Eur J Med Chem. 2025 Jul 26;298:118011. doi: 10.1016/j.ejmech.2025.118011. Online ahead of print.

ABSTRACT

Autotaxin (ATX) plays a critical role in exacerbating inflammation and fibrosis, making it a promising target for fibrosis treatment. Herein, in pursuit of expanding the chemical space of novel ATX inhibitors, a series of imidazole-fused (imidazo[1,2-b]pyridazine and benzo[d]imidazole) derivatives with aliphatic amine linkers were designed through integrating the structural features of GLPG-1690 and PF-8380. Meanwhile, a terminal aromatic benzamide fragment was involved to penetrate the hydrophobic pocket. Following enzyme activity screening, compound 12 bearing N-(1H-benzo[d]imidazole-5-yl)furan-2-carboxamide showed the optimal in vitro ATX inhibitory activity (IC50 = 46 nM), accompanied by favorable drug-like properties. The docking study well elucidated the promising activity of 12 for the key H-bond interactions with Trp261 and Ser170, as well as π-π interactions with Trp255 and Phe274. Significantly, in the Bleomycin-induced pulmonary fibrosis mouse model, 12 has certainly reduced collagen deposition and ameliorated lung fibrosis. Overall, compound 12 turned out to be a well-characterized potent ATX inhibitor warranting further investigation for the treatment of idiopathic pulmonary fibrosis.

PMID:40738079 | DOI:10.1016/j.ejmech.2025.118011

Lung. 2025 Jul 30;203(1):85. doi: 10.1007/s00408-025-00837-z.

ABSTRACT

The genetic contribution to idiopathic pulmonary fibrosis (IPF) has become increasingly evident, enabling its translation into clinical practice. MUC5B rs35705950 has emerged as a promising prognostic biomarker. The gender-age-physiology (GAP)-model is regularly used for IPF survival prediction. In this retrospective real-world study, GAP-stages were stratified by MUC5B T-allele carriage. European patients with IPF were included in a discovery (n = 663), and replication (n = 738) cohort. The GAP+MUC5B-model was significantly more accurate compared to the GAP-model (all cohorts p < 0.001), with a modest improvement in discrimination (ΔC = 0.023; C = 0.685, 95%CI 0.665-0.704). Within each GAP-stage, T-allele carriers had significantly better median transplant-free survival outcomes than non-carriers (p < 0.001): In the combined cohort (n = 1401) survival for GAP-stage I T carriers was 70 months (m) vs 48m for T non-carriers; stage II T vs non-T: 41 vs 31m; stage III T vs non-T: 23 vs 12m. Addition of MUC5B rs35705950 T-carriership enhances GAP-based prognostication and aids clinical decision-making.

PMID:40736684 | DOI:10.1007/s00408-025-00837-z

Front Immunol. 2025 Jul 15;16:1592597. doi: 10.3389/fimmu.2025.1592597. eCollection 2025.

ABSTRACT

BACKGROUND: Pseudomonas aeruginosa (PA) causes severe respiratory infections utilizing multiple virulence functions. Previous findings on the PA secreted quorum sensing (QS)-regulated small molecule, 2'-aminoacetophenone (2-AA), revealed its impact on immune and metabolic functions, favouring a long-term presence of PA in the host. However, the 2-AA's specific effects on bronchial-airway epithelium and pulmonary endothelium remain elusive. To evaluate the spatiotemporal changes in 2AA within the human airway, considering endothelial cells as the primary point of contact when the route of lung infection is hematogenic, we utilized the airway-on-achip platform. This dynamic culture system recapitulates critical elements of the human airway microphysiological environment.

METHODS: We utilized the microfluidic airway-on-chip platform, lined by polarized primary human pulmonary microvascular endothelial cells (HPMEC) and adjacent primary normal human bronchial epithelial cells (NHBE) obtained from healthy female donors. Cells exposed to 2-AA (20 μm) through continuous flow for 12 hours were used for whole-genome RNA sequencing and analyzed for their responses and potential cross-talk. Transcriptome findings were validated through in vivo studies in mice and additional cell culture experiments.

