BMJ Case Rep. 2025 Apr 8;18(4):e265092. doi: 10.1136/bcr-2025-265092.

ABSTRACT

A subset of idiopathic pulmonary fibrosis cases has a familial component. Telomeric mutations, such as those in the Regulator of Telomere Elongation Helicase 1 (RTEL1) gene, have been associated with lung fibrosis and a minority of dyskeratosis congenita (DC) cases.We present the case of a A male in his 50s with pulmonary fibrosis, cryptogenic hepatic cirrhosis, chronic anaemia and thrombocytopenia, lacy skin hyperpigmentation, dystrophic nails and canities. Family history included pulmonary fibrosis in two brothers. Genetic testing identified a RTEL1 mutation (c.3730T>C, p.Cys1244Arg) in heterozygosity, linked to a few cases of pulmonary fibrosis and DC. This mutation was confirmed in one brother and two sons. The patient was started on pirfenidone and referred for respiratory rehabilitation, haematological and transplant evaluations.Recognising family history and extrapulmonary manifestations in familial pulmonary fibrosis can expedite diagnosis, treatment and genetic counselling. Early detection of DC allows timely management of bone marrow failure and malignancy screening.

PMID:40199602 | DOI:10.1136/bcr-2025-265092

bioRxiv [Preprint]. 2025 Mar 24:2025.03.21.644589. doi: 10.1101/2025.03.21.644589.

ABSTRACT

Pseudomonas aeruginosa (PA) causes severe respiratory infections utilizing multiple virulence functions. Our previous findings on PA quorum sensing (QS)-regulated small molecule, 2'-aminoacetophenone (2-AA), secreted by the bacteria in infected tissues, revealed its effect on immune and metabolic functions favouring a long-term presence of PA in the host. However, studies on 2-AA's specific effects on bronchial-airway epithelium and pulmonary endothelium remain elusive. To evaluate 2AA's spatiotemporal changes in the human airway, considering endothelial cells as the first point of contact when the route of lung infection is hematogenic, we utilized the microfluidic airway-on-chip lined by polarized human bronchial-airway epithelium and pulmonary endothelium. Using this platform, we performed RNA-sequencing to analyse responses of 2-AA-treated primary human pulmonary microvascular endothelium (HPMEC) and adjacent primary normal human bronchial epithelial (NHBE) cells from healthy female donors and potential cross-talk between these cells. Analyses unveiled specific signaling and biosynthesis pathways to be differentially regulated by 2-AA in epithelial cells, including HIF-1 and pyrimidine signaling, glycosaminoglycan, and glycosphingolipid biosynthesis, while in endothelial cells were fatty acid metabolism, phosphatidylinositol and estrogen receptor signaling, and proinflammatory signaling pathways. Significant overlap in both cell types in response to 2-AA was found 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 upon exposure to 2-AA in the cell types studied. Murine in-vivo and additional in vitro cell culture studies confirmed cholesterol accumulation in epithelial cells. Results also revealed specific biomarkers associated with cystic fibrosis and idiopathic pulmonary fibrosis to be modulated by 2-AA in both cell types, with the cystic fibrosis transmembrane regulator expression to be affected only in endothelial cells. The 2-AA-mediated effects on healthy epithelial and endothelial primary cells within a microphysiological dynamic environment mimicking the human lung airway enhance our understanding of this QS signaling molecule. This study provides novel insights into their functions and potential interactions, paving the way for innovative, cell-specific therapeutic strategies to combat PA lung infections.

