Radiology. 2025 Jul;316(1):e242531. doi: 10.1148/radiol.242531.

ABSTRACT

Interstitial lung disease (ILD) diagnosis is complex, continuously evolving, and increasingly reliant on thin-section chest CT. Multidisciplinary discussion aided by a thorough radiologic review can achieve a high-confidence diagnosis of ILD in the majority of patients and is currently the reference standard for ILD diagnosis. CT also allows the early recognition of interstitial lung abnormalities, possibly reflective of unsuspected ILD and progressive in a substantial proportion of patients. Beyond diagnosis, CT has also become essential for ILD prognostication and follow-up, aiding the identification of fibrotic and progressive forms. The presence of fibrosis is a critical determinant of prognosis, particularly when typical features of usual interstitial pneumonia (UIP) are identified. The UIP-centric imaging approach emphasized in this review is justified by the prognostic significance of UIP, the prevalence of UIP in idiopathic pulmonary fibrosis, and its strong radiologic-pathologic correlation. In nonidiopathic pulmonary fibrosis ILD, progressive pulmonary fibrosis carries clinically significant prognostic and therapeutic implications. With growing evidence and the emergence of novel ILD-related concepts, recent updates of several imaging guidelines aim to optimize the approach to ILD. Artificial intelligence tools are promising adjuncts to the qualitative CT assessment and will likely augment the role of CT in the ILD realm.

PMID:40590695 | DOI:10.1148/radiol.242531

Cell Biol Int. 2025 Jul 1. doi: 10.1002/cbin.70051. Online ahead of print.

ABSTRACT

Pulmonary fibrosis (PF), particularly idiopathic pulmonary fibrosis, is a chronic and fatal disease. However, the precise pathogenic mechanisms underlying this condition remain elusive. We employed LASSO regression and random forest analyses, combined with expression profiling in TGFβ1-induced MRC-5 cells and bleomycin-induced PF mouse models, to identify differentially expressed genes. These analyses revealed that cytoplasmic carboxypeptidase 1 (CCP1) was significantly downregulated in fibrotic conditions. Relevant signaling pathways were further identified through RNA sequencing (RNA-seq). Subsequent functional studies were conducted using qRT-PCR, western blot, hematoxylin and eosin (HE) staining, Masson's trichrome staining, immunohistochemistry (IHC), immunofluorescence, scratch assays, EdU assays, RNA interference, and co-immunoprecipitation (co-IP). Functional studies revealed that CCP1 knockdown promoted cell migration, proliferation, and the transformation of MRC-5 cells into a fibrotic phenotype, as evidenced by increased expression of fibrosis-associated markers (FN1, COL 1α1, and ACTA2) and dysregulated expression of apoptosis-related markers (BCL2 and BAX). Conversely, CCP1 overexpression inhibited these processes. CCP1 was discovered to inhibit the PI3K/AKT signaling pathway by binding to eukaryotic initiation factor 4B (EIF4B). Overexpression of EIF4B activated the fibrotic process and interacted with c-Myc. In vivo studies further demonstrated that CCP1 inhibited PF by suppressing EIF4B to inhibit the PI3K/AKT signaling pathway. In summary, our results demonstrate that CCP1 inhibits the development of PF by suppressing the EIF4B/PI3K/AKT axis. This study offers new perspectives into the pathogenesis of PF and underscores CCP1 as a potential therapeutic target for managing this condition.

PMID:40590568 | DOI:10.1002/cbin.70051

Clin Sci (Lond). 2025 Jun 27:CS20245138. doi: 10.1042/CS20245138. Online ahead of print.

