Pulm Circ. 2025 Feb 2;15(1):e70046. doi: 10.1002/pul2.70046. eCollection 2025 Jan.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a leading indication for lung transplantation. Pulmonary hypertension (PH), a common comorbidity in IPF, has gained renewed attention following the updated ESC/ERS guidelines, which redefine diagnostic thresholds for PH. This study evaluates the impact of the revised PH criteria on transplant waitlist outcomes among IPF patients. Specifically, we assessed the prevalence of PH under the new guidelines and its association with waitlist survival. We conducted a retrospective analysis using the OPTN/SRTR database, including 14,156 IPF candidates listed for lung transplantation. Survival analyses were performed using Kaplan-Meier and multivariate models to examine the influence of revised mPAP and PVR thresholds on waitlist mortality. The prevalence of PH, defined by the revised criteria, was significantly higher compared to the prior definition. Kaplan-Meier analysis demonstrated worse waitlist survival for patients with PH under both diagnostic thresholds. However, multivariate analysis revealed that mPAP and PVR thresholds were not independently predictive of mortality. Instead, clinical parameters, including 6MWD, functional status, BMI, FVC, PaCO2, and double lung transplant preference, were significant predictors of waitlist mortality. In conclusion, while the revised PH diagnostic criteria increase PH prevalence in IPF patients, their independent prognostic utility for waitlist survival is limited. This national transplant database study underscores the importance of comprehensive clinical evaluation and timely referral for transplantation in managing IPF with PH.

PMID:39902292 | PMC:PMC11788316 | DOI:10.1002/pul2.70046

Pediatr Emerg Care. 2025 Feb 4. doi: 10.1097/PEC.0000000000003343. Online ahead of print.

ABSTRACT

Restrictive cardiomyopathy is a rare form of cardiomyopathy in children, representing only 2.5%-3% of all pediatric cardiomyopathies, and is typically diagnosed between the ages of 6 and 10. The underlying etiology varies depending on age and region; however, idiopathic, genetic, and endomyocardial fibrosis are among the most common. Cohort studies have demonstrated mortality as high as 50% within 2 years of diagnosis, as well as high rates of adverse events including thromboembolism, pulmonary hypertension, and sudden cardiac death. There is a paucity of literature on point-of-care ultrasound (POCUS) for the diagnosis of pediatric restrictive cardiomyopathy. We present a case of a 3-year-old female whose diagnosis of heart failure was rapidly identified via POCUS which subsequently expedited life-saving treatment.

PMID:39901796 | DOI:10.1097/PEC.0000000000003343

Sci Rep. 2025 Feb 3;15(1):4120. doi: 10.1038/s41598-024-76561-0.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by excessive scarring and fibrosis due to the abnormal accumulation of extracellular matrix components, primarily collagen. This study aims to design and solve an optimal control problem to regulate M2 macrophage activity in IPF, thereby preventing fibrosis formation by controlling the anti-M1 agent. The research models the diffusion of M2 macrophages in inflamed tissue using a novel dynamical system with partial differential equation (PDE) constraints. The control problem is formulated to minimize fibrosis by regulating an anti-M1 agent. The study employs a two-step process of discretization followed by optimization, utilizing the Galerkin spectral method to transform the M2 diffusion PDE into an algebraic system of ordinary differential equations (ODEs). The optimal control problem is then solved using Pontryagin/s minimum principle, canonical Hamiltonian equations, and extended Riccati differential equations. The numerical simulations indicate that without control, M2 macrophage levels increase and stabilize, contributing to fibrosis. In contrast, the optimal control strategy effectively reduces M2 macrophages, preventing fibrosis formation within 120 days. The results highlight the potential of the proposed optimal control approach in modulating tissue repair processes and mitigating the progression of IPF. This study underscores the significance of targeting M2 macrophages and employing mathematical methods to develop innovative therapies for lung fibrosis.

PMID:39900943 | DOI:10.1038/s41598-024-76561-0

Nat Commun. 2025 Feb 3;16(1):1303. doi: 10.1038/s41467-025-56501-w.