RESULTS: Analyses revealed that 2-AA differentially regulates specific signaling and biosynthesis pathways in epithelial cells, including HIF-1 and pyrimidine signaling, glycosaminoglycan and glycosphingolipid biosynthesis. In endothelial cells, fatty acid metabolism, phosphatidylinositol, and estrogen receptor signaling, as well as proinflammatory signaling pathways, were identified. Significant overlap was found in both cell types in response to 2-AA in genes implicated in immune response and cellular functions. In contrast, we found that genes related to barrier permeability, cholesterol metabolism, and oxidative phosphorylation were differentially regulated in response to 2-AA exposure in the studied cell types. Murine in vivo and additional in vitro cell culture studies confirmed the accumulation of cholesterol in epithelial cells. Results also revealed that specific biomarkers associated with cystic fibrosis and idiopathic pulmonary fibrosis were modulated by 2-AA in both cell types, with the expression of cystic fibrosis transmembrane regulator being affected only in endothelial cells.

PMID:40735328 | PMC:PMC12305196 | DOI:10.3389/fimmu.2025.1592597

Health Sci Rep. 2025 Jul 27;8(8):e71107. doi: 10.1002/hsr2.71107. eCollection 2025 Aug.

ABSTRACT

BACKGROUND AND AIMS: The increasing prevalence of Crohn's disease (CD) and ulcerative colitis (UC)-the two main forms of inflammatory bowel disease (IBD)-has made these conditions a growing concern in global public health. While IBD primarily impacts the gastrointestinal tract, emerging evidence suggests its extraintestinal effects, especially on the respiratory system. The correlation between the lungs and the gastrointestinal system has drawn attention to the potential pulmonary complications in IBD patients. The causal link between IBD and lung function or related disease remains inconclusive.

METHODS: Leveraging publicly available genome-wide association study (GWAS) data sets, we performed a two-sample Mendelian randomization analysis to investigate potential links between ulcerative colitis, Crohn's disease, and various aspects of lung function or respiratory illness. Through meticulous quality control measures, we pinpointed SNPs with robust associations to UC and CD. The inverse-variance weighted method was our primary analytic approach. Additionally, we evaluated heterogeneity, explored potential pleiotropy, and performed sensitivity tests.

RESULTS: We conducted an analysis using GWAS data obtained from the European population, identifying 54 and 77 SNPs for association studies related to lung function and disease in UC and CD, respectively. The results from the MR analysis revealed that neither UC nor CD exhibited a discernible impact on lung function, encompassing metrics such as total lung volume, forced vital capacity, forced expiratory volume in the first second, the forced vital capacity/forced expiratory volume in the first second ratio, and peak expiratory flow. Additionally, neither UC nor CD demonstrated an elevated risk of idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, or pulmonary cancer. In contrast, CD presented a heightened risk of asthma compared to UC.

CONCLUSION: CD has been associated with a higher risk of developing asthma in the European population.

PMID:40735257 | PMC:PMC12301568 | DOI:10.1002/hsr2.71107

Front Cardiovasc Med. 2025 Jul 15;12:1623112. doi: 10.3389/fcvm.2025.1623112. eCollection 2025.

ABSTRACT

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia and is linked to increased risk of stroke, heart failure, and mortality. Circulating extracellular RNAs (exRNAs), which regulate gene expression and reflect underlying biological processes, are potential biomarkers for atrial fibrillation.

METHODS: As part of an ongoing, larger study into extracellular RNAs (exRNAs) as potential biomarkers for cardiovascular disease, we analyzed exRNA profiles in a subset of 296 survivors of acute coronary syndrome (ACS) enrolled in the Transitions, Risks, and Actions in Coronary Events Center for Outcomes Research and Education (TRACE-CORE) cohort. A total of 318 exRNAs were quantified, selected a priori based on prior findings from the Framingham Heart Study. We assessed associations between circulating exRNAs and echocardiographic intermediate phenotypes relevant to atrial fibrillation (AF), including left atrial dimension, left ventricular (LV) mass, LV end-diastolic volume, and global longitudinal strain. Subsequently, we used logistic regression models to evaluate whether the exRNAs associated with these phenotypes were also associated with a history of AF (n = 18, 5.4%). Downstream bioinformatics analyses were performed to identify putative target genes, enriched gene ontology categories, and molecular pathways regulated by these candidate microRNAs.