ABSTRACT

Angiotensin II AT2 receptor (AT2R) activation leads to significant anti-fibrotic and anti-inflammatory effects in diseased organs, which has led to clinical trial evaluation of the AT2R agonist, Compound 21 (C21), as a treatment for idiopathic pulmonary fibrosis (IPF). In this study, the anti-fibrotic effects of a more selective AT2R ligand, -pro7-angiotensin III (-pro7 Ang III), with >20,000-fold affinity for the AT2R over the AT1R, were compared to that of C21 or the currently-used IPF medication, pirfenidone, in mice with bleomycin (BLM)-induced pulmonary fibrosis. Adult female Balb/c mice received a double intranasal-instillation of BLM (20mg/kg/day) 7-apart and were maintained until 35, whilst control mice were instilled with saline 7-apart and maintained for the same time-period. Sub-groups of BLM-injured mice were then treated on 28 with vehicle (saline), C21 (0.3mg/kg/day) or -pro7 Ang III (0.1mg/kg/day) via 7-subcutaneously implanted osmotic minipumps, or daily from 28-35 via orally-administered pirfenidone (100mg/kg/day). At 35 post-injury, measures of lung fibrosis and compliance were evaluated. Compared to their saline-instilled counterparts, saline-treated BLM-injured mice presented with a significantly increased lung Ashcroft score, Masson's trichrome-stained and second harmonics generation-measured fibrosis, myofibroblast accumulation and TGF-1 expression, but reduced lung dynamic compliance at 35 post-injury. Whilst all treatments evaluated attenuated the BLM-induced lung myofibroblast accumulation and TGF-1 expression, AT2R stimulation, but not pirfenidone, attenuated lung collagen deposition after 7--pro7 Ang III also significantly restored lung compliance and promoted collagen-degrading matrix metalloproteinase-2 activity. These findings highlighted the therapeutic value of selectively targeting the AT2R for treating IPF.

PMID:40590236 | DOI:10.1042/CS20245138

Front Med (Lausanne). 2025 Jun 16;12:1593376. doi: 10.3389/fmed.2025.1593376. eCollection 2025.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) progression involves dysregulation of anoikis-related mechanisms, though the precise molecular drivers remain unclear. Through integrated analysis of IPF and normal lung tissue datasets, we identified 19 anoikis-related genes (ARGs) with EDNRB, MMP7, and CXCL12 showing significant differential expression (p < 0.05). Functional characterization revealed these ARGs predominantly regulate cell chemotaxis and inflammatory pathways, with protein network analysis identifying CXCL12 and CCL5 as central regulators. Clinically relevant findings demonstrated that EDNRB downregulation correlates with fibrotic progression, while ROC analysis validated multiple ARGs as diagnostic biomarkers (AUC > 0.8). Crucially, we discovered that FDA-approved endothelin receptor antagonists (bosentan/sitaxentan) attenuate fibrosis through EDNRB upregulation, positioning these repurposable drugs as novel therapeutic candidates. These findings establish EDNRB-mediated anoikis regulation as a key mechanism in IPF and urgently warrant clinical trials to validate endothelin receptor antagonists for targeted anti-fibrotic therapy.

PMID:40589973 | PMC:PMC12206826 | DOI:10.3389/fmed.2025.1593376

Respirology. 2025 Jul 1. doi: 10.1111/resp.70071. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is a frequent and fatal complication of IPF, with highly variable individual outcomes that are challenging to predict.

METHODS: This study included patients (≥ 19 years) who met the diagnostic criteria for AE-IPF. The primary outcome was 30-day mortality following hospital admission. Data on commonly assessed parameters at the time of emergency room presentation or hospital admission were collected. Variable selection and scoring were performed using the LASSO method and multivariable logistic regression, and the resulting model was validated in an independent cohort.

RESULTS: The derivation and validation cohorts comprised 128 and 100 patients, respectively. The final model incorporated eight variables (points): age ≥ 69 years (1), smoking status (current smoker: 2, past smoker: 1), use of home oxygen (1), history of hospital admission for non-AE events within the past 6 months (1), body mass index < 18.5 or > 23 kg/m2 (1), lymphocyte percentage < 19% (2), total protein < 6.5 g/dL (1) and lactate level ≥ 1.75 mmol/L (1). Patient scores were calculated by summing the points for each variable. This scoring system of total 10 points demonstrated good discrimination, with Harrell's C-statistics of 0.84 (95% confidence interval, 0.75-0.93) in the derivation cohort and 0.81 (95% confidence interval, 0.71-0.92) in the validation cohort, and performed well in predicting 2-week, 3-month and in-hospital mortality.

CONCLUSION: We developed and validated a scoring system based on readily available clinical parameters that effectively stratified 30-day mortality risk in patients with AE-IPF, offering a practical tool for bedside prognosis.

PMID:40589236 | DOI:10.1111/resp.70071

Pulm Pharmacol Ther. 2025 Jun 28:102376. doi: 10.1016/j.pupt.2025.102376. Online ahead of print.