PMID:40196568 | PMC:PMC11974707 | DOI:10.1101/2025.03.21.644589

J Pharm Biomed Anal. 2025 Apr 3;262:116868. doi: 10.1016/j.jpba.2025.116868. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis is a high-mortality chronic lung disease, and currently existing medications have limited therapeutic efficacy with noticeable adverse effects, urgently necessitating the exploration of more effective and safer treatment options. Our preliminary studies have demonstrated that the leech extract group with molecular weight greater than 10 kDa (>10 kDa group) exhibited superior anti-idiopathic pulmonary fibrosis efficacy. To trace the active components of > 10 kDa group, it was separated by gel electrophoresis and analyzed by Nano LC-MS/MS. To further analyze the effects of these active components on the regulation of metabolic pathways in fibrotic lung tissue, the metabolites of lung tissue were analyzed by UPLC/MS after administration of > 10 kDa group in bleomycin-induced pulmonary fibrosis (BML-induced PF) mice for 28 days at a 0.179 mg/g per day. A total of 17 proteins were identified in > 10 kDa group and 46 endogenous metabolites were identified in lung tissue, among which 18 significantly differential metabolites were screened as potential metabolomics biomarkers. Metabolic pathway analysis demonstrated that these identified differential metabolites mainly involved biosynthesis of unsaturated fatty acids, phenylalanine-tyrosine and tryptophan biosynthesis and tryptophan metabolism signaling pathway, indicating that the active components of > 10 kDa group mainly regulated the metabolic disorders of lung tissue in BLM-induced mice by up-regulating the biosynthesis of unsaturated fatty acids, down-regulating phenylalanine-tyrosine and tryptophan biosynthesis, and adjusting tryptophan metabolism signaling pathway.

PMID:40194473 | DOI:10.1016/j.jpba.2025.116868

Radiol Med. 2025 Apr 7. doi: 10.1007/s11547-025-01985-1. Online ahead of print.

ABSTRACT

Interstitial lung diseases (ILD) constitute a large and heterogeneous group of disorders affecting the lung parenchyma. While idiopathic pulmonary fibrosis (IPF), the most common type of ILD, is the prototype of progressive fibrosis, other forms, collectively termed "progressive pulmonary fibrosis" (PPF), can show a similar clinical course. Detecting chronic fibrosing ILD progression necessitates radiological evidence using high-resolution computed tomography (HRCT), which determines eligibility for treatment. However, assessing the extent of fibrosis and progression on HRCT images is difficult and lacks specific guidelines. Therefore, expert oversight and high-quality visual assessment/scoring of complex disease patterns is essential to monitor disease changes. Twelve Italian chest radiologists deliberated on the current state of quantifying lung fibrosis using existing literature to develop practice-oriented consensus statements to assist radiologists in visually assessing/scoring lung fibrosis on HRCT images in patients with PPF. The resulting statements cover three key areas: (1) technical requirements necessary for accurate HRCT image assessment; (2) an easy-to-use quantification protocol for routine clinical practice; and (3) a multiple specialist approach by combining radiological, clinical, and histopathological findings for the correct diagnosis, prompt detection of PPF, and timely start of antifibrotic treatment. In future, automated quantitative HRCT evaluation will lead to new clinical assessment tools.

PMID:40192924 | DOI:10.1007/s11547-025-01985-1

J Respir Biol Transl Med. 2025 Mar;2(1):10001. doi: 10.70322/jrbtm.2025.10001. Epub 2025 Mar 7.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and fatal disease with an increasing incidence and limited therapeutic options. It is characterized by the formation and deposition of excess extracellular matrix proteins resulting in the gradual replacement of normal lung architecture by fibrous tissue. The cellular and molecular mechanism of IPF has not been fully understood. A hallmark in IPF is pulmonary fibroblast to myofibroblast transformation (FMT). During excessive lung repair upon exposure to harmful stimuli, lung fibroblasts transform into myofibroblasts under stimulation of cytokines, chemokines, and vesicles from various cells. These mediators interact with lung fibroblasts, initiating multiple signaling cascades, such as TGFβ1, MAPK, Wnt/β-catenin, NF-κB, AMPK, endoplasmic reticulum stress, and autophagy, contributing to lung FMT. Furthermore, single-cell transcriptomic analysis has revealed significant heterogeneity among lung myofibroblasts, which arise from various cell types and are adapted to the altered microenvironment during pathological lung repair. This review provides an overview of recent research on the origins of lung myofibroblasts and the molecular pathways driving their formation, with a focus on the interactions between lung fibroblasts and epithelial cells, endothelial cells, and macrophages in the context of lung fibrosis. Based on these molecular insights, targeting the lung FMT could offer promising avenues for the treatment of IPF.