RESULTS: We identified 77 extracellular RNAs (exRNAs) that were significantly associated with increased left ventricular (LV) mass and at least one additional echocardiographic intermediate phenotype. Among these, miR-17-5p and miR-574-3p were also significantly associated with a history of atrial fibrillation (AF), with odds ratios of 1.58 (95% CI: 1.10-2.26) and 2.16 (95% CI: 1.03-4.54), respectively. Predicted gene targets of these miRNAs were enriched in pathways implicated in atrial remodeling and arrhythmogenesis. Key overlapping canonical pathways included the Senescence Pathway, Idiopathic Pulmonary Fibrosis Signaling, ERK5 Signaling, RHO GTPase Cycle, and HGF Signaling.

CONCLUSIONS: Circulating exRNAs, including miR-17-5p and miR-574-3p, are associated with cardiac remodeling and a history of AF in ACS survivors. These findings highlight their potential as biomarkers of atrial remodeling and implicate key molecular pathways involved in AF pathogenesis.

PMID:40734983 | PMC:PMC12303983 | DOI:10.3389/fcvm.2025.1623112

Medicina (Kaunas). 2025 Jun 29;61(7):1181. doi: 10.3390/medicina61071181.

ABSTRACT

Background and Objectives: Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive interstitial lung disease with an unknown etiology. It is often accompanied by skeletal muscle mass loss. Chest wall muscles play a crucial role in respiratory movements and form part of the skeletal muscles. The aim of this study is to evaluate the relationship between chest wall muscle thickness and pulmonary function test (PFT) results, as well as other prognostic markers, in patients with IPF. Materials and Methods: A retrospective analysis was conducted on 108 patients diagnosed with IPF and 53 control subjects. Chest wall muscle thickness was measured on thoracic computed tomography (CT) images at specific anatomical levels. PFT parameters, the Gender-Age-Physiology (GAP) index, number of acute exacerbations, and mortality data were evaluated in relation to muscle thickness. Results: IPF patients had significantly reduced thickness in the bilateral external scapular muscles at both the aortic and pulmonary trunk levels compared to controls. Bilateral pectoral muscle thickness at the aortic level was positively correlated with forced vital capacity (FVC) and negatively correlated with the number of exacerbations. Internal scapular muscle thickness at the aortic level showed a significant positive correlation with diffusion capacity of the lung for carbon monoxide (DLCO) and a negative correlation with both GAP scores and exacerbation frequency. External scapular muscle thickness at the pulmonary trunk level was positively associated with PFT parameters and inversely correlated with the GAP index, exacerbations, and mortality. Conclusions: In patients with IPF, the bilateral external scapular muscle thickness at the aortic and pulmonary trunk levels was significantly reduced compared to controls. Significant associations were found between some chest wall muscle thicknesses and the GAP index, pulmonary function, acute exacerbations, and mortality, underscoring the prognostic value of baseline muscle measurements. Measurement of chest wall muscle thickness using routine thoracic CT scans may offer additional prognostic value in IPF. Incorporating this parameter into clinical evaluation may help identify patients who could benefit from supportive interventions, such as nutritional therapy or pulmonary rehabilitation.

PMID:40731811 | DOI:10.3390/medicina61071181

Medicina (Kaunas). 2025 Jun 26;61(7):1157. doi: 10.3390/medicina61071157.

ABSTRACT

Background and Objectives: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease with limited therapeutic options. Current therapies (pirfenidone, nintedanib) exhibit modest efficacy and significant side effects, underscoring the need for novel strategies targeting early pathogenic drivers. Saroglitazar (SGZ), a dual PPARα/γ agonist with anti-inflammatory properties approved for diabetic dyslipidemia, has not been explored for IPF. We aimed to investigate SGZ's therapeutic potential in pulmonary fibrosis and elucidate its mechanisms of action. Materials and Methods: Using a bleomycin (BLM)-induced murine pulmonary fibrosis model, we administered SGZ therapeutically. A histopathological assessment (H&E, Masson's trichrome, collagen I immunofluorescence), Western blotting, and qRT-PCR analyzed the fibrosis progression and inflammatory markers. Flow cytometry evaluated the macrophage polarization. In vitro studies used RAW264.7 macrophages stimulated with BLM/LPS and MRC-5 fibroblast co-cultures. The NF-κB/NLRP3 pathway activation was assessed through protein and gene expression. Results: SGZ significantly attenuated BLM-induced histopathological hallmarks, including alveolar wall thickening, collagen deposition, and inflammatory infiltration. Fibrotic markers (OPN, α-SMA) and pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) were downregulated in the SGZ-treated mice. Mechanistically, SGZ suppressed the M1 macrophage polarization (reduced CD86+ populations) and inhibited the NF-κB/NLRP3 pathway activation in the alveolar macrophages. In the RAW264.7 cells, SGZ decreased the NLRP3 inflammasome components (ASC, cleaved IL-1β) and cytokine secretion. Co-cultures demonstrated that the SGZ-treated macrophage supernatants suppressed the fibroblast activation (α-SMA, collagen I) in MRC-5 cells. Conclusions: SGZ attenuates pulmonary fibrosis by suppressing macrophage-driven inflammation via NF-κB/NLRP3 inhibition and disrupting the macrophage-fibroblast crosstalk. These findings nominate SGZ as a promising candidate for preclinical optimization and future clinical evaluation in IPF.