ABSTRACT

RATIONALE: A high prevalence of smoking among idiopathic pulmonary fibrosis (IPF) patients increases the risk of emphysema. Combined pulmonary fibrosis and emphysema (CPFE) occurs predominantly in males, characterized by severe exercise-induced dyspnea, decreased diffusing capacity, and increased lung cancer risk. The exclusion of CPFE patients from clinical studies has limited understanding of its pathophysiology, treatment, and prognosis. This study aimed to close this knowledge gap by comparing CPFE with pure IPF in animal models, with the intent of developing phenotype-directed therapeutic strategies.

METHODS: Eight-week-old female C57BL/6J mice received biweekly intratracheal bleomycin (BLM, 2 U/kg/100 μL) for 3 doses. For the CPFE model, additional intranasal cigarette smoke extract (CSE) was administered twice weekly. Inflammation and fibrosis were evaluated through bronchoalveolar lavage fluid (BALF), proinflammatory cytokines, fibrosis markers, and lung histology.

RESULTS: BALF analysis showed increased cell counts in all BLM-treated groups, primarily macrophages, with elevated interleukin (IL)-6, transforming growth factor (TGF)-β1, and matrix metalloproteinases (MMP 3 and MMP 8). The BLM and CSE treated group displayed higher macrophages and lymphocytes counts than BLM alone. Lung tissue analysis revealed increased hydroxyproline, inflammation scores, Ashcroft scores, and higher α-smooth muscle actin (SMA) and collagen 1 expression in BLM-treated groups. The BLM and CSE treated group demonstrated notably higher emphysema formation as measured by mean linear intercept (MLI).

CONCLUSIONS: Through repeated BLM administrations and CSE exposure, an effective model for persistent pulmonary fibrosis and emphysema was established, enabling preclinical studies on CPFE and IPF and exploration of phenotype-directed therapeutic strategies for pulmonary fibrosis.

PMID:40588182 | DOI:10.1016/j.pupt.2025.102376

Int J Pharm. 2025 Jun 28:125883. doi: 10.1016/j.ijpharm.2025.125883. Online ahead of print.

ABSTRACT

Nintedanib is a first-line therapeutic agent for idiopathic pulmonary fibrosis and interstitial lung disease. However, its weakly basic nature leads to low dissolution in the intestines, resulting in poor oral bioavailability and limited antifibrotic efficacy. This study aimed to develop amorphous solid dispersion (ASD) systems of NIN to enhance its oral bioavailability and antifibrotic efficacy. Two types of ASDs of NIN were prepared utilizing Soluplus® and Hydroxypropyl-methylcellulose acetate succinate (HPMCAS) as polymer matrices through hot-melt extrusion. Subsequently, the ASDs were characterized using polarized light microscopy (PLM), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). Compared to pure NIN crystal, the dissolution of ASD-Soluplus and ASD-HPMCAS in simulated intestinal fluid was enhanced by 10.1-fold and 16.4-fold, respectively. Furthermore, pharmacokinetic studies in rats demonstrated that ASD-Soluplus and ASD-HPMCAS exhibited 2.5-fold and 7.9-fold increases in oral bioavailability, respectively, after a single dosage compared to NIN. The antifibrotic efficacy of ASDs was remarkably improved compared to the pure drug. No significant adverse effects on the liver and limited weight reduction were observed following oral administration of ASDs in rats. Overall, this study indicates that ASD is an effective approach to enhance the oral bioavailability and antifibrotic efficacy of NIN.

PMID:40588081 | DOI:10.1016/j.ijpharm.2025.125883

Med Oncol. 2025 Jun 30;42(8):304. doi: 10.1007/s12032-025-02843-w.

