Idiopathic Pulmonary Fibrosis

Quantitative HRCT as a surrogate outcome measure for nintedanib treatment in systemic sclerosis-interstitial lung disease and idiopathic pulmonary fibrosis

Thu, 2025-06-26 06:00

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

Categories: Literature Watch

Exploration of plasma factor profiles involved in tumor growth factors in non-small cell carcinoma patients with interstitial pneumonia

Thu, 2025-06-26 06:00

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

Categories: Literature Watch

Identification of DNA damage repair-related diagnostic markers for idiopathic pulmonary fibrosis via WGCNA

Thu, 2025-06-26 06:00

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

Categories: Literature Watch

Comparative Long-term Effects of Nintedanib and Pirfenidone in Idiopathic Pulmonary Fibrosis: A Real-life Study with Five-year Follow-up

Thu, 2025-06-26 06:00

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

Categories: Literature Watch

Discovery of HW201877: A Highly Potent and Orally Bioavailable Inhibitor of 15-Prostaglandin Dehydrogenase to Potentiate Tissue Repair and Regeneration

Thu, 2025-06-26 06:00

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

Categories: Literature Watch

LncRNA-536 and RNA-Binding Protein RBM25 Interactions in Pulmonary Artery Smooth Muscle Cells: Implications in Pulmonary Hypertension

Thu, 2025-06-26 06:00

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

Categories: Literature Watch

Radiological Insights into UIP Pattern: A Comparison Between IPF and Non-IPF Patients

Thu, 2025-06-26 06:00

J Clin Med. 2025 Jun 12;14(12):4162. doi: 10.3390/jcm14124162.

ABSTRACT

Background/Objectives: This study aims to distinguish radiological differences between primary idiopathic Usual Interstitial Pneumonia (UIP) and secondary UIP patterns Methods: This retrospective study included patients with HRCT findings consistent with a UIP pattern. Final diagnoses were established via multidisciplinary discussion and classified as primary UIP/IPF or secondary UIP, following the 2022 ATS/ERS/JRS/ALAT guidelines. An expert thoracic radiologist (>10 years of experience), blinded to clinical data, reviewed the earliest available HRCT assessing key imaging features: honeycombing (micro-, macro- or exuberant), fibrosis distribution (symmetry, anterior-upper lobe sign, etc.), ground-glass opacities (GGO), dilatation of esophagus. Additionally, AI software AVIEW Build 1.1.46.28-win Coreline (©Coreline Soft Co., Ltd. All Rights Reserved). performed lung texture analysis, quantifying total lung volume and radiological patterns. Statistical analysis was performed to reveal results. Results: Among 53 cases, 31 were classified as IPF and 22 as secondary UIP cases. The expert radiologist achieved a diagnostic sensitivity of 82.9%, specificity of 889%, with a positive predictive value of 93.5%-in distinguishing between primary and secondary UIP. Primary UIP cases exhibited typical hallmark radiological features, including uniform honeycombing with cranio-caudal distribution (90.3%). Reticulations contributed significantly to the fibrotic texture, maintaining a consistent cranio-caudal gradient and axial symmetry (84.8%). Secondary UIP displayed more significant radiological heterogeneity, including patchy fibrosis with irregular GGO distribution (84.5% versus 53.33%); other findings-such as exuberant honeycombing, four corner sign and wedge-shaped fibrosis-were mainly observed in secondary pattern with respective percentages of 31.8%, 9% and 49%. Conclusions: Experienced thoracic radiologists, leveraging hallmark imaging features, play a critical role in improving diagnostic accuracy between primary and secondary UIP patterns.

PMID:40565908 | DOI:10.3390/jcm14124162

Categories: Literature Watch

Alteration of Lipid Metabolism in Patients with IPF and Its Association with Disease Severity and Prognosis: A Case-Control Study

Thu, 2025-06-26 06:00

Int J Mol Sci. 2025 Jun 17;26(12):5790. doi: 10.3390/ijms26125790.