PMID:40731787 | DOI:10.3390/medicina61071157

ACR Open Rheumatol. 2025 Aug;7(8):e70065. doi: 10.1002/acr2.70065.

ABSTRACT

OBJECTIVE: Retroperitoneal fibrosis (RPF) complicated by mediastinal fibrosis (MF) is rare but fatal. We aimed to explore the features and indicators of poor prognosis for the population of those affected.

METHODS: Patients with idiopathic RPF were recruited in Peking University International Hospital. Literature related to RPF with MF was searched from PubMed, Web of Science, and Embase until September 2024. Systematic review and case-control studies were conducted.

RESULTS: One patient with RPF and MF from our center and nine cases identified through literature search formed the study group. The remaining 51 patients with RPF who did not have MF were enrolled as the control group. Patients with RPF and MF were more likely to present specific symptoms, including emaciation (30% vs 2%), fever (20% vs 0), pericardial effusion (30% vs 0), pleurisy (20% vs 0) and dyspnea (40% vs 0) (all P < 0.05). Hyperglobulinemia (elevated IgG levels) was also more predominant in the study group, whereas low back pain (20% vs 56.9%, P = 0.043) was less prevalent. Four of 10 patients in the study group died, but none died in the control group. A second case-control study was performed among patients with RPF and MF, with the three patients who died of fibrosis disease as the study group and the surviving six patients as the control group. It was found that pleural effusions (100% versus 16.7%, P = 0.048) and the absence of glucocorticoid treatment were risk factors for death in patients with RPF and MF.

CONCLUSION: RPF with MF has specific clinical features and poor prognosis. Early detection and glucocorticoids-based treatment could improve the outcome.

PMID:40728059 | DOI:10.1002/acr2.70065

J Clin Med. 2025 Jul 18;14(14):5100. doi: 10.3390/jcm14145100.

ABSTRACT

The neutrophil-to-lymphocyte ratio (NLR) is a simple, inexpensive and easily accessible inflammatory biomarker that reflects the balance between innate and adaptive immunity. In recent years, NLR has emerged as a potential prognostic and disease severity marker for different diseases, including idiopathic pulmonary fibrosis (IPF), a progressive and fatal interstitial lung disease with a highly variable course and poor prognosis. Several studies have highlighted that NLR can be associated with several clinical outcomes such as lung function decline, increased risk of hospitalization, acute exacerbation of IPF, and mortality over time. It might also correlate with overall survival in the course of antifibrotic therapy and validated prognostic score as a gender-age-physiology score. Despite these findings, the clinical use of NLR remains limited due to its non-specific nature, the lack of standardized cut-off values, and high variability related to demographic factors, comorbidities and medications. Hence, NLR may display the underlying immune dysregulation in IPF and could be exploited as a non-invasive tool for risk stratification and disease monitoring. Further studies are needed to confirm and validate its use in IPF and to establish reliable cut-off values in clinical applications.