ABSTRACT

Advanced lung cancer complicated by idiopathic interstitial pneumonia (IIP) is difficult to treat because anticancer agents can worsen IIP. The efficacy and risks of treatment remain unknown and no standard chemotherapy regimen has been established for this condition. The central institutional review board approved this study. Radiologists and pulmonologists independently determined the sub-type of IIP. Eligibility criteria included age > 20 years, PS 0-1, adequate organ function, and written informed consent. Chemotherapy consisted of Carboplatin (CBDCA; area under the curve = 5), day 1 and Paclitaxel (PAC) 70 mg/m2, days 1, 8, and 15. Participants received chemotherapy every 4 weeks, for 4-6 cycles. Between January 2013 and October 2018, 36 patients enrolled in the study and 35 patients underwent chemotherapy. Patient characteristics were as follows: median age 73 years (range: 66-80 years), male/female (31/4), stage IIIA/IIIB/IV/post-op recurrence = 7/8/16/4, smoking yes/no = 34/1. Subtypes of IIP included idiopathic pulmonary fibrosis in 11(31.4%), combined pulmonary fibrosis and emphysema in 7, unclassified in 16, and interstitial linear abnormality in one. The response rate was 45.7% [0.288-0.634] with Complete Response/Partial Response/Stable Disease/Progressive Disease = 0/16/15/3, progression-free survival of 5.75 [4.70-6.67] months, and median overall survival of 9.99 [7.92-17.45] months. The acute exacerbation rate of IIP was 8.6% (3/35). CBDCA + weekly PAC had an acceptable acute exacerbation rate with a reasonable response rate, suggesting that it is a promising therapy for advanced squamous cell lung cancer with IIP. The risk factors of acute exacerbation remain to be investigated.

PMID:40587012 | DOI:10.1007/s12032-025-02843-w

Commun Med (Lond). 2025 Jun 28;5(1):246. doi: 10.1038/s43856-025-00966-9.

ABSTRACT

BACKGROUND: The prevalence of idiopathic pulmonary fibrosis (IPF) is higher in men, a previously not well-understood sex bias that extends across severity and mortality. Mosaic loss of chromosome Y (mLOY) in blood is male-specific and associated with adverse outcomes, including IPF. In mLOY-mice, enhanced TGF-β signaling has been reported to contribute to fibrosis of internal organs, but it is not known if such mLOY-driven disease mechanism exists in humans.

METHODS: We focused here on IPF in men to investigate if mLOY contributes to fibrotic disease processes in humans, as demonstrated in mouse models. To this end, we investigated mLOY as a risk factor for male IPF in epidemiological and clinical datasets, as well as by re-analyses of published single-cell RNA sequencing (scRNAseq) datasets.

RESULTS: We find that men with mLOY in blood display an increased risk for IPF diagnosis and death caused by IPF in UK Biobank, and that mLOY is associated with reduced lung functions in two cohorts. Approximately 80% of the male excess in IPF prevalence occurs in the group of men with mLOY in blood leukocytes. Notably, scRNAseq analyses support that pulmonary leukocytes with Y loss exacerbate IPF by upregulating profibrotic genes and enhancing TGF-β signaling.

CONCLUSIONS: Our results contribute to explaining the profound sex bias in IPF and replicate a mLOY-driven profibrotic disease mechanism first identified in mice. Male IPF patients with mLOY represent a subgroup that may benefit from treatment with TGF-β inhibitors.

PMID:40581694 | DOI:10.1038/s43856-025-00966-9

J Biol Chem. 2025 Jun 26:110408. doi: 10.1016/j.jbc.2025.110408. Online ahead of print.

ABSTRACT

Dysfunctional interactions between fibroblasts and epithelial cells contribute to the progression of chronic lung diseases, including idiopathic pulmonary fibrosis (IPF). In this study, we developed an air-liquid interface coculture model of human-derived small airway epithelial cells and lung fibroblasts to investigate intercellular dynamics during disease progression. Our findings showed that chronic epithelial damage initiates a bidirectional fibrotic cascade between the epithelium and lung fibroblasts, exacerbating epithelial injury and the release of pro-fibrotic mediators. Conversely, our transcriptomic and proteomic analyses revealed that, in the context of acute epithelial injury, a protective signaling environment emerges that mitigates further damage. By delineating secreted regulators involved in these beneficial responses, we identified pentraxin 3 (PTX3) as a leading antifibrotic candidate. Supplementation with PTX3 in chronically injured epithelial cells alleviated the pro-fibrotic phenotype and preserved epithelial barrier integrity through modulation of the AKT/claudin-2 axis. These insights highlight key differences of acute and chronic lung injuries and underscore the importance of the complex interplay between epithelial cells and fibroblasts in lung injury and repair.