PMID:40190620 | PMC:PMC11970920 | DOI:10.70322/jrbtm.2025.10001

Int J Stem Cells. 2025 Apr 7. doi: 10.15283/ijsc25011. Online ahead of print.

ABSTRACT

The etiology of chronic and lethal interstitial lung disease, termed idiopathic pulmonary fibrosis (IPF), remains unidentified. IPF induces pathological lung scarring that results in rigidity and impairs gas exchange, eventually resulting in premature mortality. Recent findings indicate that deubiquitinating enzymes play a key role in stabilizing fibrotic proteins and contribute to pulmonary fibrosis. The ubiquitin-specific protease 11 (USP11) promotes pro-fibrotic proteins, and its expression elevated in tissue samples from patients with IPF. Thus, this study aimed to examine the effects of loss of function of USP11 gene on the progression of pulmonary fibrosis by utilizing 3D cell culture alveolar organoids (AOs) that replicate the structure and functions of the proximal and distal airways and alveoli. Here, we applied the CRISPR/Cas9 system to knock out the USP11 gene in human induced pluripotent stem cells (hiPSCs) and then differentiated these hiPSCs into AOs. Loss of USP11 gene resulted in abnormalities in type 2 alveolar epithelial cells in the hiPSC-USP11KO-AOs. Moreover, knock out of the USP11 mitigates pulmonary fibrosis caused by TGF-β in hiPSC-USP11KO-AOs by reducing collagen formation and fibrotic markers, suggesting it has the therapeutic potential to treat IPF patients.

PMID:40189830 | DOI:10.15283/ijsc25011

BMC Pulm Med. 2025 Apr 5;25(1):157. doi: 10.1186/s12890-025-03624-x.

ABSTRACT

BACKGROUND: In this research project, we examined the relationship between tracheal size and respiratory function in individuals with Idiopathic Pulmonary Fibrosis (IPF). IPF is a long-term condition that affects the functioning of the lungs.

METHODS: This retrospective study included 86 patients diagnosed with IPF. Tracheal and bronchial diameters were measured using high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs); Force vital capacity (FVC), diffusion capacity for carbon monoxide (DLCO) and the gender, age, physiology (GAP) index was calculated. Patients were grouped according to demographic characteristics such as age, gender and smoking.

RESULTS: There was a significant positive correlation between the anteroposterior (AP) and transverse diameters of the trachea in the subcricoid region and the GAP index (r = 0.318, p = 0.003 and r = 0.312, p = 0.004, respectively). Similarly, subcricoid and carina areas were significantly correlated with both GAP index (r = 0.307, p = 0.006 and r = 0.334, p = 0.003, respectively) and FVC/DLCO ratio (r = 0.218, p = 0.049 and r = 0.245, p = 0.027, respectively). The main bronchial areas were also positively correlated with the GAP index, but no significant correlation was found between FVC and DLCO values and airway measurements. Each unit increase in GAP index was associated with a 1.69-fold increase in mortality risk (p = 0.0016, 95% confidence interval: 1.22-2.34).

CONCLUSION: Tracheal and main bronchial areas can be used as potential biomarkers in the assessment of disease severity and prognosis in IPF patients. In particular, the significant correlation of subcricoid and carina areas with both GAP index and FVC/DLCO ratio suggests that these measurements may be useful in the evaluation of disease progression.

PMID:40188355 | DOI:10.1186/s12890-025-03624-x

Sci Rep. 2025 Apr 5;15(1):11730. doi: 10.1038/s41598-025-94575-0.