PMID:40725793 | DOI:10.3390/jcm14145100

Biomolecules. 2025 Jul 20;15(7):1050. doi: 10.3390/biom15071050.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disorder characterized by excessive scarring of lung tissue, predominantly affecting middle-aged and elderly populations. Oxidative stress plays a pivotal role in the pathogenesis of pulmonary fibrosis, disrupting redox homeostasis and driving fibrotic progression. Glutathione reductase (GSR), a key antioxidant enzyme, is essential for maintaining cellular glutathione (GSH) levels and mitigating oxidative damage. However, the specific involvement of GSR in IPF remains poorly understood. This study found that GSR levels were downregulated in IPF patients and mice treated with bleomycin (BLM). GSR knockdown enhanced epithelial-to-mesenchymal transition (EMT) in A549 cells and promoted the activation of MRC5 cells. Additionally, GSR depletion promoted cellular migration and senescence in both A549 and MRC5 cells. Mechanistically, silencing GSR in A549 and MRC5 cells led to a marked reduction in intracellular GSH levels, resulting in elevated reactive oxygen species (ROS) accumulation, thereby promoting the activation of the TGF-β/Smad2 signaling pathway. In conclusion, our findings demonstrate that GSR deficiency aggravates pulmonary fibrosis by impairing antioxidant defense mechanisms, promoting EMT, and activating fibroblasts through the TGF-β/Smad2 signaling. These findings suggest that GSR may be essential in reducing the fibrotic progression of IPF.

PMID:40723921 | DOI:10.3390/biom15071050

Biomedicines. 2025 Jun 20;13(7):1509. doi: 10.3390/biomedicines13071509.

ABSTRACT

We would like to identify and amend errors in a previously published paper [...].

PMID:40722858 | DOI:10.3390/biomedicines13071509

BMC Pulm Med. 2025 Jul 28;25(1):358. doi: 10.1186/s12890-025-03825-4.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic condition. Serial FVC monitoring is most commonly used to assess progression of disease but FVC does not always reflect regional CT change in IPF. Recently there has been growing interest in quantitative CT (qCT) assessment of IPF. In this study, we compared different physiological and qCT measurements of disease progression in predicting mortality in IPF.

AIMS: We question if a composite measure of disease progression using qCT and FVC is more predictive of mortality than individual measurements, and if addition of blood leukocyte levels further enhance predictive ability of these measurements of disease progression.

METHODS: We conducted a retrospective analysis of an IPF cohort (n = 71). Annualised change (∆) in CT-measured lung volume (CTvol) and total lung fibrosis score (TLF) were calculated (using the computer software CALIPER) together with annualised change in FVC and blood leukocyte levels within 4 months of first CT. These were modelled against mortality using multivariate Cox regression. Concordance indexes (C-statistic) of different Cox regression models were used to determine the most predictive and discriminative combination for mortality.

RESULTS: 65 cases (91.5%) were male. Median (IQR) age 73.6 years (68.4-79.3). Death was reported in 24 cases (33.8%). The median annualised change in (∆)FVC was - 4.4% (-9.6-0.0), ∆TLF; + 2.9% (0.2-7.0), and ∆CTvol; -4.3% (0.0-10.9). Combined measurements of disease progression (∆CTvol, ∆FVC and ∆TLF%) out-performed single-variable measurements in predicting all-cause mortality in IPF. The composite variable of [ΔFVC >10%, ΔCTvol >10% or ΔTLF% >10%] was most predictive of mortality [HR 7.14 (2.45-20.79), p <0.001]. Inclusion of blood leukocytes improved C-statistic scores for each multivariate model.

CONCLUSION: Composite end points of ∆CTvol, ∆FVC and ∆TLF% were more predictive of mortality than single-variable measurements in this cohort. Inclusion of blood leukocytes into risk stratification models further improved mortality prediction for all measures of disease progression.

PMID:40721735 | DOI:10.1186/s12890-025-03825-4

Am J Respir Cell Mol Biol. 2025 Jul 28. doi: 10.1165/rcmb.2024-0527OC. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, interstitial lung disease lacking efficient drug to reverse it. Thus, to elucidate the complex pathogenesis of IPF and identify new therapeutic targets are urgently needed. It has been revealed that the pathophysiology of IPF is a highly orchestrated process including multiple cell types, where the contribution of endothelial cells (ECs) has also been attracted researchers' attention. However, although the involvement of ECs in fibrosis has been recognized, the underlying key molecules driving these changes are not well-defined. Here, we revealed that von Willebrand factor (VWF), a marker of damaged ECs, and endothelial dysfunction are positively correlated with IPF progression based on reanalysis of gene expression profiles of patients with IPF. Next, we discovered that VWF deficiency attenuated fibrosis in experimental models, including human cell lines (in vitro) and mice (in vivo). Mechanistically, VWF deficiency inhibited endothelial-to-mesenchymal transition (EndoMT), regulated vascular abnormalities and limited M2 macrophage infiltration, which were achieved, at least in part, by the inhibition of Wnt signaling. Our findings provided evidence for the pivotal role of ECs in IPF and revealed VWF might be a driving factor of EndoMT, suggesting that VWF can develop as a potential therapeutic target against IPF. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PMID:40720796 | DOI:10.1165/rcmb.2024-0527OC