PMID:40581116 | DOI:10.1016/j.jbc.2025.110408

Comput Biol Chem. 2025 Jun 19;119:108560. doi: 10.1016/j.compbiolchem.2025.108560. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an independent risk factor for lung cancer, especially squamous cell carcinoma (SCC). The prognosis of patients with both IPF and SCC is poorer than that of patients with only IPF, and preventive measures against SCC in patients with IPF remain elusive. Understanding the distinct mechanisms that induce both diseases is crucial for mitigating SCC onset in patients with IPF. We developed highly accurate machine learning (ML) models to classify patients with IPF or SCC using public RNA sequencing data. To construct the ML models, a random restart technique was applied to the five algorithms. To identify the differentially expressed genes (DEGs) between IPF and SCC, feature importance was calculated in the classification models. Furthermore, we detected somatic mutations affecting gene expression using SCC data. The ML models identified VCX2, TMPRSS11B, PRUNE2, PRG4, PZP, SCARA5, DES, HPSE2, HOXD11, S100A7A, and PLA2G2A as DEGs. Somatic mutations were detected in four transcription factors, BHLHE40, MYC, STAT1, and E2F4, which regulate the expression of these 11 genes. Furthermore, a molecular network comprising four transcription factors and 11 downstream genes was discovered. This newly identified molecular network enhances our understanding of the distinct mechanisms underlying IPF and SCC onset, and provides new insights into preventing SCC complications in patients with IPF.

PMID:40580591 | DOI:10.1016/j.compbiolchem.2025.108560

Vaccines (Basel). 2025 May 22;13(6):548. doi: 10.3390/vaccines13060548.

ABSTRACT

Coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccines have been associated with numerous side effects since their widespread release to the public. Cardiovascular complications include myocarditis and pericarditis, Takotsubo cardiomyopathy, postural orthostatic tachycardia syndrome (POTS), arrhythmias, sudden cardiac death, and cardiac tamponade. Pulmonary complications are pulmonary embolism (PE), interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPF), pneumonia, eosinophilic granulomatosis with polyangiitis, pneumonitis, and pulmonary hypertension. Despite these complications, the risk-benefit analysis still strongly favors vaccination, as these events occur more frequently with natural infection and confer a significantly worse prognosis. This study outlines the evidence surrounding each attributed effect, the clinical course including diagnosis and management, and the proposed pathophysiology. To our knowledge, this is the most comprehensive review of the cardiopulmonary effects of COVID-19 vaccination to date.

PMID:40573879 | DOI:10.3390/vaccines13060548

Pharmaceuticals (Basel). 2025 Jun 11;18(6):872. doi: 10.3390/ph18060872.

ABSTRACT

Background: Cancer and fibrotic diseases represent major global health challenges, underscoring the need for safe, multifunctional natural therapies. Although natural products possess notable anticancer properties, their clinical translation is often hindered by non-selective cytotoxicity toward normal cells. Moreover, their therapeutic potential against chronic conditions such as idiopathic pulmonary fibrosis (IPF) remains insufficiently explored. This study aimed to evaluate the efficacy and safety of a natural hydrosol blend, The Greatest Love of Nature (TGLON), in inhibiting cancer cell proliferation and mitigating IPF. Methods: TGLON, composed of 12 steam-distilled plant hydrosols, was chemically characterized by gas chromatography-mass spectrometry (GC-MS). Its cytotoxicity was assessed using the MTT assay against five human cancer cell lines (A-549, HepG2, MCF-7, MKN-45, and MOLT-4) and normal human lung fibroblasts (MRC-5). In vivo safety and therapeutic efficacy were evaluated in Sprague Dawley rats and a bleomycin-induced IPF mouse model, following protocols approved by the Institutional Animal Care and Use Committee (IACUC). Results: TGLON maintained >90% viability in MRC-5 cells at an 80-fold dilution and significantly inhibited the proliferation of A-549 (41%), HepG2 (84%), MCF-7 (50%), MKN-45 (38%), and MOLT-4 (52%) cells. No signs of toxicity were observed in rats administered TGLON orally at 50% (v/v), 10 mL/kg. In mice, TGLON alleviated bleomycin-induced pulmonary inflammation and fibrosis. Conclusions: TGLON exhibited selective anticancer and anti-fibrotic activities under non-toxic conditions, supporting its potential as a bioactive agent for early-stage disease prevention and non-clinical health maintenance.

PMID:40573267 | DOI:10.3390/ph18060872

Pharmaceuticals (Basel). 2025 Jun 9;18(6):859. doi: 10.3390/ph18060859.