ABSTRACT

The pathogenesis of idiopathic pulmonary fibrosis (IPF) involves complex interactions between epithelial, mesenchymal, immune, and endothelial cells, often aggravated by lipid metabolism dysfunction, mitochondrial, and peroxisomal abnormalities. Changes in lipid metabolism may drive fibrotic processes, suggesting the potential of lipid biomarkers for disease monitoring. We compared here the cholesterol metabolism and very-long-chain fatty acid profiles of patients with IPF with healthy controls. The IPF patients' lipidic profiles were also evaluated according to disease severity and progression rate. This prospective, observational study involved 50 IPF patients at disease diagnosis before antifibrotic treatment initiation and 50 age- and gender-matched healthy controls. Using a serum lipidomic profile, we focused on cholesterol synthesis, mitochondrial and peroxisomal markers, inflammatory lipids, and oxidative stress markers. Disease severity was evaluated using the Gender-Age-Physiology (GAP) index, while the prognosis was assessed by classifying patients as rapid or slow progressors based on a 24-month follow-up. IPF patients exhibited lower levels of cholesterol synthesis precursors (e.g., lathosterol), mitochondrial oxysterols, and inflammatory mediators (e.g., arachidonic acid) compared to controls. Reduced levels of these biomarkers were also associated with higher disease severity and rapid disease progression. Conversely, some peroxisomal markers (e.g., brassidic acid and nervonic acid) showed altered trends depending on disease severity. Our findings indicate that patients with IPF, compared to healthy controls, may show lipidomic alterations, particularly a reduction in cholesterol precursors and docosahexaenoic acids, which are also associated with IPF severity and progression. While preliminary, this study suggests lipidomics to be a promising tool to stratify IPF severity and prognosis.

PMID:40565254 | DOI:10.3390/ijms26125790

Categories: Literature Watch

Disease-Specific Novel Role of Growth Differentiation Factor 15 in Organ Fibrosis

Thu, 2025-06-26 06:00

Int J Mol Sci. 2025 Jun 14;26(12):5713. doi: 10.3390/ijms26125713.

ABSTRACT

Growth Differentiation Factor 15 (GDF15), also known as non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1) or macrophage inhibitory cytokine 1 (MIC-1), is a stress- and inflammation-induced cytokine distantly related to the TGF-β superfamily. Its highly elevated levels showed close association with various pathological conditions, making it an emerging biomarker of disease prognosis. However, most GDF15-mediated effects under normal physiology and various pathological conditions are poorly understood. This is partly because the only known GDF15 receptor is exclusively localized in the brain, and how GDF15 functions peripherally is currently unknown. Mounting recent evidence has shown GDF15's critical role in fibrosis in multiple organs, such as the liver, lung, and kidney. Evidence further suggests that it can either contribute to fibrosis by promoting inflammation and fibroblast activation or confer protective effects by modulating the immune response and mitigating fibrosis severity. Thus, the exact role of GDF15 in fibrosis can vary depending on the organ involved and the specific disease context. For example, increased GDF15 in idiopathic pulmonary fibrosis (IPF) promotes fibrosis via fibroblast activation and collagen deposition. Conversely, GDF15 might have a protective role in liver fibrosis, with decreased GDF15 levels causing increased fibrosis severity, while GDF15 treatment ameliorates fibrosis. Due to its close association with fibrosis, GDF15 is being investigated as a potential biomarker for disease severity and monitoring treatment response. However, further research unraveling its mechanisms of action is needed to explore the potential of GDF15 as a therapeutic target for treating fibrosis, either by modulating its expression or utilizing its immunomodulatory properties. This review marshals the limited studies addressing the recently appreciated differential role of GDF15 in regulating the fibrotic process in different organs. The review also discusses the aspects of further research needed to highlight GDF 15 as a novel predictor and therapeutic target for fibrosis in different organs.

