Am J Physiol Cell Physiol. 2025 May 24. doi: 10.1152/ajpcell.00022.2025. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal aging-related disease characterized by aberrant lung remodeling and progressive scarring, leading to organ failure and death. Current FDA approved anti-fibrotic treatments are unable to reverse established disease, highlighting the need for innovative therapeutic approaches targeting novel pathways and cell types. Mounting evidence, including our own, has recently highlighted the pathogenic role of aging-related endothelial abnormalities, including vascular inflammation and oxidative stress, in the progression of lung fibrosis, offering new therapeutic opportunities to block IPF progression. Unexplored, however, are the modalities to restore vascular abnormalities associated with progressive lung fibrosis, representing a critical gap to effective treatments for IPF. In this study, we demonstrate that circulating extracellular vesicles (cEVs) isolated from young mice are capable of reversing the aging-associated transcriptional alterations of the pulmonary vasculature, reducing transcripts associated with innate immunity, oxidative stress and senescence, while simultaneously increasing transcripts linked to endothelial identity. Using the bleomycin model of persistent lung fibrosis in aged mice, we then demonstrate that the pre-treatment with cEVs improves the vascular response to injury and attenuates lung fibrosis progression, as demonstrated by reduced lung collagen content and preserved vascular network and lung architecture. These findings support the efficacy of interventions targeting endothelial aging-associated transcriptional alterations, such as young cEV delivery, in mitigating pulmonary fibrosis progression in animal models of persistent fibrosis and indicate the potential benefits of combined therapies that simultaneously address vascular and non-vascular aspects of IPF.

PMID:40411768 | DOI:10.1152/ajpcell.00022.2025

BMC Pulm Med. 2025 May 23;25(1):259. doi: 10.1186/s12890-025-03719-5.

ABSTRACT

BACKGROUND: Cryptogenic organizing pneumonia (COP), a rare interstitial lung disease, can mimic community-acquired pneumonia (CAP), often leading to delayed diagnosis. This case highlights the importance of recognizing COP in elderly patients and brings attention to pulmonary embolism (PE) as a potential but underrecognized complication associated with glucocorticosteroid therapy, providing novel insights into hypercoagulability risks during treatment.

CASE PRESENTATION: An 80-year-old woman from Xinjiang presented with a 4-week history of cough, dyspnea, and weight loss that was unresponsive to antibiotics. Chest Computed tomography (CT) revealed bilateral subpleural consolidations with air bronchograms. Bronchoscopy ruled out infection, and a multidisciplinary evaluation confirmed COP based on clinical, radiological, and pathological correlation. Oral prednisone at 0.75 mg/kg/day led to symptom resolution within 14 days. However, during steroid tapering (10% weekly reduction), she developed hypoxemia at 3 months. CT angiography revealed segmental PE, despite the absence of conventional thrombosis risk factors. Treatment with anticoagulation and continued glucocorticoid therapy resulted in full recovery after 6 months.

CONCLUSIONS: Clinicians should consider COP in elderly patients with pneumonia unresponsive to antibiotics, confirm the diagnosis through biopsy, and remain vigilant for hypercoagulable states during glucocorticoid tapering. Anticoagulation should be tailored even in the absence of traditional thrombosis risk factors. The temporal association between steroid tapering and PE suggests that glucocorticoids may modulate endothelial function and coagulation pathways, highlighting the need for mechanistic studies to inform thromboembolic surveillance in COP management.

PMID:40410735 | DOI:10.1186/s12890-025-03719-5

Brain Res Bull. 2025 May 21:111402. doi: 10.1016/j.brainresbull.2025.111402. Online ahead of print.

ABSTRACT

BACKGROUND: The mechanistic relationship between respiratory disorders and brain function remains poorly understood, despite growing evidence of cognitive and neurological manifestations in respiratory diseases. We aim to identify whether specific brain network connectivity patterns causally influence respiratory disease susceptibility, while respiratory conditions might reciprocally affect brain network architecture.

METHODS: We performed bidirectional Mendelian randomization analyses using genome-wide association studies (GWAS) of brain network connectivity from UK Biobank resting-state functional MRI data (N=31,453) and GWAS data from ten major respiratory conditions: chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), sleep apnea syndrome (SAS), lung squamous carcinoma (LUSC), lung adenocarcinoma (LUAD), small cell lung carcinoma (SCLC), hospitalized COVID-19, very severe COVID-19, and bronchiectasis. Five MR methods, inverse variance weighted (IVW) with multiplicative random-effect model, weighted median, weighted mode, MR Egger, and MR-robust adjusted profile score (MR-RAPS) were employed to ensure causal inference.