Am J Respir Cell Mol Biol. 2025 Jul 28. doi: 10.1165/rcmb.2024-0628OC. Online ahead of print.

ABSTRACT

Identifying molecular biomarkers of pulmonary fibrosis (PF) would improve monitoring the disease progression and response to treatment. Hermansky-Pudlak syndrome (HPS) PF is an inherited type of progressive PF with accelerated onset of PF in patients with HPS type 1 (HPS-1). HPSPF could serve as a model to study biomarkers of progressive PF, given that all HPS-1 subjects eventually develop HPSPF. We utilized a multi-omics strategy to discover progressive blood biomarkers that can recognize factors contributing to the fibrotic cascade in the lungs of HPS subjects. Metabolomic and cytokine/chemokine profiling were performed on serum samples from patients with HPS-1, HPS-1 with PF (HPSPF), HPS-3 or HPS-5, idiopathic PF (IPF), and normal volunteers. Metabolomics, cytokine/chemokine, pulmonary function, and age data from HPS-1 and HPSPF subjects were integrated into a multi-omics network. The analysis highlighted alterations in the transsulfuration pathway, arginine metabolism, and redox balance with the progression of PF in HPS-1. Among those, CCL22 and choline were significantly elevated in HPSPF compared to HPS-1 in two independent cohorts together with age and associated with decline of pulmonary function. In ROC curve analysis, both CCL22 and choline demonstrated high accuracy in predicting PF in HPS-1 subjects, could serve as prognostic blood biomarkers of HPSPF. We noted similarity in molecular signatures of CCL22 in progressive IPF and HPSPF. We found that inducible nitric oxide synthase (iNOS) is an upstream regulator of releasing profibrotic mediators (CCL22, CCL24, IL-18, IL1α, IL1β), suggesting therapeutic potential of iNOS inhibition in progressive HPSPF.

PMID:40720784 | DOI:10.1165/rcmb.2024-0628OC

Adv Healthc Mater. 2025 Jul 28:e01952. doi: 10.1002/adhm.202501952. Online ahead of print.

ABSTRACT

Current anti-fibrotic therapeutics for idiopathic pulmonary fibrosis (IPF) slow disease progression but are non-curative and have systemic side effects, promoting interest in therapies that can repolarize macrophages away from their pro-fibrotic phenotype. While yeast beta-glucan (YBG) offers therapeutic potential in reprogramming macrophages toward an anti-fibrotic phenotype, YBG processing must be optimized to promote inhalability while preserving its biological activity. Herein, the biological and inhalation performance of YBG processed via Pressurized Gas eXpanded liquids technology (PGXTEC-YBG) relative to conventionally spray-dried YBG (SD-YBG) is compared. The significantly smaller size and lower density of PGXTEC-YBG relative to SD-YBG result in a smaller aerodynamic diameter (3-4 µm) and double the fine particle fraction in cascade impaction studies, variables correlated with improved inhalability and thus deposition in the distal regions of the lung. Correspondingly, PGXTEC-YBG shows an approximately double phagocytic index in vitro and enhanced suppression of CD206 expression and arginase-1 activity, lower levels of macrophage stress, and comparable capacity for promoting pro-inflammatory cytokine release in ex vivo murine precision cut lung slices relative to SD-YBG. These findings highlight PGXTEC-YBG's utility as a promising inhalable therapeutic that can offer improved delivery to the disease site while maintaining strong biological anti-fibrotic effects and reduced systemic toxicity.

PMID:40719359 | DOI:10.1002/adhm.202501952

Semin Respir Crit Care Med. 2025 Jul 24. doi: 10.1055/a-2649-9359. Online ahead of print.