ABSTRACT

There are well-documented differences in idiopathic pulmonary fibrosis (IPF) between sexes. The sex-specific prevalence of interstitial lung disease (ILD) subtypes in patients who require a full diagnostic work-up, including transbronchial cryobiopsy (TCB), after initial multidisciplinary discussion (MDD) is still unknown. Retrospective analysis of sex dispareties in patients with ILD who received an interdisciplinary indication for lung biopsy and underwent bronchoalveolar lavage, TCB and, if necessary, surgical lung biopsy at our ILD centre in Heidelberg between 11/17 and 12/21. The analysis included clinical parameters, visual assessment of computed tomography (CT), automated histogram analyses of lung density by validated software and final MDD-ILD classifications. A total of 402 patients (248 men, 154 women; mean age 68 ± 12 years) were analysed. Smoking behaviour was similar between the sexes, but women were more exposed to environmental factors, whereas men were more exposed to occupational factors. Women had higher rates of thyroid disease (29.9% vs. 12.5%; p < 0.001) and extrathoracic malignancies (16.2% vs. 9.3%; p = 0.041), but lower rates of coronary heart disease (7.1% vs. 19.8%; p < 0.001), stroke (1.3% vs. 6.5%; p = 0.014) and sleep apnoea (5.8% vs. 17.7%; p < 0.001). There were no sex differences regarding CT lung density. On visual inspection, women were less likely to have reticular opacities (65% vs. 76%; p = 0.017) and features of usual interstitial pneumonia (17% vs. 34%; p < 0.001). Among final diagnoses, hypersensitivity pneumonitis was more common in women (34.4%) compared to men (21.8%; p = 0.007). In contrast, IPF was more common in men (22.6%) than in women (7.1%; p < 0.001), and unclassifiable interstitial lung disease was also more frequent in men (21.8%) compared to women (6.5%; p < 0.001). This study highlights significant sex-based differences in the prevalence and characteristics of ILD requiring comprehensive diagnostic work-up. These findings underscore the importance of considering sex-specific factors in the diagnosis and management of ILD.

PMID:40188253 | DOI:10.1038/s41598-025-94575-0

Gene. 2025 Apr 3:149464. doi: 10.1016/j.gene.2025.149464. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disorder that is characterized by the disruption of lung architecture and respiratory failure. Notwithstanding the advent of novel therapeutic agents such as pirfenidone and nintedanib, there remains a pressing need for the development of innovative diagnostic and therapeutic strategies. Next-generation sequencing allows for the analysis of gene expression and the discovery of biomarkers. The objective of our study was to identify IPF-specific gene signatures, construct a diagnostic nomogram, and explore the role of the extracellular matrix (ECM) and epithelial-to-mesenchymal transition (EMT) in IPF pathogenesis. Utilizing data from the Gene Expression Omnibus (GEO) database, we identified differentially expressed genes (DEGs), performed weighted correlation network analysis (WGCNA), and constructed a nomogram. The present study has identified a group of key genes that are associated with IPF. The identified genes include GREM1, ITLN2, MAP3K15, RGS9BP, and SLCO1A2. The results of the immunohistochemical analysis indicated a significant correlation between these central genes and immune cell infiltration. Furthermore, Gene Set Enrichment Analysis (GSEA) revealed that these genes play a critical role in the pathogenesis of IPF. To validate the diagnostic potential of these core genes, we performed confirmatory analyses in independent Gene Expression Omnibus (GEO) datasets. We observed a significant upregulation of GREM1 expression in IPF animal and cellular models. These findings provide new insights into the molecular mechanisms of IPF and suggest potential targets for future diagnostic and therapeutic strategies.

PMID:40187620 | DOI:10.1016/j.gene.2025.149464

Nat Commun. 2025 Apr 5;16(1):3251. doi: 10.1038/s41467-025-58568-x.

ABSTRACT

Inhaled therapeutics have high potential for the treatment of chronic respiratory diseases of high unmet medical need, such as idiopathic pulmonary fibrosis (IPF). Preclinical and early clinical evidence show that cellular communication network factor 2 (CCN2), previously called connective tissue growth factor (CTGF), is a promising target for the treatment of IPF. In recent phase 3 clinical trials, however, systemic CCN2 inhibition failed to demonstrate a clinically meaningful benefit. Here, we present the preclinical profile of the inhaled anti-CCN2 Anticalin® protein PRS-220. Our study demonstrates that efficient pulmonary delivery directly translates into superior efficacy in relevant models of pulmonary fibrosis when compared to systemic CCN2 inhibition. Moreover, we present a holistic approach for the preclinical characterization of inhaled PRS-220 from state-of-the art in vitro and in vivo models to novel human ex vivo and in silico models, highlighting the advantage of inhaled drug delivery for treatment of respiratory disease.