RESULTS: In forward analysis, five respiratory disorders - asthma, IPF, SAS, LUSC, and very severe COVID-19 - showed significant causal associations (p<1.31×10-4) with 11 rs-fMRI phenotypes, spanning multiple brain networks including the central executive, subcortical-cerebellum, motor, limbic, attention, salience, visual, and default mode networks. In reverse analysis, twelve brain functional networks demonstrated genetic associations with eight respiratory conditions (COPD, asthma, IPF, SAS, LUSC, SCLC, hospitalized COVID-19, and very severe COVID-19), predominantly involving attention, salience, default mode, visual, and central executive networks.

CONCLUSIONS: Our study provides preliminary genetic evidence suggesting potential causal relationships between brain network connectivity and respiratory disorders, contributing to our understanding of the lung-brain axis. While the identification of disease-specific network alterations offers promising insights, further clinical validation is needed before these findings can be translated into therapeutic interventions.

PMID:40409599 | DOI:10.1016/j.brainresbull.2025.111402

Cell Rep Med. 2025 May 14:102144. doi: 10.1016/j.xcrm.2025.102144. Online ahead of print.

ABSTRACT

Efficient gene delivery vectors are crucial for respiratory and lung disease therapies. We report that AAV.CPP.16, an engineered adeno-associated virus (AAV) variant derived from AAV9, efficiently transduces airway and lung cells in mice and non-human primates via intranasal administration. AAV.CPP.16 outperforms AAV6 and AAV9, two wild-type AAVs with demonstrated tropism for respiratory tissues, and efficiently targets key respiratory cell types. It supports gene supplementation and editing therapies in two clinically relevant mouse models of respiratory and lung diseases. A single intranasal dose of AAV.CPP.16 expressing a dual-target, vascular endothelial growth factor (VEGF)/transforming growth factor (TGF)-β1-neutralizing protein protected lungs from idiopathic pulmonary fibrosis, while a similar application of AAV.CPP.16 carrying an "all-in-one" CRISPR-Cas13d system inhibited transcription of the SARS-CoV-2-derived RNA-dependent RNA polymerase (Rdrp) gene. Our findings highlight AAV.CPP.16 as a promising vector for respiratory and lung gene therapy.

PMID:40409263 | DOI:10.1016/j.xcrm.2025.102144

Eur J Med Chem. 2025 May 16;294:117768. doi: 10.1016/j.ejmech.2025.117768. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with high mortality and limited treatment options. Targeting multiple kinase-driven pathological processes offers a promising strategy. Using epithelial-mesenchymal transition (EMT) phenotypic screening, we optimized a series of o-aminopyridinyl alkynyl compounds derived from CSF-1R relatively selective inhibitor, compound 1, through a structure-activity relationship (SAR) study, integrating liver and kidney cytotoxicity evaluations. Compound 22, emerged as the potent antifibrotic candidate, exhibiting low cytotoxic effects against human kidney (HEK293) and hepatocyte (L02) cell lines, and minimal hERG inhibition. In addition, 22 showed significant inhibition against other IPF-related processes, including fibroblast-to-myofibroblast transition (FMT)-driven fibrosis in both human fetal lung fibroblasts cell line (HFL1) and primary human lung fibroblasts (HLFs), as well as pro-fibrotic M2 polarization. In vivo, compound 22 exhibited the acceptable PK properties and low toxicity profiles. In addition, oral administration of 22 demonstrated superior anti-fibrotic efficacy compared to Nintedanib, significantly attenuating bleomycin-induced lung fibrosis, reducing inflammation and pro-fibrotic M2-associated cytokine levels, and improving lung function. Preliminary kinase profiling indicates that compound 22 likely targets CSF-1R, PDGFR-α and Src family kinases to inhibit IPF progression, while sparing VEGFRs, FGFRs and Abl to minimize off-target toxicity commonly associated with multi-kinase inhibitor treatment. These findings highlight the advantages and therapeutic potential of a multi-kinase targeting strategy, enabling selective inhibition key IPF-associated kinases to develop more effective and safer anti-IPF agents.

PMID:40409055 | DOI:10.1016/j.ejmech.2025.117768

Br J Hosp Med (Lond). 2025 May 23;86(5):1-6. doi: 10.12968/hmed.2024.0679. Epub 2025 May 8.

ABSTRACT

Aims/Background Antifibrotic medication aims to slow disease progression for those with pulmonary fibrosis and is expensive with a known side effect profile. We have reviewed antifibrotic adherence in a real-world patient cohort. Methods We selected a random sample of 30 patients prescribed nintedanib for idiopathic pulmonary fibrosis, conducted telephone interviews collecting demographic data and evaluated adherence using the Medication Adherence Report Scale (MARS-5) and the Adherence Starts with Knowledge (ASK-20) survey. Results 21 (70%) of patients were male and 9 (30%) were female, the median age was 73.8 years. 13 (43%) had no qualifications, 6 (20%) had GCSE/O levels or equivalent, 6 (20%) had AS/A levels or equivalent and 5 (17%) had a higher degree. The median MARS-5 score was 23.5 (range 16-25) suggesting an extremely high level of adherence among this patient group. Conclusion This study offers insights into medication adherence in a patient group that has not been extensively reviewed before. In this single centre study, there is good adherence to antifibrotic medication. This is likely related to the extensive clinical support provided, which is responsive, accessible, and individualised. Participants specifically mentioned this support when questioned.

