated with venules and angiogenic tip/stalk cells, respectively. Relative to pulmonary capillary and arterial ECs, bronchial ECs show low expression of transcripts associated with vascular barrier integrity. The pan-bronchial EC marker COL15A1 showed positive staining in lung parenchyma from patients with IPF, SSc-ILD, and NSCLC, whereas positive staining was limited to subpleural and peri-bronchial regions in non-fibrotic controls. In conclusion, expansion of a subset of ECs expressing markers of the bronchial circulation is one of the most pronounced changes in vascular cell composition across multiple ILDs and NSCLC. These data support additional studies to determine the role of the bronchial vasculature in ILD progression.

PMID:40463493 | PMC:PMC12130637 | DOI:10.1002/pul2.70102

bioRxiv [Preprint]. 2025 May 14:2025.05.08.652970. doi: 10.1101/2025.05.08.652970.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease with limited therapeutic options. The development of effective therapies has been hindered by the lack of models that recapitulate key features of human disease. Here we report a bleomycin-induced ferret PF model characterized by an irreversible decrease in pulmonary compliance and an increase of opacification, accompanied by "honeycomb cyst-like" structures and "proximalization" of distal lung epithelium. Cellular and molecular analysis by single-nucleus RNA sequencing revealed a significant shift in distal lung epithelium towards proximal epithelial phenotype. Importantly, a histopathological pattern of bronchiolization encompassing divergent atypical epithelial cells and KRT17 + /TP63 + /KRT5 low "basaloid-like" cells was present in the distal fibrotic lung lesions. Trajectory analysis revealed AT2 cells transition through multiple cell-states in bleomycin injured ferret lungs, particularly AT2 to KRT8 high /KRT7 low /SOX4 + and eventually to KRT8 high /KRT7 high /SFN + /TP63 + /KRT5 low "basaloid-like" cells. Further, immunofluorescence analyses demonstrated KRT7 and KRT8 populations reside overlaying the ACTA2-positive myofibroblasts in fibrotic foci, implying their pro-fibrogenic activity similar to human IPF lungs. Collectively, our results provide evidence that bleomycin-induced lung injury in ferrets recapitulates pathophysiological, cellular, and molecular features of human IPF, suggesting that they may be a reliable model for understanding mechanisms of IPF pathogenesis and for testing therapeutic strategies for treatment of IPF.

TAKE HOME MESSAGE: Bleomycin-induced acute lung injury in the ferret recapitulates pathophysiological, cellular, and molecular features of human IPF; thus the ferret may be a reliable species for studying mechanisms of IPF pathogenesis and testing therapeutic strategies.

PMID:40462941 | PMC:PMC12132224 | DOI:10.1101/2025.05.08.652970

World J Pediatr. 2025 Jun 3. doi: 10.1007/s12519-025-00916-4. Online ahead of print.

ABSTRACT

BACKGROUND: Pediatric lung transplant (pLTX) is a rare procedure globally; its characteristics and survival outcomes in China remain unknown.

METHODS: This retrospective study analyzed data from pLTX recipients aged ≤ 17 years between January 2019 and December 2023 from the China Lung Transplantation Registry. Pre-, intra-, and post-operative characteristics were described and compared between children aged 2-11 years and 12-17 years and between pLTX conducted in centers with high and low transplant volumes. The Kaplan‒Meier method was used to estimate the postoperative survival rates and 95% confidence intervals (CIs). One-year postoperative survival rates were compared between pediatric and adult lung transplant (LTX) patients via log-rank tests.

RESULTS: Between 2019 and 2023, 63 transplants were performed in 62 pediatric patients, accounting for 1.8% of the total LTX in China. The primary indication for pLTX was bronchiolitis obliterans syndrome (46.0%), followed by cystic fibrosis (12.7%) and idiopathic pulmonary arterial hypertension (11.1%). Infection was the most common complication after pLTX (63.9%), and the incidence of bronchial anastomotic stenosis was slightly higher among recipients aged 2-11 years than among those aged 12-17 years (14.3% vs. 2.9%, P = 0.244). High-volume hospitals had a higher incidence of infections (72.7% vs. 41.2%, P = 0.021) and primary graft failure (20.0% vs. 5.9%, P = 0.260) among pediatric recipients. However, acute rejection was exclusively observed in low-volume hospitals (0.0% vs. 17.6%, P = 0.018). The in-hospital mortality rate was 16.1% (95% CI = 6.7-25.5). The 30-day and one-year survival rates after pLTX were 93.5% (95% CI = 87.6-99.9) and 80.6% (95% CI = 71.4-91.1), respectively, and were significantly higher than those of adult recipients (82.0% and 58.7%, all P < 0.05).