ABSTRACT

Background: Pulmonary fibrosis (PF) is a progressive interstitial lung disease characterized by chronic inflammation and excessive extracellular matrix deposition, with fibrocytes playing a pivotal role in fibrotic remodeling. This study aimed to identify upstream molecular mechanisms regulating fibrocyte recruitment and activation, focusing on the SPHK1 pathway as a potential therapeutic target. Methods: We utilized Mendelian Randomization and phenome-wide association analyses on genes involved in sphingolipid metabolism to identify potential regulators of idiopathic pulmonary fibrosis (IPF). A bleomycin-induced mouse model was employed to examine the role of the SPHK1-S1P axis in fibrocyte recruitment, using SKI-349 to target SPHK1 and FTY720 to antagonize S1PR1. Results: Our analyses revealed SPHK1 as a significant genetic driver of IPF. Targeting SPHK1 and S1PR1 led to a marked reduction in fibrocyte accumulation, collagen deposition, and histopathological fibrosis. Additionally, PAXX and RBKS were identified as downstream effectors of SPHK1. Our protein-protein interaction mapping indicated potential therapeutic synergies with existing anti-fibrotic drug targets. Conclusions: Our findings establish the SPHK1-S1P-S1PR1 axis as a key regulator of fibrocyte-mediated pulmonary fibrosis and support SPHK1 as a promising therapeutic target.

PMID:40573254 | DOI:10.3390/ph18060859

Joint Bone Spine. 2025 Jun 24:105934. doi: 10.1016/j.jbspin.2025.105934. Online ahead of print.

ABSTRACT

OBJECTIVE: We assessed the effect of nintedanib (NIN) in terms of quantitative HRCT changes in both idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated progressive interstitial lung disease (SSc-ILD), evaluating the relationships between imaging variations and clinical-functional outcomes.

METHODS: We prospectively enrolled SSc-ILD and IPF patients treated with NIN and retrospectively selected the same number of subjects from a historical untreated cohort comparable for disease, age, gender and follow-up period. HRCT scans were processed with CALIPER software, obtaining the percentage of normal parenchyma, ILD and vascular-related structures (VRS).

RESULTS: Quantitative HRCT changes of 36 NIN treated patients (12 SSc-ILD and 24 IPF) were compared with 36 untreated subjects with pulmonary fibrosis. After a mean follow-up period of 22 months, NIN therapy was associated with a percentage stabilization of normal parenchyma (from 81.3 ±11.8% to 78.6 ±15.6%; p= not significant) and ILD (from 14.5 ±10.4% to 16.7 ±14.2%; p= not significant) both in SSc-ILD and IPF, avoiding the loss of normal parenchyma (from 87.4 ±7.3% to 78.8 ±16.7%; p<0.001) and ILD worsening (from 9.0 ±5.9% to 16.5 ±14.8%; p<0.001) observed in the untreated cohort. VRS was significantly increased regardless of antifibrotic therapy (p<0.001). NIN treated patients who experienced a clinically meaningful worsening at pulmonary function tests or at the reported dyspnoea, presented a significant loss of normal parenchyma in parallel with a greater increase in ILD (p<0.05 for all).

CONCLUSION: NIN appears effective in reducing the radiological decline of pulmonary fibrosis. Quantitative HRCT is proposed as a surrogate outcome measure for clinical practice and future trials.

PMID:40571119 | DOI:10.1016/j.jbspin.2025.105934

Respir Investig. 2025 Jun 25;63(5):780-786. doi: 10.1016/j.resinv.2025.06.012. Online ahead of print.

ABSTRACT

BACKGROUND: Interstitial pneumonia (IP) is a known complication of lung cancer (LC), but the mechanisms that trigger development of LC are not fully understood. In this study, we aimed to identify factors that promote development of LC in patients with IP by comprehensively measuring levels of inflammatory cytokines and chemokines in stored plasma samples from patients who were diagnosed with IP and who developed LC during follow-up.

METHODS: We used a bead-based multiplex assay to comprehensively measure the levels of 87 soluble immune mediators in plasma stored at the time of IP diagnosis in the groups of patients with IP that did (LC-IP, n = 25) and did not (IP, n = 45) develop LC, and used a logistic regression analysis to examine the correlation between plasma factors and LC development. The LC-IP group included 25 patients, who were matched with patients with IP without LC for several factors to increase comparability as much as possible.