PMID:40405843 | DOI:10.12968/hmed.2024.0679

Physiol Rep. 2025 May;13(10):e70335. doi: 10.14814/phy2.70335.

ABSTRACT

Obstructive sleep apnoea (OSA) leading to chronic intermittent hypoxia (CIH) is a common comorbidity associated with idiopathic pulmonary fibrosis (IPF), a progressive fatal disease characterized by adverse lung remodeling and parenchymal stiffening. In the mouse model of lung fibrosis induced by intra-tracheal instillation (ITI) of bleomycin, we have previously shown that CIH exacerbates fibrosis, similar to pre-exposure to ITI. It has been suggested that correction of OSA and CIH with positive airway pressure may have a beneficial effect on the progression of fibrosis in IPF patients. Therefore, we designed this study to determine the benefits of stopping CIH in mice pre-exposed to CIH for 3 weeks prior to bleomycin ITI. Interruption of CIH exposure was associated with less diffuse lung fibrosis, reduced ratio of damaged area, alveolar destruction, collagen deposition, and fibrosis score. Interruption of CIH exposure significantly reduced macrophage density in fibrotic areas without significant changes in either lymphocyte or neutrophil density. In conclusion, this study demonstrates that early treatment of OSA-associated CIH can limit or reduce the development of severe forms of pulmonary fibrosis associated with a reduction in macrophage infiltrate and supports the beneficial effect of CIH exposure interruption on ongoing fibrosis severity.

PMID:40405523 | DOI:10.14814/phy2.70335

BMC Pulm Med. 2025 May 22;25(1):253. doi: 10.1186/s12890-025-03713-x.

ABSTRACT

BACKGROUND: Antifibrotics have been approved for use in many countries, including Japan, based on the results of several phase III clinical trials in patients with IPF, SSc-ILD, and PPF, which showed slower lung function decline with antifibrotic treatment. There is a paucity of information on the real-world use of antifibrotics in clinical practice.

METHODS: Baseline characteristics, comorbidities, and drugs used prior to and concomitant with antifibrotics were collected for patients with IPF, SSc-ILD, and PPF using a health insurance claims database in Japan from 1 January 2013 to 30 June 2023. Descriptive statistics were generated for all study variables.

RESULTS: This study included 657 nintedanib users with IPF; 418 pirfenidone users with IPF; 4160 nintedanib users with PPF; 18,403 users of glucocorticoids/immunosuppressants for ILD treatment with PPF; 676 nintedanib users with SSc-ILD; and 698 users of glucocorticoids/immunosuppressants for ILD treatment with SSc-ILD. At index, pirfenidone users with IPF were the oldest (mean [SD] 74.8 [7.3] years), and nintedanib users with SSc-ILD were the youngest (mean [SD] 65.6 [11.7] years). In nintedanib users with IPF, 76.7% were prescribed nintedanib as monotherapy, and 75.6% of pirfenidone users were prescribed pirfenidone, as monotherapy. In patients with IPF, 75.2% were prescribed nintedanib, and 76.1% were prescribed pirfenidone, as first-line therapy. In patients with SSc-ILD, 34.9% were prescribed nintedanib as monotherapy for ILD treatment, and 38.6% as first-line therapy. Approximately half of patients with PPF were prescribed nintedanib concomitantly with other glucocorticoids/immunosuppressant drugs, and after one or more glucocorticoids/immunosuppressant drugs. The most common concomitant drug in all patient groups was glucocorticoids. In patients with IPF, 18.6% of nintedanib users and 18.2% of pirfenidone users were prescribed glucocorticoids concomitantly. Concomitant glucocorticoid use was 52.7% for nintedanib users with SSc-ILD, and 44.1% for nintedanib users with PPF.

CONCLUSIONS: These results provide real-world evidence of antifibrotic use in clinical practice. Most patients with IPF were prescribed antifibrotics as monotherapy for ILD treatment whereas antifibrotics were used concomitantly with glucocorticoids/immunosuppressants in many patients with SSc-ILD and PPF. While most patients with IPF were prescribed antifibrotics as first-line therapy, patients with SSc-ILD and PPF were more likely to be prescribed nintedanib as second-line or later-line treatment after glucocorticoids/immunosuppressants.

PMID:40405141 | DOI:10.1186/s12890-025-03713-x

BMJ Open Respir Res. 2025 May 22;12(1):e002614. doi: 10.1136/bmjresp-2024-002614.