CONCLUSIONS: This research identified the trends, indications, donor and recipient characteristics, and complications of pLTX in China. Despite its small size, pLTX is growing gradually and has favorable outcomes. Future research on the long-term follow-up of pLTX recipients is needed to identify factors associated with the prognosis of pLTX patients.

PMID:40461919 | DOI:10.1007/s12519-025-00916-4

Nat Med. 2025 Jun 3. doi: 10.1038/s41591-025-03743-2. Online ahead of print.

ABSTRACT

Despite substantial progress in artificial intelligence (AI) for generative chemistry, few novel AI-discovered or AI-designed drugs have reached human clinical trials. Here we present the results of the first phase 2a multicenter, double-blind, randomized, placebo-controlled trial testing the safety and efficacy of rentosertib (formerly ISM001-055), a first-in-class AI-generated small-molecule inhibitor of TNIK, a first-in-class target in idiopathic pulmonary fibrosis (IPF) discovered using generative AI. IPF is an age-related progressive lung condition with no current therapies available that reverse the degenerative course of disease. Patients were randomized to 12 weeks of treatment with 30 mg rentosertib once daily (QD, n = 18), 30 mg rentosertib twice daily (BID, n = 18), 60 mg rentosertib QD (n = 18) or placebo (n = 17). The primary endpoint was the percentage of patients who have at least one treatment-emergent adverse event, which was similar across all treatment arms (72.2% in patients receiving 30 mg rentosertib QD (n = 13/18), 83.3% for 30 mg rentosertib BID (n = 15/18), 83.3% for 60 mg rentosertib QD (n = 15/18) and 70.6% for placebo (n = 12/17)). Treatment-related serious adverse event rates were low and comparable across treatment groups, with the most common events leading to treatment discontinuation related to liver toxicity or diarrhea. Secondary endpoints included pharmacokinetic dynamics (Cmax, Ctrough, tmax, AUC0-t/τ/∞ and t1/2), changes in lung function as measured by forced vital capacity, diffusion capacity of the lung for carbon monoxide, forced expiry in 1 s and change in the Leicester Cough Questionnaire score, change in 6-min walk distance and the number and hospitalization duration of acute exacerbations of IPF. We observed increased forced vital capacity at the highest dosage with a mean change of +98.4 ml (95% confidence interval 10.9 to 185.9) for patients in the 60 mg rentosertib QD group, compared with -20.3 ml (95% confidence interval -116.1 to 75.6) for the placebo group. These results suggest that targeting TNIK with rentosertib is safe and well tolerated and warrants further investigation in larger-scale clinical trials of longer duration. ClinicalTrials.gov registration number: NCT05938920 .

PMID:40461817 | DOI:10.1038/s41591-025-03743-2

Sci Rep. 2025 Jun 3;15(1):19415. doi: 10.1038/s41598-025-04259-y.

ABSTRACT

The pathological classification of nonspecific interstitial pneumonia (NSIP) with organizing pneumonia (OP) overlap (NSIP/OP overlap) remains complex due to overlapping pathological features, and its heterogeneity is not well understood. We retrospectively analysed adult patients with interstitial lung disease (ILD) diagnosed with NSIP/OP overlap via surgical lung biopsy. Patients were pathologically subclustered using an unbiased clustering method, and clinical, radiological, and prognostic differences were examined. Among 38 patients, two pathological clusters were identified: Cluster 1, characterized by fibrotic changes with mild inflammation, and Cluster 2, exhibiting intense inflammation with fibrosis. While both clusters initially responded well to treatment, Cluster 2 demonstrated progressive ILD deterioration and a higher frequency of pulmonary fibrosis. Cluster 2 was also associated with hypoxia, reduced pulmonary function, elevated erythrocyte sedimentation rate, and greater consolidation on chest computed tomography. Based on these findings, we have identified NSIP/OP overlap is a heterogeneous and progressive disease and pathological findings at diagnosis significantly influence both initial ILD severity and long-term prognosis. Our findings highlight the need for tailored long-term management strategies based on early histopathological evaluation.

PMID:40461660 | DOI:10.1038/s41598-025-04259-y