ABSTRACT

Irreversible damage of the lung epithelium in idiopathic pulmonary fibrosis (IPF) patients causes high mortality worldwide, with no lung repair approaches available currently. Here we show that in murine and monkey models, the KRT5+ P63+ progenitor cells in airway basal layer can enter the alveolar area post fibrotic injury. Aided with an automated culture system, we clone and characterize airway basal progenitor cells from 44 donors with various lung conditions. Transplantation of human progenitor cells into the mouse lung efficiently re-epithelializes the injured alveolar area, forms new respiratory tract and saccule-like structures, which ameliorates fibrotic lesions and improves survival of mice. Mechanistically, the engrafted human progenitor cells do not function by differentiating into mature alveolar cells in mouse lung; instead, they differentiate into saccular cells expressing multiple tight junction proteins such as CLDN4, which help the lung to re-establish epithelial barriers. Furthermore, by cloning P63+ airway basal progenitors from larger mammals and birds, we construct multiple lung-chimerism animals and uncover the evolutionarily conserved roles of these progenitor cells in lung repair. Overall, our data highlight the fate of airway basal progenitor cells in fibrotic lung and provide a potential therapeutic strategy for pulmonary diseases that lack inherent recovery mechanisms.

PMID:39900892 | DOI:10.1038/s41467-025-56501-w

OMICS. 2025 Feb 3. doi: 10.1089/omi.2024.0213. Online ahead of print.

ABSTRACT

Innovation in drug discovery for human diseases stands to benefit from systems science and next-generation phenomics approaches. An example is idiopathic pulmonary fibrosis (IPF) that is a chronic pulmonary disorder leading to respiratory failure and for which preventive and therapeutic medicines are sorely needed. Matrix metalloproteinases (MMPs), particularly MMP1 and MMP7, have been associated with IPF pathogenesis and are thus relevant to IPF drug discovery. This study evaluates the comparative therapeutic potentials of doxycycline, pirfenidone, and nintedanib in relation to MMP1 and MMP7 using molecular docking, molecular dynamics simulations, and a next-generation phenomics approach. Adsorption, distribution, metabolism, excretion, and toxicity analysis revealed that doxycycline and nintedanib adhered to Lipinski's rule of five, while pirfenidone exhibited no violations. The toxicity analysis revealed favorable safety profiles, with lethal dose 50 values of doxycycline, pirfenidone, and nintedanib being 2240kg, 580, and 500 mg/kg, respectively. Homology modeling validated the accuracy of the structures of the target proteins, that is, MMP1 and MMP7. The Protein Contacts Atlas tool, a next-generation phenomics platform that broadens the scope of phenomics research, was employed to visualize protein contacts at atomic levels, revealing interaction surfaces in MMP1 and MMP7. Docking studies revealed that nintedanib exhibited superior binding affinities with the candidate proteins (-6.9 kcal/mol for MMP1 and -7.9 kcal/mol for MMP7) compared with doxycycline and pirfenidone. Molecular dynamics simulations further demonstrated the stability of protein-ligand complexes. These findings highlight the notable potential of nintedanib in relation to future IPF therapeutics innovation. By integrating in silico and a next-generation phenomics approach, this study opens up new avenues for drug discovery and development for IPF and possibly, for precision/personalized medicines that consider the molecular signatures of therapeutic candidates for each patient.

PMID:39899320 | DOI:10.1089/omi.2024.0213

Front Immunol. 2025 Jan 17;15:1437984. doi: 10.3389/fimmu.2024.1437984. eCollection 2024.

ABSTRACT

BACKGROUND: Growing evidence indicates an association between circulating immune cell phenotypes and idiopathic pulmonary fibrosis (IPF). Although studies have attempted to elucidate the causal relationship between the two, further clarification of the specific mechanisms and causal linkages is warranted.

OBJECTIVE: We aimed to conduct a two-sample Mendelian randomization (MR) analysis with transcriptomics data analysis to elucidate the causal relationship between circulating immune cells and IPF and to explore potential biomarkers.

METHODS: We first explored the bidirectional causal association between IPF and immune cell phenotypes using two-sample MR analysis. Genome-wide association studies data for immune cell phenotype and IPF were obtained from publicly available databases. A standardized instrumental variable screening process was used to select single nucleotide polymorphisms (SNPs) for inclusion in the MR. Five methods represented by IVW were used to assess causal effects. Subsequently, SNP-nearest genes combined with the transcriptomics data of IPF were subjected to multiple bioinformatics analyses such as TIMER, WGCNA, functional enrichment analysis, protein-protein interaction analysis, and ROC to identify IPF biomarkers. Finally, the single-cell RNA sequencing (scRNA-seq) data was used to validate our findings by single-cell analysis.