ABSTRACT

Pulmonary fibrosis is characterized by scarring and thickening of the lung parenchyma due to excessive deposition of collagen and other extracellular matrix (ECM) proteins. This leads to disruption of gas exchange areas and ultimately respiratory failure, a pathology shared across multiple interstitial lung diseases. Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease characterized by exertional dyspnea, dry cough, and restrictive lung defects. Clinical progression is marked by worsening lung function, declining exercise tolerance, and hypoxemia. High-resolution computed tomography (HRCT) in IPF typically shows reticular opacities and honeycombing, predominantly distributed in the subpleural regions and lower lobes of the lungs. The disease course is variable, with episodes of acute exacerbation associated with high mortality. Myofibroblasts and fibroblasts are central drivers of fibrogenesis through uncontrolled proliferation, migration, survival, senescence, myofibroblast differentiation, and ECM production. Myofibroblasts represent a heterogeneous population in both origin and function, arising from diverse precursor cells, including lung resident fibroblasts, endothelial cells, and mesothelial cells, and are shaped by tissue-specific niches. Persistent activation of (myo)fibroblasts is sustained by a complex network of profibrotic growth factors and their downstream transcriptional regulators. In this review, we comprehensively examine the cellular origins and molecular pathways underlying fibroblast activation, with an emphasis on mechanistic insights that may inform the development of targeted antifibrotic therapies to attenuate disease progression and improve patient outcomes.

PMID:40719115 | DOI:10.1055/a-2649-9359

Cureus. 2025 Jun 26;17(6):e86806. doi: 10.7759/cureus.86806. eCollection 2025 Jun.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown etiology. It has been demonstrated in European, American, and Asian populations that genetic factors, particularly the MUC5B rs35705950 SNP, represent a significant risk factor for the development of this disease. To date, no studies have been performed within African populations, thereby necessitating the execution of the present investigation. Methods: A case-control study was conducted from September 2021 to May 2024. It included 55 patients diagnosed with IPF and 61 control subjects. Comprehensive demographic, clinical, radiological, functional, and therapeutic data were collected. Additionally, genetic analysis for the MUC5B rs35705950 SNP was carried out in the genetic department of the University Hospital Hassan II of Fez (Morocco). Results: The patient cohort predominantly consisted of men, with a sex ratio of 49 men to six women. The mean age was 67.72 ± 6.406 years. Of the subjects, 58.2% were former smokers. Dyspnea was the most prevalent symptom (89.1%). Radiological assessments revealed that 70.9% of patients exhibited definite usual interstitial pneumonia. The median survival time was recorded at 4.75 years. Statistical analysis indicated a significant association between the MUC5B rs35705950 SNP and IPF (p = 0.0001). Conclusions: This study confirms that the MUC5B rs35705950 SNP is a major risk factor for IPF within the African population. It represents the first investigation of its kind on the African continent, with the hope that it will motivate further research efforts in Africa to yield more representative data.

PMID:40718325 | PMC:PMC12296943 | DOI:10.7759/cureus.86806

Cureus. 2025 Jul 24;17(7):e88645. doi: 10.7759/cureus.88645. eCollection 2025 Jul.

ABSTRACT

Background The clinical course of patients with idiopathic pulmonary fibrosis (IPF) and other progressive interstitial lung diseases (F-ILDs) varies from mild to severe worsening, which makes the development of new diagnostic and prognostic methods even more urgent. A number of studies have shown that plasma connective tissue growth factor (CTGF) is elevated during IPF, and that the levels of this substance are correlated with the changes in forced vital capacity (FVC). The aim of our study was to investigate CTGF levels in patients with F-ILDs group, including its subgroups IPF and other F-ILDs, as well as post-COVID-19 cases, and to assess their association with lung function changes over a 12-month period. Methods A prospective cohort study was conducted with patients observed over 30 months. The involvement period was 18 months, followed by a 12-month observation period. A total of 86 subjects were enrolled in the study. FVC (measured by spirometry), diffusing lung capacity for carbon monoxide (DLCO), and CTGF levels in blood serum (measured by enzyme-linked immunosorbent assay (ELISA)) were assessed at the beginning and end of the study. Results Regression analysis of the correlations between mean serum CTGF levels, FVC, and DLCO changes in the F-ILDs group demonstrated a significant negative correlation between the changes in mean serum CTGF levels, FVC, and DLCO. Similarly, in the IPF, idiopathic nonspecific interstitial pneumonia (iNSIP) and chronic sarcoidosis (IV stage) subgroups, there was a significant negative correlation between changes in mean serum CTGF levels, FVC, and DLCO. However, in the post-COVID-19 group, regression analysis did not reveal any correlations between changes in mean serum CTGF concentrations, FVC, and DLCO. Conclusion Our data suggest a correlation between decreased pulmonary function and increased CTGF levels in patients with IPF and other PPF conditions. Therefore, CTGF emerges as a potential surrogate marker for fibrosis progression in these patients. In contrast, post-COVID-19 fibrosis appears to be a non-progressive fibrotic disease; however, further monitoring is necessary.