PMID:40565178 | DOI:10.3390/ijms26125713

Categories: Literature Watch

Predictive Biomarkers and Novel Treatments for the Progressive Fibrosing Phenotype in Interstitial Lung Disease Associated with Connective Tissue Disease

Thu, 2025-06-26 06:00

Biomedicines. 2025 Jun 13;13(6):1463. doi: 10.3390/biomedicines13061463.

ABSTRACT

Progressive fibrosing interstitial lung disease (PF-ILD) is a significant complication of connective tissue diseases (CTDs), particularly in systemic sclerosis (SSc), rheumatoid arthritis (RA), and idiopathic inflammatory myopathies (IIM). Despite clinical similarities with idiopathic pulmonary fibrosis (IPF), CTD-associated ILDs exhibit distinct pathogenetic and immunologic features. Objective: This review aims to summarize key predictive biomarkers and current treatment strategies associated with the progressive fibrosing phenotype in SSc-ILD, RA-ILD, and IIM-ILD. Methods: We conducted a focused literature search of PubMed and Scopus databases covering publications from January 2010 to February 2024. Included studies evaluated serum, cellular, or genetic biomarkers with predictive value for disease progression or treatment response. Only peer-reviewed English-language articles were included. Exclusion criteria encompassed single case reports and editorials. Results: Several biomarkers, including KL-6, SP-D, CXCL4, and anti-MDA5, demonstrate potential in predicting fibrotic progression in CTD-ILDs. However, variability in sensitivity and specificity across CTD subtypes limits broad clinical applicability. Therapeutic agents such as nintedanib and pirfenidone show efficacy in slowing lung function decline. Biologics including rituximab and tocilizumab offer additional options, particularly in immunologically active diseases. Conclusion: Although promising biomarkers and therapies are emerging, no single marker or intervention currently predicts or modifies PF-ILD outcomes across all CTD subsets. Prospective studies and integrative biomarker panels are needed to improve patient stratification and guide therapy.

PMID:40564181 | DOI:10.3390/biomedicines13061463

Categories: Literature Watch

Comorbidities' Effect on IPF: Pathogenesis and Management

Thu, 2025-06-26 06:00

Biomedicines. 2025 Jun 1;13(6):1362. doi: 10.3390/biomedicines13061362.

ABSTRACT

In recent years, there has been a growing recognition within the medical community that idiopathic pulmonary fibrosis (IPF) cannot be effectively managed through a singular focus on the disease itself. Instead, a dual approach is essential, one that not only aims to prolong survival by targeting the underlying pathological mechanisms of IPF but also addresses the numerous comorbidities that frequently complicate the clinical picture for affected individuals. This narrative review seeks to provide a detailed and comprehensive exploration of the various comorbid conditions associated with IPF, which may include cardiovascular disease (CVD), lung cancer (LC), gastroesophageal reflux disease (GERD), obstructive sleep apnea (OSA), and anxiety/depression, among others. By understanding the interplay between these comorbidities and IPF, healthcare providers can better tailor treatment regimens to meet the holistic needs of patients. Furthermore, this review delves into both current management strategies and emerging therapeutic approaches for these comorbidities, emphasizing the importance of interdisciplinary collaboration in clinical practice. By synthesizing the latest research and clinical insights, this review aims to enhance awareness and understanding of the complexities surrounding IPF management, ultimately guiding clinicians in developing more effective, individualized care plans that address not only the fibrotic lung disease but also the broader spectrum of health challenges faced by patients. Through this comprehensive overview, we hope to contribute to the ongoing dialogue about improving quality of life and survival rates for individuals living with IPF.

PMID:40564081 | DOI:10.3390/biomedicines13061362

Categories: Literature Watch

Spatial Transcriptomics in Lung Cancer and Pulmonary Diseases: A Comprehensive Review

Thu, 2025-06-26 06:00

Cancers (Basel). 2025 Jun 9;17(12):1912. doi: 10.3390/cancers17121912.