RESULTS: The MR study identified 27 immune cell phenotypes causally associated with IPF, of which 20 were associated with a decreased risk of developing IPF and 7 were associated with an increased risk. CTSB (AUC=0.98), IL10 (AUC=0.83), and AGER (AUC=0.87) were identified as promising biomarkers of IPF. Single cell analysis showed differences in CD14+ CD16+ monocytes, CD16+ monocytes and Granulocyte-monocyte progenito between the IPF group and the healthy control group. The three hub genes were highly expressed in three immune cell subsets of IPF patients. It underscores the potential feasibility of three genes as biomarkers.

CONCLUSIONS: Our study demonstrates the causal associations of specific immune cell phenotypes with IPF through genetic methods and identifies CTSB, IL10, and AGER as biomarkers of IPF through bioinformatics analysis. These findings provide guidance for future clinical and basic research.

PMID:39896814 | PMC:PMC11782250 | DOI:10.3389/fimmu.2024.1437984

Cell Signal. 2025 Jan 30:111635. doi: 10.1016/j.cellsig.2025.111635. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a terminal lung disease with high mortality rate. Although Nintedanib (Nin) is an effective treatment for IPF, its precise mechanism of action remains unclear. In this study, we performed an integrated analysis of single-cell sequencing and RNA-seq data from lung tissues of both fibrotic and Nin-treated fibrotic mice to uncover new therapeutic mechanisms of Nin in IPF. Our results revealed an increase in interstitial macrophages following bleomycin (BLM) treatment. We used Monocle2, Cellchat, and in vivo experiments to demonstrate that Nin can inhibit Clec7a in interstitial macrophages, thereby suppressing the SPP1-mediated profibrotic pathway. Additionally, we utilized Scenic to predict transcription factors and identified NFκB as a major transcription factor in interstitial macrophages. In the in vitro experiments, we found that inhibiting Clec7a improved the secretion of SPP1 by M2 macrophages through the NFκB pathway. In subsequent in vivo experiments, we found that inhibiting of Clec7a improves pulmonary fibrosis through the NFκB/SPP1 pathway, and Nin alleviated BLM-induced pulmonary fibrosis by inhibiting Clec7a in interstitial macrophages. In summary, our study indicates that interstitial macrophages are upregulated in pulmonary fibrosis, and Nin reduces fibrosis by inhibiting Clec7a in interstitial macrophages, which in turn diminishes the NFκB /SPP1 pathway. These findings provided a new perspective on the mechanism of action of Nin in treating pulmonary fibrosis.

PMID:39892726 | DOI:10.1016/j.cellsig.2025.111635

Respir Investig. 2025 Jan 31;63(2):216-223. doi: 10.1016/j.resinv.2025.01.007. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic interstitial pneumonias (IIPs) may remain unclassifiable owing to inadequate, nonspecific, or conflicting clinical, radiological, or histopathological findings despite multidisciplinary discussion (MDD). Unclassifiable IIP (UCIIP) is a heterogeneous disease that can present with progressive pulmonary fibrosis (PPF). This study aimed to investigate the prevalence and clinical features of PPF in patients with UCIIP.

METHODS: In this post hoc analysis of a prospective multicenter registry of 222 patients with IIPs, 71 with UCIIP diagnosed using MDD were enrolled. PPF was defined based on worsening symptoms and radiological and physiological progression using the guideline criteria within 12 months or the criteria from the INBUILD trial within 24 months.

RESULTS: The median age was 72 years, and surgical lung biopsy was performed in 19.7%. Of the 66 patients with adequate follow-up data, 30 (45.5%) met either criterion and were diagnosed with PPF. UCIIP patients with PPF had significantly higher serum surfactant protein-D level and percentage of bronchoalveolar fluid neutrophils, lower %forced vital capacity and %diffusing capacity for carbon monoxide, and a higher proportion of honeycombing on high-resolution computed tomography and desaturation on exertion than those without PPF. Additionally, they had significantly more anti-fibrotic therapy and long-term oxygen therapy, a higher incidence of acute exacerbation, and a poorer prognosis than those without PPF. Cox proportional hazards analysis revealed that PPF was a significant poor prognostic factor, regardless of the criteria.

CONCLUSIONS: PPF is common and associated with poor prognosis in patients with UCIIP. Appropriate evaluation and management of PPF are essential for UCIIP.

PMID:39892159 | DOI:10.1016/j.resinv.2025.01.007

BMC Pulm Med. 2025 Jan 31;25(1):52. doi: 10.1186/s12890-025-03522-2.