PMID:40717875 | PMC:PMC12289458 | DOI:10.7759/cureus.88645

Respir Med. 2025 Jul 24;247:108269. doi: 10.1016/j.rmed.2025.108269. Online ahead of print.

ABSTRACT

BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) critically affects patient survival. This study aimed to determine whether an early treatment response could accurately predict prognostic outcomes in patients with AE-IPF.

METHODS: This retrospective cohort study conducted at Kobe City Medical Centre General Hospital analysed 100 patients with AE-IPF treated with steroid pulse therapy during January 2012-December 2021. The initiation day was defined as Day 1. Patients were classified into Responder or Non-Responder groups based on the changes in peripheral capillary oxygen saturation/fraction of inspired oxygen (S/F) ratios from Days 1-4. The primary outcome was 28-day mortality. Cox proportional hazards models assessed the association between 28-day mortality and potential prognostic factors, including age, KL-6 levels, S/F ratios on Day 1, and Responder group status.

RESULTS: The study cohort included 60 and 40 patients in the Responder and Non-Responder groups, respectively. The Responder group has significantly higher median IgG levels (1519 mg/dL vs. 1014 mg/dL) and lower mortality rates (12 % vs. 42.5 % at 28 days). On Day 1, the S/F ratios were comparable between the two groups. Similarly, age and levels of Krebs von den Lungen-6 also showed no significant differences. Multivariable Cox proportional hazards analysis revealed that higher initial S/F ratios (HR: 0.18, 95 % CI: 0.06-0.52) and classification in the Responder group (HR: 0.22, 95 % CI: 0.10-0.53) were associated with lower 28-day mortality.

CONCLUSION: Early improvements in S/F ratios may indicate improved survival in patients with AE-IPF, suggesting their potential importance in early therapeutic decisions.

PMID:40714207 | DOI:10.1016/j.rmed.2025.108269

Biochim Biophys Acta Mol Basis Dis. 2025 Jul 23:167992. doi: 10.1016/j.bbadis.2025.167992. Online ahead of print.

ABSTRACT

Accumulating evidence suggests that abnormalities in airway epithelial cells involve in the development of idiopathic pulmonary fibrosis (IPF). However, whether ciliary impairment contributes to IPF pathogenesis is unspecified. In this study, we evaluated the ciliogenesis potency of IPF-derived small airway epithelial cells (SAECs), assessed the effect of aberrant ciliogenesis on lung fibroblast activation and further identified whether improving ciliogenesis could attenuate pulmonary fibrosis. Here, we showed that upon external injury or serial cell passage, IPF-derived SAECs had greater decline in ciliogenesis potency as compared to healthy control (HC). Conditioned medium harvested from SAECs post injury, serial passage or silencing the ciliogenesis regulator FOXJ1 promoted the expression of α-smooth muscle actin (α-SMA) and fibronectin (FN) in human lung fibroblasts as compared to their corresponding controls. Mice with bleomycin (BLM)-induced lung fibrosis had reduced number of ciliated cells as compared to the saline control, while overexpressing Foxj1 in mouse lung attenuated the extent of pulmonary fibrosis. LY450139, a γ-secretase inhibitor, could also improve ciliogenesis in IPF-derived SAECs and inhibit lung fibroblast activation induced by ciliogenesis impairment. We demonstrated the contributing role of ciliogenesis impairment in IPF pathogenesis. Targeting the ciliogenesis abnormality may be a potential therapeutic strategy for IPF.

PMID:40712987 | DOI:10.1016/j.bbadis.2025.167992