RESULTS: In IP patients, the following soluble immune mediators were significantly associated with LC development: GM-CSF, IL-4, IL-1ra, PDGF-BB, IFN-a2, MMP1, CXCL1, TGF-β2, CXCL16, CCL11, IL-2, CCL2, IFN-γ, and IL-16. Meanwhile, PDGF-BB, CXCL2, and TGF-β1 were identified as being associated with LC development in patients with idiopathic pulmonary fibrosis (IPF).

CONCLUSION: PDGF-BB, CXCL2, and TGF-β1 may be factors in the development of LC in patients with IPF. Further elucidation of the mechanism and prospective follow-up of patients with IPF are needed for validation of these findings.

PMID:40570814 | DOI:10.1016/j.resinv.2025.06.012

Comput Biol Chem. 2025 Jun 23;119:108563. doi: 10.1016/j.compbiolchem.2025.108563. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease of unknown etiology with limited diagnostic and therapeutic options. DNA damage repair (DDR) plays an important role in the pathogenesis of lung diseases. The aim of this study was to identify core DDR genes involved in IFP progression and to assess their diagnostic potential and immunological relevance.

METHODS: Utilizing Gene Expression Omnibus (GEO) database and previous research, we obtained publicly available IPF disease data and DDR gene set data. Through WGCNA, LASSO, and protein-protein interaction (PPI) network analysis, we identified DDR-related hub genes, which were subsequently validated using external validation sets. ROC analysis was employed to assess and identify IPF diagnostic markers. Immune microenvironment of IPF group and its correlation with diagnostic genes were evaluated by ssGSEA algorithm and Spearman correlation analysis. Potential miRNAs and functional genes regulating diagnostic genes were predicted utilizing Network Analyst and GeneMANIA platforms.

RESULTS: We identified HMGB2 and PRPF19 as diagnostic markers for IPF, both of which exhibited excellent diagnostic performance across three datasets. Comparisons at both single-cell and transcriptome levels revealed that HMGB2 was overexpressed in IPF, while PRPF19 was underexpressed. Immune microenvironment assessments indicated high infiltration of macrophages and neutrophils in IPF group, suggesting presence of an inflammatory fibrotic immune microenvironment. Correlation analysis showed that various immune cells in IPF immune microenvironment were significantly associated with HMGB2 and PRPF19, indicating that these genes may influence immune microenvironment.

CONCLUSION: By combining WGCNA and LASSO analyses, this study identified two hub genes, HMGB2 and PRPF19, that can serve as diagnostic markers for IPF and modulate its immune microenvironment. This finding provides new directions for clinical diagnosis of IPF and research into DDR-related mechanisms.

PMID:40570466 | DOI:10.1016/j.compbiolchem.2025.108563

Thorac Res Pract. 2025 Jun 26. doi: 10.4274/ThoracResPract.2025.2025-3-5. Online ahead of print.

ABSTRACT

OBJECTIVE: This study aimed to compare the clinical, radiological, and functional outcomes of idiopathic pulmonary fibrosis (IPF) patients treated with nintedanib or pirfenidone, focusing on long-term efficacy, safety, and survival.

MATERIAL AND METHODS: A retrospective cross-sectional real-life study was conducted at a tertiary healthcare center between 2016 and 2021, including 93 IPF patients treated with either nintedanib (n = 41) or pirfenidone (n = 52). Data on demographics, pulmonary function tests [forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and diffusing capacity for carbon monoxide], radiological assessments, exacerbations, mortality, and side effects were analyzed using appropriate statistical methods.

RESULTS: Both groups were comparable in age (nintedanib: 68.6 years; pirfenidone: 71.3 years) and gender distribution. Patients on pirfenidone had a higher body mass index (27.7 vs. 26.0 kg/m2, P = 0.049) and more radiological involvement (P = 0.034). Baseline: Gender, Age, Physiology scores were lower in the nintedanib group (3.39 vs. 4.21, P = 0.007). Lung function (FVC, FEV1) was significantly better in the nintedanib group at two years; though differences were not sustained over five years. Side effects were more frequent with nintedanib (73.2% vs. 46.2%, P = 0.009), particularly affecting the gastrointestinal system. At five years after follow-up, mortality was higher in the pirfenidone group (53.4% vs. 17.5%, P = 0.02), although time from diagnosis to death was longer (33.8 vs. 19.0 months, P = 0.020).