ABSTRACT

BACKGROUND: Pulmonary fibrosis is characterized by the destruction of normal lung tissue and then replacement by abnormal fibrous tissue, leading to an overall decrease in gas exchange function. The effective treatment for pulmonary fibrosis remains unknown. The upstream pathogenesis of pulmonary fibrosis may involve cellular senescence of the lung tissue. Previously, a new gene therapy technology using Box A of the HMGB1 plasmid (Box A) was used to reverse cellular senescence and cure liver fibrosis in aged rats.

METHODS: Here, we show that Box A is a promising medicine for the treatment of lung fibrosis. In a bleomycin-induced pulmonary fibrosis model in the male Wistar rats, Student's t-test and one-way ANOVA were used to compare groups of samples.

RESULTS: Box A effectively lowered fibrous tissue deposits (from 18.74 ± 0.62 to 3.45 ± 1.19%) and senescent cells (from 3.74 ± 0.40% to 0.89 ± 0.18%) to levels comparable to those of the negative control group. Moreover, after eight weeks, Box A also increased the production of the surfactant protein C (from 3.60 ± 1.68% to 6.82 ± 0.65%).

CONCLUSIONS: Our results demonstrate that Box A is a promising therapeutic approach for pulmonary fibrosis and other senescence-promoted fibrotic lesions.

PMID:39891078 | DOI:10.1186/s12890-025-03522-2

J Biotechnol. 2025 Jan 29:S0168-1656(25)00025-2. doi: 10.1016/j.jbiotec.2025.01.019. Online ahead of print.

ABSTRACT

Metabolic dysfunction-associated steatotic liver disease (MASLD) is now the most common chronic liver disease worldwide, affecting more than 30 percent of adults. The most severe form of MASLD, metabolic dysfunction-associated steatohepatitis (MASH), is characterized by necrotizing inflammation and rapid fibrosis progression, often leading to cirrhosis and hepatocellular carcinoma. Currently, only Resmetirom is approved for the treatment of MASH one of the main reasons is the absence of representative in vivo or in vitro models for MASH. To address this challenge, we developed a high-throughput 3D spheroid model consisting of human hepatocellular carcinoma cells (HepG2) and human hepatic stellate cells (LX-2) on microwell arrays. This model, induced with free fatty acids (FFA) to simulate steatosis and fibrosis, enables the assessment of efficacy and mechanisms for potential anti-MASH drugs. Our findings demonstrate that this in vitro spheroid model replicates key pathological features of human MASLD, including steatosis, oxidative stress, and fibrosis. Upon validation, we selected pirfenidone (PFD) and yinfenidone (AC-003), which are commonly used to treat idiopathic pulmonary fibrosis (IPF), to test their anti-MASH efficacy. Treatment with these drugs showed that they could regulate lipid synthesis and metabolism genes, reduce lipid accumulation, oxidative stress, and fibrosis levels. This 3D spheroid model represents a straightforward and efficient tool for screening anti-MASH drugs and investigating the molecular mechanisms of drug action.

PMID:39889902 | DOI:10.1016/j.jbiotec.2025.01.019

Clin Transl Med. 2025 Feb;15(2):e70217. doi: 10.1002/ctm2.70217.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fibrotic disease driven by both environmental and genetic factors. Epigenetics refers to changes in gene expression or cellular phenotype that do not involve alterations to DNA sequence. KMT2A is a member of the SET family which catalyses H3K4 methylation.

RESULTS: Through microarray and single-cell sequencing data, we discovered KMT2A-positive fibroblasts were increased in IPF lung tissues. KMT2A level was increased in IPF and bleomycin-induced pulmonary fibrosis mice lung tissues collected in our centre. Mice with AAV6-induced KMT2A knockdown in fibroblast showed attenuated pulmonary fibrosis after bleomycin treatment. Bioinformation also revealed that transcription factor PU.1 was a target of KMT2A. We demonstrated that PU.1 levels were increased in IPF tissues, bleomycin-induced mice lung tissues and primary fibrotic fibroblasts. KMT2A knockdown decreases PU.1 expression in vitro while KMT2A overexpression induces PU.1 activation. PU.1 fibroblast-specific knockout mice showed attenuated lung fibrosis induced by bleomycin. Furthermore, we demonstrated KMT2A up-regulated PU.1 in fibroblasts by catalysing H3K4me3 at the promoter of the PU.1 gene. The KMT2A transcription complex inhibitor mm102 treatment attenuated bleomycin-induced pulmonary fibrosis.

CONCLUSION: The current study indicated that histone modification participates in the pathogenesis of IPF and KMT2A may have the potential to be a therapeutic target of IPF treatment.