PMID:40185752 | DOI:10.1038/s41467-025-58568-x

Radiother Oncol. 2025 Apr 2:110837. doi: 10.1016/j.radonc.2025.110837. Online ahead of print.

ABSTRACT

The incidence of radiation pneumonitis (RP) has decreased significantly compared to historical series, mainly due to improved radiotherapy techniques and patient selection. Nevertheless, some patients still develop RP. This guideline provides user-friendly flowcharts to address common clinical practice questions regarding RP. We summarize the current state of the art regarding the mechanisms, risk factors, diagnosis and treatment of RP. Dosimetric constraints to minimize the incidence of RP, as well as risk factors for developing RP, such as idiopathic pulmonary fibrosis (IPF) were identified. The combination of radiotherapy and medication as a risk factor for the development of RP was reviewed. RP remains a diagnosis of exclusion, but an algorithm for reaching the diagnosis has been proposed. Finally, practical approaches to the treatment of RP are outlined.

PMID:40185160 | DOI:10.1016/j.radonc.2025.110837

Colloids Surf B Biointerfaces. 2025 Mar 26;252:114652. doi: 10.1016/j.colsurfb.2025.114652. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal, progressive lung disease characterized by extensive scarring and thickening of lung tissue that leads to respiratory failure. Early and accurate diagnosis is crucial for monitoring disease progression and assessing therapeutic efficacy. While imaging modalities such as radiological X-rays and high-resolution computed tomography (HRCT) are commonly employed, magnetic resonance imaging (MRI) offers significant advantages, including superior soft tissue contrast and the absence of ionizing radiation. However, in lung MRIs are hindered by short transverse relaxation times, low proton density, and motion artifacts which is addressed herein by developing theranostic platform combining MRI imaging with targeted drug delivery using melanin nanoparticles conjugated with nintedanib (MNP-NIN). Chelation with ferric ions (MNP-NIN-Fe³⁺) enhanced MRI visibility enabling non-invasive imaging and drug tracking. MNP-NIN and MNP-NIN-Fe³ ⁺ nanoparticles were built with mean diameters of 189 ± 44 nm and 182 ± 35 nm, respectively and demonstrating successful NIN conjugation. Controlled NIN release followed zero-order kinetics over 36 days. MNP conjugation reduced cytotoxicity in BEAS-2B and A549 cells improving the drug's safety. MRI experiments conducted with a 7.0 T animal scanner demonstrated enhanced imaging contrast with MNP-NIN-Fe solutions compared to saline underscoring their potential for localized visualization and tracking within lung tissues. By integrating MRI diagnostics and targeted drug delivery, the MNP-NIN-Fe³ ⁺ system offers a promising solution to overcome current challenges in IPF management. This theranostic platform addresses the limitations of conventional imaging techniques while providing an innovative strategy for reducing drug-related systemic side effects and improving therapeutic efficacy.

PMID:40184721 | DOI:10.1016/j.colsurfb.2025.114652

Front Med (Lausanne). 2025 Mar 20;12:1543571. doi: 10.3389/fmed.2025.1543571. eCollection 2025.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial lung disease characterized by high mortality rates. An expanding body of evidence highlights the critical role of targeted therapies in the management of IPF. Nevertheless, there is a paucity of bibliometric studies that have comprehensively assessed this domain. This study seeks to examine global literature production and research trends related to targeted therapies for IPF.

METHOD: A literature search was conducted using the Web of Science Core Collection, encompassing publications from 2004 to 2024, focusing on targeted therapies for IPF. The bibliometric analysis utilized tools such as VOSviewer, CiteSpace, and the "bibliometrix" package in R.

RESULTS: A total of 2,779 papers were included in the analysis, demonstrating a general trend of continuous growth in the number of publications over time. The United States contributed the highest number of publications, totaling 1,052, while France achieved the highest average citation rate at 75.74. The University of Michigan Medical School was the leading institution in terms of publication output, with 88 papers. Principal Investigator Naftali Kaminski was identified as the most prolific researcher in the field. The American Journal of Respiratory Cell and Molecular Biology emerged as the journal with the highest number of publications, featuring 98 articles. In recent years, the research has emerged surrounding targeted therapies for IPF, particularly focusing on agents such as TGF-β, pathogenesis, and autotaxin inhibitor.