CONCLUSION: Pirfenidone may prolong survival in patients with severe disease and greater radiological involvement, while nintedanib showed lower mortality in milder disease. Treatment outcomes appear influenced by baseline characteristics, highlighting the need for individualized therapeutic strategies. Comprehensive studies involving more homogeneous patient groups are needed to clarify the comparative efficacy of these treatments.

PMID:40569699 | DOI:10.4274/ThoracResPract.2025.2025-3-5

J Med Chem. 2025 Jun 26. doi: 10.1021/acs.jmedchem.5c01361. Online ahead of print.

ABSTRACT

Prostaglandin E2 (PGE2), a crucial lipid mediator governing tissue stem cell expansion and regeneration, represents a promising therapeutic target for tissue repair. Based on the premise that inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the principal enzyme responsible for PGE2 catabolism, could enhance endogenous PGE2 levels and accelerate tissue regeneration, we rationally designed and synthesized a novel series of tetrahydro-1H-cyclopropa[c][1,8]naphthyridine derivatives as potential 15-PGDH inhibitors. HW201877 was identified as the lead candidate, demonstrating exceptional enzymatic inhibition (IC50 = 3.6 nM) and robust cellular efficacy in elevating PGE2 levels in A549 cells (4.8-fold increase vs control). Crucially, with favorable pharmacokinetic profiles, HW201877 demonstrated notable therapeutic efficacy in murine models of inflammatory bowel disease (IBD) and idiopathic pulmonary fibrosis (IPF). These findings establish HW201877 as a promising clinical candidate targeting 15-PGDH with therapeutic potential for treating IBD and IPF, providing a novel pharmacological strategy for tissue regeneration therapy.

PMID:40568827 | DOI:10.1021/acs.jmedchem.5c01361

Arterioscler Thromb Vasc Biol. 2025 Jun 26. doi: 10.1161/ATVBAHA.125.322734. Online ahead of print.

ABSTRACT

BACKGROUND: In this study, we define the mechanistic association between long noncoding RNA: ENST00000495536 (lnc-536) and transcription factor HOXB13 in mediating proproliferative smooth muscle phenotype associated with pulmonary hypertension.

METHODS: In vitro knockdown or knockin, along with RNA pull-down and immunoprecipitation studies, were used to evaluate the role of lnc-536 and HOXB13 in regulating pulmonary arterial smooth muscle cell (PASMCs) phenotype. The in vivo role was determined by injecting lnc-536 antisense oligos in pulmonary hypertensive rats.

RESULTS: Increased levels of lnc-536 promote the proliferative phenotype of PASMCs by downregulating the expression of the tumor suppressor: HOXB13. Knockdown of lnc-536 and overexpression of HOXB13 in proliferative PASMCs resulted in increased expression of VGLL4, a negative regulator of Hippo and Wnt signaling pathways, with a corresponding decrease in TEAD4 expression. The lnc-536 pull-down assay and RNA-immunoprecipitation demonstrated the interactions of lnc-536 with RBP (RNA-binding protein): RBM25 (RNA-binding motif 25) and direct interactions of RBM25 with SFPQ (splicing factor proline/glutamine-rich), a transcriptional regulator that has a binding motif on HOXB13. The knockdown of RBM25 in the hyperproliferative PASMCs resulted in increased interactions of SFPQ and HOXB13 mRNA while attenuating PASMC proliferation. Furthermore, the increased levels of lnc-536 and decreased levels of HOXB13 were observed in PASMCs from idiopathic pulmonary hypertension patients but not in cells from familial pulmonary hypertension patients. We confirmed that lnc-536 contributes to the RBM25-mediated remodeling of the SFPQ-HOXB13 complex in the idiopathic PAH-PASMCs as well. Finally, in vivo inhibition of lnc-536 using GapmeRs in Sugen-hypoxia and HIV-transgenic pulmonary hypertension rats prevented the increase in right ventricular systolic pressure, right ventricular hypertrophy/fibrosis, and pulmonary vascular remodeling with a parallel increase in HOXB13 expression in rat PASMCs.

CONCLUSIONS: Lnc-536 acts as a decoy for RBM25, which in turn sequesters SFPQ, leading to a decrease in HOXB13 expression and hyperproliferation of smooth muscle cells by potentially regulating Wnt and Hippo signaling associated with PAH development.

PMID:40567228 | DOI:10.1161/ATVBAHA.125.322734