ABSTRACT

Recent advancements in spatial transcriptomics (ST) have revolutionized our understanding of the lung's cellular organization and pathological alterations. By preserving the spatial distribution of gene expression, ST reveals localized immune niches, stromal-epithelial interactions, and disease-associated transcriptional "hotspots" that cannot be captured by conventional sequencing methods alone. In lung cancer, ST-based investigations have delineated distinct tumor microenvironments between tumor cores and invasive fronts, revealing prognostically significant gene signatures and identifying subpopulations with differential responses to immunotherapy and chemotherapy. Similarly, in chronic obstructive pulmonary disease, asthma, and idiopathic pulmonary fibrosis, ST has mapped the ecosystem, including immune cells, inflammatory mediators, and fibroblast subtypes, of discrete regions within diseased lung tissue, offering mechanistic insights into disease progression and tissue remodeling. In addition, a more recent ST study provides spatial information for where drugs act within tissues. This review highlights the emerging role of spatial transcriptomics in respiratory research, demonstrating its potential to refine disease classification, elucidate mechanisms of therapeutic resistance, and inform spatially guided personalized interventions in respiratory diseases.

PMID:40563563 | DOI:10.3390/cancers17121912

Categories: Literature Watch

Inhibiting mitoNEET restores mitochondrial redox homeostasis and attenuates myofibroblast differentiation

Wed, 2025-06-25 06:00

Free Radic Biol Med. 2025 Jun 23:S0891-5849(25)00794-4. doi: 10.1016/j.freeradbiomed.2025.06.045. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis is a chronic and incurable lung disease characterized by progressive destruction and scarring of lung tissue. A hallmark of Idiopathic pulmonary fibrosis is the accumulation of extracellular matrix produced by differentiated myofibroblasts. Recent studies have highlighted the role of reactive oxygen species and mitochondrial dysfunction in myofibroblast differentiation and disease progression. MitoNEET, also known as CDGSH iron-sulfur (Fe-S) domain-containing protein 1 (CISD1), is an outer mitochondrial membrane protein that contains iron-sulfur clusters and regulates mitochondrial function by controlling iron homeostasis and reactive oxygen species generation. However, the role of mitoNEET in redox signaling during fibrosis remains unclear. In this study, we investigated the role of mitoNEET in TGF-β-induced myofibroblast differentiation. We found that TGF-β treatment increased mitoNEET mRNA and protein levels in lung fibroblasts. Notably, pharmacological inhibition or short hairpin RNA-mediated knockdown of mitoNEET effectively attenuated TGF-β-induced myofibroblast differentiation, which was accompanied by a reduction in mitochondrial reactive oxygen species levels. Our findings indicate that mitoNEET regulates myofibroblast differentiation through redox-mediated mechanisms, highlighting its role as a redox regulator in fibrosis progression. Targeting mitoNEET to restore redox balance may provide a novel therapeutic strategy for idiopathic pulmonary fibrosis.

PMID:40562129 | DOI:10.1016/j.freeradbiomed.2025.06.045

Categories: Literature Watch

Prognosis and prognostic factors for chronic fibrosing idiopathic interstitial pneumonias

Wed, 2025-06-25 06:00

Respir Investig. 2025 Jun 24;63(5):762-770. doi: 10.1016/j.resinv.2025.06.005. Online ahead of print.