CONCLUSION: In this bibliometric study, we systematically analyze research trends related to targeted therapies for IPF, elucidating recent research frontiers and emerging directions. The selected keywords-idiopathic pulmonary fibrosis, targeted therapy, bibliometric analysis, transforming growth factor β, and autotaxin inhibitor-capture the essential aspects of this research domain. This analysis serves as a reference point for future investigations into targeted therapies.

PMID:40182841 | PMC:PMC11967194 | DOI:10.3389/fmed.2025.1543571

Immunol Lett. 2025 Aug;274:107006. doi: 10.1016/j.imlet.2025.107006. Epub 2025 Apr 1.

ABSTRACT

OBJECTIVE: This study investigates the involvement of heparanase in IPF pathogenesis and evaluates the therapeutic potential of heparanase inhibition.

METHODS: Plasma heparanase levels were measured in IPF patients and healthy controls. Macrophage infiltration and heparanase expression in bronchoalveolar lavage fluid (BALF) were analyzed using immunofluorescence. Bleomycin (BLM)-induced pulmonary fibrosis mouse models were treated with the heparanase inhibitor OGT2115. Disease severity, macrophage polarization, and heparanase expression were assessed through histological staining, hydroxyproline content measurement, flow cytometry, immunofluorescence, Transmission Electron Microscopy and Western blot analysis.

RESULTS: Elevated heparanase levels were found in the plasma of IPF patients and in macrophages from BALF. In BLM-induced mice, heparanase was predominantly expressed in M2 macrophages. OGT2115 treatment significantly reduced mortality, body weight loss, and fibrosis severity. Additionally, OGT2115 decreased M2 macrophage infiltration, attenuated lung fibrosis, and reduced autophagy markers LC3 I/II and P62.

CONCLUSION: Heparanase plays a crucial role in modulating M2 macrophage polarization and the progression of IPF. Targeting heparanase with OGT2115 effectively ameliorates pulmonary fibrosis and represents a promising therapeutic strategy for IPF management.

PMID:40180131 | DOI:10.1016/j.imlet.2025.107006

Sci Rep. 2025 Apr 3;15(1):11390. doi: 10.1038/s41598-025-90910-7.

ABSTRACT

Pirfenidone is an antifibrotic and anti-inflammatory drug used for the management of idiopathic pulmonary fibrosis. The current oral delivery of PD has multiple drawbacks, including first-pass metabolism and gastrointestinal discomfort. Efforts have been made to create nanostructured lipid carriers (NLCs) using solid lipids, liquid lipids, and surfactants through an emulsification process followed by ultrasonication to achieve sustained drug release. A central composite design (CCD) utilizing response surface methods (RSMs) was employed to develop and optimize the formulation. The assessed characteristics included particle size distribution, surface topography, drug entrapment efficiency, in vitro drug release, and kinetic profiles in animal models. Cytotoxicity experiments were performed on HepG2 and Caco-2 cell lines and compared with that of PD-NLCs. The optimized formulation yielded a particle size of 159.8 ± 3.46 nm and an encapsulation efficiency of 81.4 ± 7.1% after 10 freeze-thaw cycles of homogenized lipid carriers. In vitro tests assessing various tested flow rates revealed that over 95% of the released drug was retrieved. In vitro studies showed that the PD-loaded nanostructured lipid carrier (NLC) was more cytotoxic to HepG2 and Caco-2 cells than a pure aqueous solution of the drug. Using 25% w/w sorbitol as a cryoprotectant, the findings showed no variation in the properties of NLC before and after freeze-drying. PD-NLCs carriers were shown to have better bioavailability, longer retention time in the lung, and a 15.94-targeting factor related to the PD aqueous solution. Hence, the outcomes confirmed the potential of the PD-NLCs formulation to improve the efficacy of the drug in inhalation therapy.

PMID:40181013 | DOI:10.1038/s41598-025-90910-7

Eur Respir J. 2025 Apr 3:2402418. doi: 10.1183/13993003.02418-2024. Online ahead of print.