ABSTRACT

BACKGROUND: Advanced interstitial lung disease (ILD) often necessitates lung transplantation, and identifying accessible prognostic markers is essential for effective management. However, the link between serum tumour markers and survival in waitlisted lung transplant candidates with advanced ILD remains underexplored.

OBJECTIVE: To evaluate associations between serum tumour marker levels and long-term survival in lung transplant candidates with advanced ILD.

METHODS: This study included 282 patients with end-stage ILD who were waitlisted for lung transplantation from November 2012 to March 2021. Baseline data and serum tumour marker levels were assessed before listing. Vital status and transplant outcomes were retrospectively reviewed as of 31 May 2023. Associations between tumour markers, clinical variables and mortality were analysed using Cox proportional hazards models with competing risk regression.

RESULTS: During a median wait time of 17.8 months (IQR: 7.8-44.1), 107 patients received transplants, 38 survived on the list and 137 died while waiting. Multivariable analysis identified higher CA-125 levels (HR 1.03, 95% CI 1.01 to 1.06, p=0.001), older age (HR 1.03, 95% CI 1.01 to 1.06, p=0.001), female gender (HR 1.43, 95% CI 1.01 to 2.04, p<0.04), elevated C-reactive protein (HR 1.17, 95% CI 1.03 to 1.34, p=0.01) and cerebrovascular disease (HR 2.03, 95% CI 1.38 to 2.98, p=0.01) as significant predictors of mortality.

CONCLUSION: Among waitlisted lung transplant candidates with advanced ILD, elevated serum carbohydrate antigen (CA)-125 and CA19-9 levels are associated with higher mortality risk. Routine assessment of these markers may enhance risk stratification for this patient population.

PMID:40404187 | DOI:10.1136/bmjresp-2024-002614

BMJ Open Respir Res. 2025 May 22;12(1):e002566. doi: 10.1136/bmjresp-2024-002566.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease found primarily in older people, with the use of systemic steroids linked to poor outcomes. However, the role of inhaled corticosteroids (ICSs) in IPF remains unclear. This study investigated the association between ICS use and IPF risk using national insurance data, particularly in individuals with chronic airway diseases.

METHODS: Using the National Health Insurance Service-National Sample Cohort database, our study included patients diagnosed with chronic obstructive pulmonary disease or asthma. ICS exposure was assessed via treatment claims, and IPF cases were identified using broad and narrow criteria. We used inverse probability of treatment weighting (IPTW) with propensity scores for balanced covariate analysis.

RESULTS: Of 57 456 patients (mean age: 55.9 years, 42.3% men), 16.5% used ICS and 83.5% did not. ICS users showed higher rates of broad (0.98 vs 0.41 per 1000) and narrow IPF (0.61 vs 0.21 per 1000) than non-users. Pre-IPTW, ICS use was associated with increased IPF risk; however, this was not significant post-IPTW. Post-IPTW, both ICS dose as a continuous variable (broad adjusted HR per 100 µg/day: 1.03, 95% CI: 1.02 to 1.04; narrow adjusted HR per 100 µg/day: 1.03, 95% CI: 1.01 to 1.04 post-IPTW) and high-dose ICS (≥1000 µg/day) (broad adjusted HR: 3.89, 95% CI: 1.61 to 9.41; narrow adjusted HR: 3.99, 95% CI: 1.19 to 13.41) use correlated with an elevated IPF risk.

CONCLUSION: While no overall significant association between ICS use and IPF risk was observed post-IPTW, there may be an increased risk in patients using high-dose ICS.

PMID:40404186 | DOI:10.1136/bmjresp-2024-002566

BMJ Open Respir Res. 2025 May 22;12(1):e003038. doi: 10.1136/bmjresp-2024-003038.

ABSTRACT

INTRODUCTION: Proof-of-concept (POC) studies are vital in determining the feasibility of further drug development, primarily by assessing preliminary efficacy signals with credible endpoints. However, traditional POC studies in idiopathic pulmonary fibrosis (IPF) can suffer from low credibility due to small sample sizes and short durations, leading to non-replicable results in larger phase III trials. To address this, we are conducting a 24-week POC study with 120 patients with IPF, using a statistically supported sample size and incorporating exploratory CT-based imaging biomarkers, to support decision-making in the case of non-significant primary endpoint results. This approach aims to provide data to enable a robust decision-making process for advancing clinical development of BBT-877.

METHODS AND ANALYSIS: In this phase II, double-blind, placebo-controlled study, approximately 120 patients with IPF will be randomised in a 1:1 ratio to receive placebo or 200 mg of BBT-877 two times per day over 24 weeks, with stratification according to background use of an antifibrotic treatment (pirfenidone background therapy, nintedanib background therapy or no background therapy). The primary endpoint is absolute change in forced vital capacity (FVC) (mL) from baseline to week 24. Key secondary endpoints include change from baseline to week 24 in %-predicted FVC, diffusing capacity of the lung for carbon monoxide, 6 min walk test, patient-reported outcomes, pharmacokinetics and safety, and tolerability. Key exploratory endpoints include eLung-based CT evaluation and biomarker-based assessment of pharmacodynamics.