ABSTRACT

Progressive lung fibrosis is frequently observed in patients with idiopathic interstitial pneumonias (IIPs), especially in those with idiopathic pulmonary fibrosis (IPF) being a representative form of IIPs characterized by a poor prognosis, even in the era of antifibrotic therapy. Predicting prognosis is essential for informing patients and determining future treatment strategies. Multiple prognostic factors have been reported for these diseases. The international clinical practice guidelines for IPF were repeatedly revised in 2010, 2018, and 2022, and the multidisciplinary classification of IIPs was updated in 2013. These updates have led to changes in how patients are classified under various IIP subtypes. Recent advances in the areas of genetic polymorphisms, radiological image analysis, and deep learning technology have helped identify multiple prognosis predictive factors for IPF and other forms of IIPs. This review provides an updated summary of the prognosis and prognostic predictors of IPF and other chronic fibrotic IIPs, incorporating recent reports published since antifibrotic therapy became the standard treatment for IPF and other forms of progressive pulmonary fibrosis, and covers other latest advancements and technologies as well.

PMID:40561889 | DOI:10.1016/j.resinv.2025.06.005

Categories: Literature Watch

Relationship between fibroblastic foci and respiratory function: Does the abundance of fibroblastic foci reflect a recent decline in respiratory function?

Wed, 2025-06-25 06:00

Ann Diagn Pathol. 2025 Jun 22;79:152522. doi: 10.1016/j.anndiagpath.2025.152522. Online ahead of print.

ABSTRACT

AIMS: Fibroblastic foci (FF) are main findings in idiopathic pulmonary fibrosis (IPF) but are not specific to IPF. Pirfenidone and nintedanib are standard antifibrotic treatments for IPF and affect factors associated with fibroblasts. A proportion of interstitial lung diseases (ILDs) are progressive fibrosing ILDs (PF-ILDs). This progressive fibrosing phenotype includes various ILDs, including fibrotic hypersensitivity pneumonitis (FHP) and connective tissue disease-related ILD (CTD-ILD). We examined the relationship between FF and a relative decline in respiratory function.

METHODS AND RESULTS: Among patients with lung transplantation (LT), those diagnosed with IPF, nonspecific interstitial pneumonia (NSIP), CTD-ILD, and FHP for whom respiratory function test results within 24 months before LT were retrospectively available were included (n = 67). Patients were classified as PF-ILD+ or PF-ILD- based on the criteria for the progression of a relative decline in the predicted value of forced vital capacity (FVC) within 24 months before LT. We classified FF into peripheral (pFF), alveolar (aFF), centrilobular (cFF), and distorted or dense fibrotic lesions (dFF). The number of FF/cm2 at each location was counted, and its percentage was calculated. Spearman's rank correlation coefficient between a relative decline in %FVC and total FF/cm2 in NSIP was 0.721. The dFF/cm2 and dFF/total FF ratios were higher and the aFF/total FF ratio was lower in the PF-ILD+ group than in the PF-ILD- group.

CONCLUSION: Total FF correlated with relative declines in %FVC in NSIP. Higher dFF/total FF ratios were associated with progressive status, and higher aFF/total FF ratios were associated with less progressive status.

PMID:40561677 | DOI:10.1016/j.anndiagpath.2025.152522

Categories: Literature Watch

Secreted Phosphoprotein 1 in Lung Diseases

Wed, 2025-06-25 06:00

Metabolites. 2025 May 30;15(6):365. doi: 10.3390/metabo15060365.

ABSTRACT

Secreted phosphoprotein 1 (SPP1), also known as osteopontin (OPN) or early T lymphocyte activation protein 1 (ETA-1), is a multifunctional protein involved in numerous biological processes, including immune modulation, stress response, and tissue remodeling. The role of SPP1 in interstitial lung diseases (ILDs) has become an area of increasing interest, given its elevated expression in various ILDs such as idiopathic pulmonary fibrosis (IPF), connective tissue disease-associated ILD (CTD-ILD), and pneumoconiosis, especially with recent data derived from single-cell RNA sequencing. In addition to ILDs, SPP1 has been implicated in infectious granulomatous lung diseases, lung and pleural malignancies, airway diseases, and COVID-19. In most cases, higher SPP1 levels in serum, bronchoalveolar lavage fluid, or lung tissue carry a poor prognosis. SPP1 is expressed in multiple cells critical for fibrogenesis, including macrophages, epithelial cells, and fibroblasts, and SPP1 has emerged as a potential target for therapeutic interventions. Here, we review the proposed mechanisms by which SPP1 contributes to the development of lung disease, with an emphasis on ILD.