KEY POINTS: KMT2A plays a role in pulmonary fibrogenesis. KMT2A regulates PU.1 transcription in fibroblasts through H3K4me3 at promoter. KMT2A inhibitor attenuates pulmonary fibrosis in mice.

PMID:39888275 | DOI:10.1002/ctm2.70217

ChemMedChem. 2025 Jan 30:e202401001. doi: 10.1002/cmdc.202401001. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and chronic interstitial lung disease characterized by irreversible loss of lung function and a poor prognosis. Type I collagen, a major component of the extracellular matrix, plays a central role in the pathogenesis of fibrosis and is considered a key molecular target for therapeutic intervention. While current anti-fibrotic therapies demonstrate limited efficacy in slowing disease progression, their clinical impact remains suboptimal due to poor pharmacokinetic properties and non-curative therapy. Moreover, the development of effective anti-fibrotic agents targeting collagen synthesis is hindered by the absence of robust, cost-effective, high-throughput drug screening platforms. In this study, we established a novel screening system designed to identify small molecules that inhibit the expression of the COL1A2 gene, which encodes type I collagen. Utilizing this system, we screened a library of natural and synthetic compounds developed at Nagasaki University and identified lamellarin D as a potent inhibitor of COL1A2 expression and subsequent type I collagen production. These findings suggest that lamellarin D, through its unique molecular mechanism, may serve as the foundation for the development of a new class of IPF treatments aimed at targeting the underlying fibrotic processes.

PMID:39887929 | DOI:10.1002/cmdc.202401001

Drug Metab Dispos. 2025 Jan;53(1):100010. doi: 10.1124/dmd.124.001917. Epub 2024 Nov 22.

ABSTRACT

Pirfenidone (PIR) is used in the treatment of idiopathic pulmonary fibrosis. After oral administration, it is metabolized by cytochrome P450 1A2 to 5-hydroxylpirfenidone (5-OH PIR) and further oxidized to 5-carboxylpirfenidone (5-COOH PIR), a major metabolite excreted in the urine (90% of the dose). This study aimed to identify enzymes that catalyze the formation of 5-COOH PIR from 5-OH PIR in the human liver. 5-COOH PIR was formed from 5-OH PIR in the presence of NAD+ by human liver microsomes (HLMs) more than by human liver cytosol (HLC), with the concomitant formation of the aldehyde form (5-CHO PIR) as an intermediate metabolite. By purifying enzymes from HLMs, alcohol dehydrogenases (ADHs) were identified as candidate enzymes catalyzing 5-CHO PIR formation, although ADHs are localized in the cytoplasm. Among constructed recombinant ADH1-5 expressed in HEK293T cells, only ADH4 efficiently catalyzed 5-CHO PIR formation from 5-OH PIR with a Km value (29.0 ± 4.9 μM), which was close to that by HLMs (59.1 ± 4.6 μM). In contrast to commercially available HLC, HLC prepared in-house clearly showed substantial 5-CHO PIR formation, and ADH4 protein levels were significantly (rs = 0.772, P < .0001) correlated with 5-CHO PIR formation in 25 HLC samples prepared in-house. Some components of the commercially available HLC may inhibit ADH4 activity. Disulfiram, an inhibitor of aldehyde dehydrogenases (ALDH), decreased 5-COOH PIR formation and increased 5-CHO PIR formation from 5-OH PIR in HLMs. ALDH2 knockdown in HepG2 cells by siRNA decreased 5-COOH PIR formation by 61%. SIGNIFICANCE STATEMENT: This study clarified that 5-carboxylpirfenidone formation from 5-hydroxylpirfenidone proceeds via a 2-step oxidation reaction catalyzed by ADH4 and disulfiram-sensitive enzymes, including ALDH2. Interindividual differences in the expression levels or functions of these enzymes could cause variations in the pharmacokinetics of pirfenidone.

PMID:39884816 | DOI:10.1124/dmd.124.001917

Pulmonology. 2025 Dec 31;31(1):2425503. doi: 10.1080/25310429.2024.2425503. Epub 2024 Nov 12.