ETHICS AND DISSEMINATION: This study is being conducted following the Declaration of Helsinki principles, Good Clinical Practice guidance, applicable local regulations and local ethics committees. An independent data monitoring committee unblinded to individual subject treatment allocation will evaluate safety and efficacy data on a regular basis throughout the study. The results of this study will be presented at scientific conferences and peer-review publications.

TRIAL REGISTRATION NUMBER: NCT05483907.

PMID:40404183 | DOI:10.1136/bmjresp-2024-003038

Eur Radiol. 2025 May 22. doi: 10.1007/s00330-025-11689-9. Online ahead of print.

ABSTRACT

OBJECTIVES: To investigate whether a content-based image retrieval (CBIR) of similar chest CT images can help usual interstitial pneumonia (UIP) CT pattern classifications among readers with varying levels of experience.

MATERIALS AND METHODS: This retrospective study included patients who underwent high-resolution chest CT between 2013 and 2015 for the initial workup for fibrosing interstitial lung disease. UIP classifications were assigned to CT images by three thoracic radiologists, which served as the ground truth. One hundred patients were selected as queries. The CBIR retrieved the top three similar CT images with UIP classifications using a deep learning algorithm. The diagnostic accuracies and inter-reader agreement of nine readers before and after CBIR were evaluated.

RESULTS: Of 587 patients (mean age, 63 years; 356 men), 100 query cases (26 UIP patterns, 26 probable UIP patterns, 5 indeterminate for UIP, and 43 alternative diagnoses) were selected. After CBIR, the mean accuracy (61.3% to 67.1%; p = 0.011) and inter-reader agreement (Fleiss Kappa, 0.400 to 0.476; p = 0.003) were slightly improved. The accuracies of the radiologist group for all CT patterns except indeterminate for UIP increased after CBIR; however, they did not reach statistical significance. The resident and pulmonologist groups demonstrated mixed results: accuracy decreased for UIP pattern, increased for alternative diagnosis, and varied for others.

CONCLUSION: CBIR slightly improved diagnostic accuracy and inter-reader agreement in UIP pattern classifications. However, its impact varied depending on the readers' level of experience, suggesting that the current CBIR system may be beneficial when used to complement the interpretations of experienced readers.

KEY POINTS: Question CT pattern classification is important for the standardized assessment and management of idiopathic pulmonary fibrosis, but requires radiologic expertise and shows inter-reader variability. Findings CBIR slightly improved diagnostic accuracy and inter-reader agreement for UIP CT pattern classifications overall. Clinical relevance The proposed CBIR system may guide consistent work-up and treatment strategies by enhancing accuracy and inter-reader agreement in UIP CT pattern classifications by experienced readers whose expertise and experience can effectively interact with CBIR results.

PMID:40402291 | DOI:10.1007/s00330-025-11689-9

J Thorac Dis. 2025 Apr 30;17(4):2038-2049. doi: 10.21037/jtd-2024-2142. Epub 2025 Apr 28.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an idiopathic fibrotic interstitial lung disease with poor prognosis. Recently, the prognostic value of serum platelet-derived growth factor (PDGF) levels in patients with IPF has been clarified. Monocyte counts in the peripheral blood have also been reported to be an important predictor of survival in IPF. This study aimed to clarify the prognostic value of serum immunoglobulin (Ig) A levels in patients with IPF to predict survival and occurrence of acute exacerbations (AE).

METHODS: This retrospective study included 71 patients diagnosed with IPF based on the 2022 guidelines. Serum PDGF and interleukin (IL)-10 levels were measured using the Bio-Plex method. IgA levels were measured by a clinical testing company.

RESULTS: Of the enrolled patients, 59 were male, and the median age of the sample was 67 [interquartile range (IQR): 61-72] years. The median serum IgA level was 307 (IQR: 232-408) mg/dL and 18 patients had serum IgA levels of >400 mg/dL. Univariate Cox proportional hazard regression analysis revealed that high IgA levels (>400 mg/dL) were a significant predictor of poor prognosis; however, monocyte counts were not. A high IgA level was a significant prognostic factor after adjusting for the percent predicted value of forced vital capacity, age, gender, and body mass index. Serum PDGF levels tended to be higher in patients with high IgA levels than in those with low IgA levels. IL-10 was not significantly correlated with IgA levels; however, IgA levels tended to be negatively correlated with monocyte counts. High IgA levels did not significantly predict AE. High monocyte counts (>600/µL) significantly predicted the early incidence of AE by univariate Cox analysis but was not confirmed by multivariate analysis. However, monocyte counts, and a monocyte count of >600/µL were significant predictors of AE occurrence for patients with low IgA ≤400 mg/dL.