PMID:40559389 | DOI:10.3390/metabo15060365

Categories: Literature Watch

Malnutrition, Sarcopenia, and Malnutrition Sarcopenia Syndrome in Idiopathic Pulmonary Fibrosis

Wed, 2025-06-25 06:00

Adv Respir Med. 2025 May 29;93(3):11. doi: 10.3390/arm93030011.

ABSTRACT

Introduction: Idiopathic pulmonaryy fibrosis (IPF) is a progressive interstitial lung disease with a poor prognosis. While comorbidities like pulmonary hypertension and lung cancer have been studied extensively, less attention has been paid to the implications of malnutrition and sarcopenia in patients with IPF. This study aimed to assess the prevalence of malnutrition, sarcopenia, and the combined malnutrition-sarcopenia syndrome in patients with IPF using the latest diagnostic criteria from the Global Leadership Initiative on Malnutrition (GLIM) and the European Working Group on Sarcopenia in Older People 2 (EWGSOP2). Methods: A prospective, observational, multicenter study was conducted, focusing on patients with idiopathic pulmonary fibrosis (IPF). All participants provided informed consent, and the study followed ethical guidelines. Malnutrition was diagnosed based on the GLIM criteria, requiring one phenotypic and one etiological criterion, with muscle mass assessed via bioelectrical impedance analysis (BIA). Sarcopenia was screened following the EWGSOP2 recommendations. The statistical analysis was performed using JAMOVI version 2.3.22, with significance set at p < 0.05. Results: The findings revealed that 77.65% of the participants were malnourished, and 20% had sarcopenia. The malnourished patients had significantly lower body weight, height, and muscle mass compared to the non-malnourished patients. Furthermore, the patients with malnutrition exhibited poorer health-related quality of life scores. This study also identified the malnutrition-sarcopenia syndrome in 8.23% of the participants. Conclusions: Malnutrition, based on the GLIM criteria was identified in three out of four patients with IPF, while sarcopenia according to the EWGSOP2 was present in one out of five. This study underscores the necessity for routine screening for malnutrition and sarcopenia in patients with IPF.

PMID:40558110 | DOI:10.3390/arm93030011

Categories: Literature Watch

Cellular senescence-related gene signatures in idiopathic pulmonary fibrosis: insights from bioinformatics

Wed, 2025-06-25 06:00

Front Immunol. 2025 Jun 10;16:1557848. doi: 10.3389/fimmu.2025.1557848. eCollection 2025.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by irreversible lung tissue scarring. Cellular senescence (CS) plays a significant role in IPF pathogenesis, yet the specific molecular mechanisms remain unclear. This study aimed to identify key CS-related differentially expressed genes (CS-DEGs) and investigate their potential as diagnostic biomarkers and therapeutic targets for IPF.

METHODS: Bioinformatics analysis was conducted on the GSE53845 dataset to identify CS-DEGs in IPF. Gene set enrichment analysis (GSEA), protein-protein interaction (PPI) network analysis, and functional enrichment analyses were performed to explore the biological functions and pathways associated with CS-DEGs. External validation of the identified CS-DEGs was performed using two independent datasets, GSE32537 and GSE24206. Immunofluorescence staining on lung tissue samples from IPF patients and normal controls was performed to validate the expression of key CS-DEGs.

RESULTS: A total of 122 DEGs were identified, and 8 core CS-DEGs were selected. CDKN2A, VEGFA, SOX2, and FOXO3 were validated as key CS-DEGs, with high diagnostic potential for IPF. Functional enrichment analysis revealed their involvement in critical biological pathways, including cellular senescence, immune response, and fibrosis regulation. Immunofluorescence staining confirmed higher expression of CDKN2A and SOX2, and lower expression of FOXO3 and VEGFA in IPF lung tissues compared to normal controls.