ABSTRACT

Fibrotic hypersensitivity pneumonitis (f-HP) is an interstitial lung disease in which various antigens in susceptible individuals may play a pathogenetic role. This study evaluates the role of transbronchial lung cryobiopsy (TBLC) and bronchoalveolar lavage (BAL) in identifying a UIP-like pattern and its association with fibrosis progression. We conducted a multicentre retrospective cohort study of patients diagnosed with f-HP who underwent BAL and TBLC between 2011 and 2023. A UIP-like pattern was defined by the presence of (A) patchy fibrosis and fibroblastic foci or (B) honeycombing ± (A). We investigated BAL's role in predicting UIP-like patterns within a clinical-radiological-serological framework, examining disease progression in these patients using spirometry and mortality data. A total of 195 patients were enrolled, 59 (30%) of whom exhibited a UIP-like pattern. These patients showed greater lung function decline, lower BAL lymphocytosis (14.4% vs. 37.4%, p < 0.001), higher nintedanib prescription (35% vs. 14%, p < 0.001), and higher 10-year mortality (HR 2.8, 95% CI 1.3-5.8, p = 0.004). f-HP patients with a UIP-like pattern exhibit worse clinical outcomes and higher mortality. In cases of low BAL lymphocytosis with a high pre-test clinical suspicion of f-HP, lung biopsy may not be necessary as it increases the likelihood of identifying a UIP-like pattern.

PMID:39883494 | DOI:10.1080/25310429.2024.2425503

Pulmonology. 2025 Dec 31;31(1):2424637. doi: 10.1080/25310429.2024.2424637. Epub 2024 Nov 6.

NO ABSTRACT

PMID:39883507 | DOI:10.1080/25310429.2024.2424637

Front Med (Lausanne). 2025 Jan 15;11:1526531. doi: 10.3389/fmed.2024.1526531. eCollection 2024.

ABSTRACT

BACKGROUND: There is a paucity of real-world data on patients with interstitial lung diseases (ILDs) that are progressive, other than idiopathic pulmonary fibrosis (IPF), including treatment patterns and attitudes toward treatment. This study aimed to investigate the diagnosis, clinical characteristics, treatment paradigm and current decision-making practices of IPF and progressive pulmonary fibrosis (PPF) in a Japanese real-world setting.

METHODS: Data were drawn from the Adelphi Real World PPF-ILD Disease Specific Programme™, a cross-sectional survey with retrospective data collection of pulmonologists and rheumatologists in Japan from April to October 2022. Physicians provided data for up to 12 consecutive patients with a physician-confirmed diagnosis of progressive ILD; patients were also invited to complete patient self-completion forms. Analyses were descriptive.

RESULTS: A total of 63 physicians (43 pulmonologists and 20 rheumatologists) provided data on 312 patients with PPF and 70 patients with IPF. Patients had a mean (standard deviation [SD]) age at survey date of 68.0 (11.6) years, 43.5% were female, 50.3% were former smokers and 18.1% were employed full time. For breathlessness, 26.5% of patients had Grade 2 physician-reported breathlessness; this was 16.7% when reported by patients themselves. A total of 81.4% of patients were currently receiving treatment for ILD. Mean (SD) duration of current treatment was 1.5 (1.4) years. Slowing disease progression was the primary reason influencing physicians' choice of current ILD treatment (48.5%). A total of 16.0% had never been treated (most frequent physician-reported reason: disease was manageable without treatment, 55.7%) and 2.6% had treatment discontinued (most frequent reason: patient request, 70.0%). Physicians reported 82.3% of patients as fully compliant with their treatment regimen. As reported by patients themselves (n = 53), 49.1% never and 37.7% rarely missed a dose.

CONCLUSION: This analysis of real-world data from Japan provides insights into the clinical profile of patients with IPF and PPF in Japan, and highlights differences between physicians and patients in perception of symptom severity and attitudes to treatment.

PMID:39882519 | PMC:PMC11775758 | DOI:10.3389/fmed.2024.1526531

BMC Pulm Med. 2025 Jan 29;25(1):47. doi: 10.1186/s12890-025-03520-4.

ABSTRACT

BACKGROUND: Fibrotic types of interstitial lung abnormalities seen on high-resolution computed tomography scans, characterised by traction bronchiolectasis/bronchiectasis with or without honeycombing, are predictors of progression and poor prognostic factors of interstitial lung abnormalities. There are no reports on the clinical characteristics of fibrotic interstitial lung abnormalities on high-resolution computed tomography scans. Therefore, we aimed to examine these clinical characteristics and clarify the predictive factors of fibrotic interstitial lung abnormalities on high-resolution computed tomography scans.