CONCLUSIONS: The serum IgA level is an independent prognostic predictor of survival in patients with IPF. Serum IgA levels might suggest serum fibrogenic cytokine levels. Serum IgA levels might be associated with prognosis differently from peripheral monocyte counts. The pathophysiological role of IgA needs to be elucidated in future studies.

PMID:40400959 | PMC:PMC12090133 | DOI:10.21037/jtd-2024-2142

J Pharm Biomed Anal. 2025 May 14;264:116967. doi: 10.1016/j.jpba.2025.116967. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible respiratory disease with poor survival rates. Despite significant research efforts, IPF still lacks a curative treatment. Excessive epithelial-mesenchymal transition (EMT) contributes to approximately one-third of fibroblasts in pulmonary fibrosis and plays a critical role in IPF pathogenesis. Identifying factors that regulate EMT is essential for developing effective therapeutic strategies for IPF. In this study, functional metabolomics revealed significant alterations in multiple metabolites in transforming growth factor-beta 1 (TGF-β1)-induced A549 cells, with pyroglutamic acid and 5-oxoprolinase (OPLAH) being identified as the most critical factors. Cellular experiments demonstrated that pyroglutamic acid effectively inhibited TGF-β1-induced EMT in A549 cells. Mechanistically, pyroglutamic acid inhibited IPF by suppressing EMT through the inhibition of Smad2/3 expression in TGF-β1-induced A549 cells. Bioinformatics analysis further elucidated the pyroglutamate is a potential metabolite that inhibits EMT. In addition, this study is the first to highlight the pivotal role of pyroglutamic acid and OPLAH in regulating EMT in IPF, offering novel insights into the metabolic mechanisms involved in IPF inhibition and providing a foundation for developing innovative therapeutic approaches for IPF.

PMID:40398246 | DOI:10.1016/j.jpba.2025.116967

Am J Surg Pathol. 2025 May 21. doi: 10.1097/PAS.0000000000002424. Online ahead of print.

ABSTRACT

Transbronchial cryobiopsies (CB) are increasingly replacing surgical biopsies (video-assisted thoracoscopic/VATS biopsies) for diagnosing diffuse parenchymal lung disease (interstitial lung disease, ILD), but there is very little guidance for pathologists on CB interpretation. Here we propose a fairly simple approach. First, if the diagnosis can be made on a traditional forceps biopsy, it can be made on a cryobiopsy. Many diseases with specific features will fall into this category (eg, sarcoidosis or Langerhans cell histiocytosis). More problematic are patterns such as usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia (NSIP), in which low-power architecture is the key to diagnosis. In this circumstance, an adequate sample is crucial to look for features such as fibroblast foci, because a combination of fibroblast foci plus any patchy old fibrosis, fibrotic architectural remodeling, or honeycombing, allows a diagnosis of a UIP pattern. However, in most instances, CB will not separate the UIP patterns seen in idiopathic pulmonary fibrosis, fibrotic hypersensitivity pneumonitis, or connective tissue disease-interstitial lung disease (CTD-ILD), although giant cells/granulomas (uncommon findings) in this setting favor fibrotic hypersensitivity pneumonitis. Fibroblast foci can be difficult to differentiate from organizing pneumonia (OP), but granulation tissue plugs clearly in airspaces favor OP. Absent fibroblast foci, patchy old fibrosis, architectural distortion, and honeycombing by themselves do not allow a specific diagnosis. NSIP in CB microscopically looks like NSIP in VATS biopsies, and the presence of an NSIP or an NSIP+OP pattern is typical of CTD-ILD. All the above diagnoses require correlation with clinical and radiologic findings.

PMID:40396574 | DOI:10.1097/PAS.0000000000002424

MAbs. 2025 Dec;17(1):2505090. doi: 10.1080/19420862.2025.2505090. Epub 2025 May 21.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by scarring and tissue remodeling. Current treatments have limited efficacy and significant side effects. To address these limitations, we developed AD-214, an anti-CXCR4-Fc-fusion protein composed of an anti-CXCR4 i-body (AD-114) tethered at its C terminus to constant domains 2 and 3 of the Fc region of a mutated human IgG1 lacking effector function. AD-214 binds with high affinity and specificity to CXCR4, modulates intracellular signaling, and inhibits key fibrotic pathways. Using fibrosis models, we demonstrate that AD-214 treatment significantly reduces collagen deposition and lung remodeling and has a unique mode of action. In Phase 1 clinical trials, intravenous infusion of AD-214 led to high and sustained CXCR4 receptor occupancy (RO), but whether RO and efficacy are causally linked remained to be determined. Herein, we demonstrate that CXCR4 RO by AD-214 inhibits primary human leukocyte migration, a model fibrotic process, and that migration inhibition is achievable at concentrations of AD-214 present in the serum of healthy human volunteers administered AD-214. Taken together, these data provide proof of concept for AD-214 as a novel treatment strategy for IPF and suggest that clinically feasible dosing regimens may be efficacious.