ABSTRACT

The complex pathogenic relationships between idiopathic pulmonary fibrosis (IPF) and its usually associated comorbidities remain poorly understood. While evidence suggests that some comorbidities may directly influence the development or progression of IPF or vice versa, whether these associations are causal or arise independently due to shared risk factors, such as aging, smoking, lifestyle, and genetic susceptibility, is still uncertain. Some comorbidities, such as metabolic syndromes, gastro-esophageal reflux disease, and obstructive sleep apnea, precede the development of IPF. In contrast, others, like pulmonary hypertension or lung cancer, often become apparent after its onset or during its progression. These timing patterns suggest a directional relationship in their associations. The issue is further complicated by the fact that patients often have multiple comorbidities, which may interact and exacerbate one another, creating a vicious cycle. To clarify these correlations, some studies have used causal inference methods (e.g., Mendelian randomisation) and exploration of underlying mechanisms; however, these efforts have not yet generated conclusive insights. In this review, we provide a general overview of the relationship between IPF and its comorbidities, emphasizing the pathogenic mechanisms underlying each comorbidity, potential shared pathobiology with IPF, and, when available, causal insights from Mendelian randomisation studies.

PMID:40180336 | DOI:10.1183/13993003.02418-2024

Respir Med. 2025 Apr 1:108081. doi: 10.1016/j.rmed.2025.108081. Online ahead of print.

ABSTRACT

BACKGROUND: Abnormal α-Klotho (KL) levels play an essential role in the pathogenesis of aging-related lung diseases. However, the correlation between circulating KL levels and aging-related lung diseases has not been determined. This study aimed to determine whether circulating KL levels causally affect aging-related lung diseases using Mendelian randomization (MR).

METHODS: Five KL-associated Single-nucleotide polymorphisms (SNPs) were analyzed using two-sample MR to assess their effects on three aging-related lung diseases: idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and lung cancer.

RESULTS: Based on a main casual effects model with MR analyses by the inverse variance weighted (IVW) method including multiplicative random-effects model (IVW-mre) and fixed-effects inverse variance-weighted model (IVW-fe), genetically predicted circulating KL levels were negatively related with risk of IPF (Odds ratio (ORIVW-mre), 0.999, 95% CI, 0.999-1.000, PIVW-mre = 0.008; OR IVW-fe, 0.999, 95% CI, 0.999-1.000, PIVW-fe = 0.042). Inversely, the circulating levels of KL displayed no clear association with COPD and lung cancer. No pleiotropy was detected.

CONCLUSIONS: Genetically predicted circulating KL was causally associated with a lower risk of IPF, suggesting a protective effect in preventing IPF risk. Therefore, KL may be a promising target for the prevention and therapeutic intervention in patients with IPF.

PMID:40180194 | DOI:10.1016/j.rmed.2025.108081

STAR Protoc. 2025 Apr 1;6(2):103721. doi: 10.1016/j.xpro.2025.103721. Online ahead of print.

ABSTRACT

Autotaxin (ATX), a secreted lysophospholipase D responsible for the extracellular production of the bioactive phospholipid lysophosphatidic acid (LPA), is a therapeutic target in idiopathic pulmonary fibrosis and pancreatic cancer, among other disorders, promoting the synthesis of novel ATX inhibitors. Here, we present a protocol for detecting and characterizing ATX inhibitors using a fluorometry-based microplate assay. We describe steps for a first screening of compounds, half-maximal inhibitory concentration (IC50) quantification of initial hits, screening for false positives, and identification of the hits' mode of inhibition. For complete details on the use and execution of this protocol, please refer to Stylianaki et al.1.

PMID:40178971 | DOI:10.1016/j.xpro.2025.103721

Eur J Phys Rehabil Med. 2025 Apr 3. doi: 10.23736/S1973-9087.25.08778-7. Online ahead of print.

ABSTRACT

INTRODUCTION: The efficacy of pulmonary rehabilitation (PR) in improving health-related quality of life (HRQoL) in patients with interstitial lung disease (ILD) still have some unresolved issues. This study aimed to identify this gap by using the 36-Item Short Form Survey (SF-36) to assess the advantages and disadvantages of PR in improving the HRQoL of patients with ILD.