METHODS: Clinical and paraclinical data of 164 patients enrolled in the initial year of a multicentre prospective observational study (Kumamoto interstitial lung abnormalities study in Japan) involving over 62,000 examinees during routine health examinations were analysed. Clinical laboratory evaluations are expressed as medians and interquartile ranges for each evaluation time point, and boxplots were created for graphical representation. The percentages of abnormal clinical laboratory results were compared between the groups using chi-square or Fisher's exact tests. Univariate or multivariate logistic regression analyses were performed to analyse the relationship between fibrotic interstitial lung abnormalities and other clinical factors.

RESULTS: Fibrotic interstitial lung abnormalities were observed on high-resolution computed tomography scans in 135 (82%) patients at the time of diagnosis. Multivariate analysis showed that older age (Odds ratio, 1.06; 95% confidence interval, 1.01-1.12; p = 0.021), auscultatory fine crackles (Odds ratio, 3.39; 95% confidence interval, 1.33-8.65; p < 0.01), and elevated serum surfactant protein-D (Odds ratio, 2.68; 95% confidence interval, 1.02-8.64; p = 0.045) were independent predictive factors of fibrotic interstitial lung abnormalities. The predicted area under the curve of the fibrotic interstitial lung abnormalities based on these three factors was 0.77 (95% confidence interval, 0.68-0.86). The proportion of undecided diagnoses in the fibrotic interstitial lung abnormalities group (14%) was significantly lower than that in the non-fibrotic interstitial lung abnormalities group (41%) (p = 0.0027).

CONCLUSIONS: Fine crackles on auscultation and elevated serum surfactant protein-D levels are predictors of fibrotic interstitial lung abnormalities in older patients with interstitial lung abnormalities. These findings may assist non-radiological physicians in referring patients to specialists for early intervention in progressive fibrotic interstitial lung diseases.

TRIAL REGISTRATION NUMBER/DATE: UMIN000045149/2021.12.1.

PMID:39881354 | DOI:10.1186/s12890-025-03520-4

Biochem Genet. 2025 Jan 29. doi: 10.1007/s10528-024-11012-z. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a rapidly progressive interstitial lung disease of unknown pathogenesis with no effective treatment currently available. Given the regulatory roles of lncRNAs (TP53TG1, LINC00342, H19, MALAT1, DNM3OS, MEG3), miRNAs (miR-218-5p, miR-126-3p, miR-200a-3p, miR-18a-5p, miR-29a-3p), and their target protein-coding genes (PTEN, TGFB2, FOXO3, KEAP1) in the TGF-β/SMAD3, Wnt/β-catenin, focal adhesion, and PI3K/AKT signaling pathways, we investigated the expression levels of selected genes in peripheral blood mononuclear cells (PBMCs) and lung tissue from patients with IPF. Lung tissue and blood samples were collected from 33 newly diagnosed, treatment-naive patients and 70 healthy controls. Gene expression levels were analyzed by RT-qPCR. TaqMan assays and TaqMan MicroRNA assay were employed to quantify the expression of target lncRNAs, mRNAs, and miRNAs. Our study identified significant differential expression in PBMCs from IPF patients compared to healthy controls, including lncRNAs MALAT1 (Fold Change = 3.809, P = 0.0001), TP53TG1 (Fold Change = 0.4261, P = 0.0021), and LINC00342 (Fold Change = 1.837, P = 0.0448); miRNAs miR-126-3p (Fold Change = 0.102, P = 0.0028), miR-200a-3p (Fold Change = 0.442, P = 0.0055), and miR-18a-5p (Fold Change = 0.154, P = 0.0034); and mRNAs FOXO3 (Fold Change = 4.604, P = 0.0032) and PTEN (Fold Change = 2.22, P = 0.0011). In lung tissue from IPF patients, significant expression changes were observed in TP53TG1 (Fold Change = 0.2091, P = 0.0305) and DNM3OS (Fold Change = 4.759, P = 0.05). Combined analysis of PBMCs expression levels for TP53TG1, MALAT1, miRNA miR-126-3p, and PTEN distinguished IPF patients from healthy controls with an AUC = 0.971, sensitivity = 0.80, and specificity = 0.955 (P = 6 × 10-8). These findings suggest a potential involvement of the identified ncRNAs and mRNAs in IPF pathogenesis. However, additional functional validation studies are needed to elucidate the precise molecular mechanisms by which these lncRNAs, miRNAs, and their targets contribute to PF.

PMID:39881079 | DOI:10.1007/s10528-024-11012-z

Ann Am Thorac Soc. 2025 Jan 29. doi: 10.1513/AnnalsATS.202409-906OC. Online ahead of print.