PMID:40395177 | DOI:10.1080/19420862.2025.2505090

Respir Res. 2025 May 19;26(1):192. doi: 10.1186/s12931-025-03270-1.

ABSTRACT

The standard approach to diagnosing idiopathic pulmonary fibrosis (IPF) includes identifying the usual interstitial pneumonia (UIP) pattern via high resolution computed tomography (HRCT) or lung biopsy and excluding known causes of interstitial lung disease (ILD). However, limitations of manual interpretation of lung imaging, along with other reasons such as lack of relevant knowledge and non-specific symptoms have hindered the timely diagnosis of IPF. This review proposes the definition of early IPF, emphasizes the diagnostic urgency of early IPF, and highlights current diagnostic strategies and future prospects for early IPF. The integration of artificial intelligence (AI), specifically machine learning (ML) and deep learning (DL), is revolutionizing the diagnostic procedure of early IPF by standardizing and accelerating the interpretation of thoracic images. Innovative bronchoscopic techniques such as transbronchial lung cryobiopsy (TBLC), genomic classifier, and endobronchial optical coherence tomography (EB-OCT) provide less invasive diagnostic alternatives. In addition, chest auscultation, serum biomarkers, and susceptibility genes are pivotal for the indication of early diagnosis. Ongoing research is essential for refining diagnostic methods and treatment strategies for early IPF.

PMID:40390073 | DOI:10.1186/s12931-025-03270-1

Ann Am Thorac Soc. 2025 May 19. doi: 10.1513/AnnalsATS.202408-882OC. Online ahead of print.

ABSTRACT

RATIONALE: Combined pulmonary fibrosis and emphysema (CPFE) is a unique phenotype with important prognosis and management implications in patients with idiopathic pulmonary fibrosis (CPFE-IPF) and other forms of fibrotic interstitial lung disease (CPFE-fILD). However, the epidemiology of CPFE is not well characterized, creating a barrier to clinical research needed to advance our understanding and management.

OBJECTIVES: To investigate the incidence, prevalence, and long-term outcomes of CPFE among a regional cohort of Veterans.

METHODS: We retrospectively reviewed records for Veterans in the Veterans Affairs Mid-Atlantic Health Care Network (includes North Carolina and Virginia) with International Classification of Disease (ICD)-9 codes for pulmonary fibrosis between January 1, 2008, and December 31, 2015. We stratified pulmonary fibrosis into IPF and fILD using diagnostic codes and chart review. We reviewed CT reports and classified cases as having CPFE according to documented emphysema; a thoracic radiologist overread a subset of scans for validation. We calculated annual incidence and prevalence of CPFE and compared characteristics between Veterans with CPFE and Veterans with fibrosis without emphysema using Chi-squared testing, Mann Whitney U testing, and paired t-tests. We used Kaplan-Meier and Cox models to determine overall survival from diagnosis.

RESULTS: We identified 2,414 Veterans with fibrotic ILD. Among 1,880 Veterans with IPF, 734 (39.0%) had CPFE-IPF; among 534 Veterans with fILD, 194 (36.3%) had CPFE-fILD. Agreement between CT reports and thoracic radiologist review was high (Kappa = 0.78). Annual CPFE prevalence ranged 71-100 per 100,000 Veterans, and incidence ranged 16-39 per 100,000 Veterans. CPFE was associated with male sex, lower BMI, greater tobacco history, higher FVC, reduced FEV1/FVC ratio, reduced DLCO, and increased oxygen utilization. CPFE was associated with increased mortality in unadjusted models. However, after adjustment for age, sex, and BMI, CPFE was not associated survival for both CPFE-IPF versus IPF without emphysema (HR 1.13, 95% CI 0.96-1.33) as well as CPFE-fILD versus fILD without emphysema (HR 1.16, 95% CI 0.82-1.63).

CONCLUSIONS: CPFE has high incidence and prevalence among Veterans with IPF and fILD and has a distinct phenotype with diagnostic and therapeutic implications. Further studies are merited investigating diagnosis, treatment considerations, and long-term impacts in CPFE.

OBJECTIVES: To investigate the incidence, prevalence, and long-term outcomes of CPFE among a regional cohort of Veterans.

METHODS: We retrospectively reviewed records for Veterans in the Veterans Affairs Mid-Atlantic Health Care Network (includes North Carolina and Virginia) with International Classification of Disease (ICD)-9 codes for pulmonary fibrosis between January 1, 2008, and December 31, 2015. We stratified pulmonary fibrosis into IPF and fILD using these ICD9 codes. We reviewed CT reports and classified cases as having CPFE according to documented emphysema; a thoracic radiologist overread a subset of scans for validation. We compared characteristics between Veterans with CPFE and Veterans with fibrosis without emphysema using Chi-squared testing, Mann Whitney U testing, and paired t-tests as appropriate. We used Kaplan-Meier and Cox models to estimate and compare overall survival from diagnosis.