EVIDENCE ACQUISITION: Self-controlled before-and-after interventional design research related to PR and ILD published in English were retrieved from PubMed, Embase, Web of Science, Scopus, Ovid, and Cochrane Library from inception to May 19, 2024. Data collected from the included studies were general clinical characteristics, study sample size, SF-36 physical component summary (PCS) score, SF-36 mental component summary (MCS) score, scores of the eight domains (physical function, role physical, bodily pain, general health, vitality, social function, role emotional, and mental health), PR time, and main elements of PR. Subgroup analysis was performed based on the PR time and ILD type. Sensitivity analysis was conducted by excluding one study at a time. Publication bias was assessed using Egger's Test, and the reliability of the studies was determined using the funnel plot and trim-and-fill method. Changes in SF-36 domain scores after PR were presented in a radar chart.

EVIDENCE SYNTHESIS: Pooled analysis of 15 studies involving 1289 patients with ILD who underwent PR showed that the patients had significantly higher PCS scores (weighted mean difference [WMD]=2.07, 95% CI: 1.06, 3.09) and MCS scores (WMD=4.48, 95% CI: 3.21, 5.76) after PR. According to disease types, subgroup analyses showed that patients with idiopathic pulmonary fibrosis had significantly higher PCS scores (WMD=3.15, 95% CI: 0.05, 6.24) but no change in MCS scores after PR (WMD=1.97, 95% CI: -1.91, 5.85). Additionally, subgroup analysis based on PR time revealed that the PCS scores of patients with ILD were significantly increased after <8 weeks of PR (WMD=2.09, 95% CI: 1.02, 3.17) but not after ≥8 weeks of PR (WMD=1.94, 95% CI: -1.05, 4.93, P=0.204). All included studies were of good quality, and the pooled and subgroup results were robust without publication bias.

CONCLUSIONS: In patients with ILD, PR less than 8 weeks effectively improved the physical and mental HRQoL, but not the social function. Future studies should focus on determining the optimal PR time for enhancing HRQoL in patients with ILD and evaluating the efficacy of PR in different ILD types and other HRQoL domains.

PMID:40178411 | DOI:10.23736/S1973-9087.25.08778-7

Respir Res. 2025 Apr 2;26(1):123. doi: 10.1186/s12931-025-03195-9.

ABSTRACT

BACKGROUND: Cardiopulmonary exercise testing (CPET) is feasible, valid, reliable, and clinically useful in interstitial lung disease (ILD). However, maximal CPET values are often presented relative to body mass, whereas fat-free mass (FFM) may better reflect metabolically active muscle during exercise. Moreover, despite the value of maximal parameters, people with ILD do not always exercise maximally and therefore clinically relevant submaximal parameters must be identified. Therefore, this study assessed peak oxygen uptake (VO2peak) relative to FFM, identifying the validity of common scaling techniques; as well as characterising the oxygen uptake efficiency slope (OUES) and plateau (OUEP) as possible submaximal parameters.

METHODS: Participants with ILD underwent assessment of body composition and CPET via cycle ergometry during a single study visit. To determined effectiveness of scaling for body size, both body mass and FFM were scaled using ratio-standard (X/Y) and allometric (X/Yb) techniques. Pearsons's correlations determined agreement between OUES, OUEP, and parameters of lung function. Cohens kappa (κ) assessed agreement between OUES, OUEP and VO2peak.

RESULTS: A total of 24 participants (7 female; 69.8 ± 7.5 years; 17 with idiopathic pulmonary fibrosis) with ILD completed the study. Maximal exercise parameters did not require allometric scaling, and when scaled to FFM, it was shown that women have a significantly higher VO2peak than men (p = 0.044). Results also indicated that OUEP was significantly and positively correlated with DLCO (r = 0.719, p < 0.001), and held moderate agreement with VO2peak (κ = 0.50, p < 0.01).

CONCLUSION: This study identified that ratio-standard scaling is sufficient in removing residual effects of body size from VO2peak, and that VO2peak is higher in women when FFM is considered. Encouragingly, this study also identified OUEP as a possible alternative submaximal marker in people with ILD, and thus warrants further examination.

PMID:40176026 | DOI:10.1186/s12931-025-03195-9