CONCLUSION: This study highlights the significant role of CS-related genes in the pathogenesis of IPF and identifies four key CS-DEGs (CDKN2A, SOX2, FOXO3, and VEGFA) that could serve as potential biomarkers and therapeutic targets for IPF, providing a basis for further research.

PMID:40557159 | PMC:PMC12185296 | DOI:10.3389/fimmu.2025.1557848

Categories: Literature Watch

Successful Tepotinib Treatment in MET Exon 14 Skipping Mutation-Positive Lung Adenocarcinoma With Idiopathic Pulmonary Fibrosis Through Nintedanib Combination

Wed, 2025-06-25 06:00

Respirol Case Rep. 2025 Jun 23;13(6):e70241. doi: 10.1002/rcr2.70241. eCollection 2025 Jun.

ABSTRACT

The mesenchymal-epithelial transition exon 14 (METex14) skipping mutation is a driver of non-small cell lung cancer (NSCLC). MET tyrosine kinase inhibitors (TKIs), such as tepotinib, are effective against METex14 skipping-positive NSCLC but carry a risk of acute exacerbation of interstitial lung disease (AE-ILD) in patients with idiopathic pulmonary fibrosis (IPF). Here, we present a case of a 54-year-old man with IPF and METex14 skipping-positive lung adenocarcinoma. Following first-line platinum-based chemotherapy, disease control was not achieved for either lung cancer or IPF. Therefore, the patient underwent second-line treatment with tepotinib and the antifibrotic agent nintedanib. This combination effectively controlled both lung cancer and IPF, resulting in a partial response without AE-ILD. Our case suggests that nintedanib treatment may offer a safe and effective option for progressive IPF during MET-TKI therapy, presenting a novel therapeutic approach for patients with lung cancer complicated by IPF.

PMID:40556834 | PMC:PMC12185779 | DOI:10.1002/rcr2.70241

Categories: Literature Watch

Target organ the lungs: diversity of fibrotic pulmonary diseases

Tue, 2025-06-24 06:00

Inn Med (Heidelb). 2025 Jun 24. doi: 10.1007/s00108-025-01911-7. Online ahead of print.

ABSTRACT

BACKGROUND: Fibrotic lung diseases are part of the large and heterogeneous group of interstitial lung diseases (ILD), which are characterized by a progressive fibrotic remodelling of alveolar lung parenchyma.

OBJECTIVE: Overview of the spectrum of fibrotic lung diseases.

MATERIAL AND METHODS: A literature search was carried out in the PubMed and MEDLINE database.

RESULTS: The etiology of fibrotic ILD is diverse and includes inhaled exogenous noxious substances (dust, gases), infections, drug reactions, ionizing radiation and endogenous autoimmune or rare genetically determined metabolic and storage disorders; however, the etiology of some ILDs, so-called idiopathic interstitial pneumonia (IIP), is not fully understood although environmental pollution, tobacco smoke and genetic polymorphisms have been identified as risk factors. The most important and best studied representative of IIP is idiopathic pulmonary fibrosis (IPF). The diagnosis of ILD is complex and requires an interdisciplinary approach taking the clinical presentation, radiological patterns, and possibly bronchoalveolar lavage and histological findings into account. Characteristic of progressive fibrotic lung disease is progressive fibrotic tissue remodeling, which is manifested as clinical, functional and radiological deterioration and is referred to as progressive pulmonary fibrosis (PPF). Antifibrotic drugs delay the progression of IPF and PPF but are not curative.

DISCUSSION: In addition to early diagnosis and preventive strategies, a better understanding of the causes of fibrotic ILD is required in order to avoid triggering noxious agents, identify dysregulated signalling pathways and develop targeted treatment.

PMID:40555758 | DOI:10.1007/s00108-025-01911-7

Categories: Literature Watch

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