RESULTS: We identified 2,414 Veterans with fibrotic ILD. Among 1,880 Veterans with IPF, 734 (39.0%) had CPFE-IPF; among 534 Veterans with fILD, 194 (36.3%) had CPFE-fILD. Agreement between CT reports and thoracic radiologist review was high (Kappa = 0.78). Overall CPFE prevalence was 107.48 per 100,000, and incidence was 28.53 per 100,000. CPFE was associated with male sex, lower BMI, greater tobacco history, higher FVC, reduced FEV1/FVC ratio, reduced DLCO, and increased oxygen utilization. CPFE was associated with increased mortality in unadjusted models. However, after adjustment for age, sex, and BMI, CPFE was not associated survival for both CPFE-IPF versus IPF without emphysema (HR 1.13, 95% CI 0.96-1.33) as well as CPFE-fILD versus fILD without emphysema (HR 1.16, 95% CI 0.82-1.63).

CONCLUSIONS: CPFE has high incidence and prevalence among Veterans with IPF and fILD and has a distinct phenotype with diagnostic and therapeutic implications. Further studies are merited investigating care utilization, treatment considerations, and long-term impacts in CPFE.

PMID:40388887 | DOI:10.1513/AnnalsATS.202408-882OC

N Engl J Med. 2025 May 19. doi: 10.1056/NEJMoa2503643. Online ahead of print.

ABSTRACT

BACKGROUND: Nerandomilast (BI 1015550) is an orally administered preferential inhibitor of phosphodiesterase 4B with antifibrotic and immunomodulatory properties. Nerandomilast has been shown to slow the progression of idiopathic pulmonary fibrosis, but an assessment of its effects in other types of progressive pulmonary fibrosis is needed.

METHODS: In a phase 3, double-blind trial, we randomly assigned patients with progressive pulmonary fibrosis in a 1:1:1 ratio to receive nerandomilast at a dose of 18 mg twice daily, nerandomilast at a dose of 9 mg twice daily, or placebo, with stratification according to background therapy (nintedanib vs. none) and fibrotic pattern on high-resolution computed tomography (usual interstitial pneumonia-like pattern vs. other patterns). The primary end point was the absolute change from baseline in the forced vital capacity (FVC), measured in milliliters, at week 52.

RESULTS: A total of 1176 patients received at least one dose of nerandomilast or placebo, of whom 43.5% were taking background nintedanib therapy at baseline. The adjusted mean change in the FVC at week 52 was -98.6 ml (95% confidence interval [CI], -123.7 to -73.4) in the nerandomilast 18-mg group, -84.6 ml (95% CI, -109.6 to -59.7) in the nerandomilast 9-mg group, and -165.8 ml (95% CI, -190.5 to -141.0) in the placebo group. The adjusted difference between the nerandomilast 18-mg group and the placebo group was 67.2 ml (95% CI, 31.9 to 102.5; P<0.001), and the adjusted difference between the nerandomilast 9-mg group and the placebo group was 81.1 ml (95% CI, 46.0 to 116.3; P<0.001). The most frequent adverse event was diarrhea, reported in 36.6% of the patients in the nerandomilast 18-mg group, 29.5% of those in the nerandomilast 9-mg group, and 24.7% of those in the placebo group. Serious adverse events occurred in similar percentages of patients in the trial groups.

CONCLUSIONS: In patients with progressive pulmonary fibrosis, treatment with nerandomilast led to a smaller decline in the FVC than placebo over a period of 52 weeks. (Funded by Boehringer Ingelheim; FIBRONEER-ILD ClinicalTrials.gov number, NCT05321082.).

PMID:40388329 | DOI:10.1056/NEJMoa2503643

Adv Ther. 2025 May 19. doi: 10.1007/s12325-025-03215-6. Online ahead of print.

ABSTRACT

The latest clinical practice guidelines for idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) were jointly published by the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Asociacion Latinoamericana de Thorax (ALAT) in 2022, and a new term-"PPF"-has been proposed to describe patients with non-IPF fibrosing interstitial lung diseases (ILDs), with defined criteria. However, the proposal of this new term has caused confusion amongst experts at a time when use of the term "progressive fibrosing interstitial lung disease" (PF-ILD), proposed in the phase 3 INBUILD trial of nintedanib, has become widely adopted by pulmonologists and rheumatologists in clinical practice. In this commentary, we discuss the background and concepts underpinning the terms PPF and PF-ILD and seek to provide pulmonologists and rheumatologists with a deeper understanding of the concept of PPF.

PMID:40388091 | DOI:10.1007/s12325-025-03215-6