ABSTRACT

RATIONALE: Tobacco smoking is a well-established risk factor for idiopathic pulmonary fibrosis (IPF), yet the influence of early-life tobacco exposure on future IPF risk remains poorly understood.

OBJECTIVES: To test the hypothesis that early-life tobacco exposure may elevate the risk of developing IPF, with this effect potentially modified by genetic susceptibility to IPF and mediated through accelerated biological aging.

METHODS: Using data from over 430,000 participants in the UK Biobank, we performed a prospective cohort study to examine the associations of maternal smoking around birth and age of smoking initiation with IPF risk. We evaluated the combined effects and interactions between early-life tobacco exposure and genetic susceptibility to IPF, quantified using polygenic risk scores. We assessed biological aging, as measured by telomere length and phenotypic age, as potential mediators in the associations between early-life tobacco exposure and IPF risk. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).

RESULTS: Maternal smoking around birth was associated with a higher risk of IPF (HR: 1.26; 95% CI: 1.11-1.43). Compared to never-smokers, individuals who initiated smoking in childhood (HR: 3.65; 95% CI: 3.02-4.41), adolescence (HR: 2.64; 95% CI: 2.28-3.05), and adulthood (HR: 2.09; 95% CI: 1.79-2.44) exhibited increased IPF risk (P for trend < 0.001). An additive interaction was observed between age of smoking initiation and genetic risk for IPF. Individuals with high genetic risk, maternal smoking exposure, and childhood smoking initiation had a 16-fold greater risk of IPF (HR: 16.47; 95% CI: 9.57-28.32), compared to those with low genetic risk and no tobacco exposure. Telomere length and phenotypic age each mediated approximately 10% of the effect of maternal smoking on IPF, with weaker mediation effects observed for later ages of smoking initiation.

CONCLUSION: Early-life tobacco exposure may elevate the risk of IPF, with effect modified by genetic susceptibility and partially mediated through accelerated biological aging.

PMID:39879538 | DOI:10.1513/AnnalsATS.202409-906OC

PLoS One. 2025 Jan 29;20(1):e0316484. doi: 10.1371/journal.pone.0316484. eCollection 2025.

ABSTRACT

BACKGROUND AND AIMS: Predicting progression and prognosis in Interstitial Lung Diseases (ILD), especially Idiopathic Pulmonary Fibrosis (IPF) and Progressive Pulmonary Fibrosis (PPF), remains a challenge. Integrating patient-centered measurements is essential for earlier and safer detection of disease progression. Home monitoring through e-health technologies, such as spirometry and oximetry connected to smartphone applications, holds promise for early detection of ILD progression or acute exacerbations, enabling timely therapeutic interventions.

METHODS: The European ILD Registry Algorithm for Self-Assessment in ILD (eurILDreg ASA-ILD), developed by all eurILDreg principal investigators, includes questionnaires on symptom burden, respiratory infections, and quality of life (EQ5D VAS, K-BILD, LCQ). The algorithm also incorporates spirometry and oxygen saturation measurements, both at rest and during exercise (one-minute sit-to-stand test, 1STST). This ASA-ILD algorithm is integrated into the patientMpower Ltd. smartphone application, used for patient-led monitoring, research, and clinical care since 2016, and available on both Apple and Android platforms.

DISCUSSION: For patient-centered measurements, participants in the multicenter eurILDreg study will receive a patientMpower account, a handheld clinical-grade spirometer (Spirobank Smart, MIR, Italy), and a pulse oximeter (Nonin Medical, Inc. Plymouth, MN, USA), along with usage instructions. Artificial intelligence software (ArtiQ) will analyze spirometry maneuvers in real-time, ensuring compliance with recent ERS/ATS criteria and providing automated feedback. Pulse oximetry is integrated into the exercise testing within the application, following an automated in-app protocol developed with clinician involvement for safety and accuracy. The application will send reminders to participants to complete patient-reported outcome measures (PROMs) according to the study protocol.

CONCLUSION: This study is designed to explore the potential of e-Health technologies, such as home monitoring via spirometry and oximetry, integrated with the eurILDreg ASA-ILD algorithm and patientMpower app, to improve early detection and management of ILD. A pilot trial showed promising adherence to spirometry, indicating that digital health interventions could enhance patient care and outcomes in ILD.

TRIAL REGISTRATION: The ethics committee of the Justus-Liebig-University of Giessen has approved the eurILDreg and this substudy with the protocol reference number 111/08. The research was conducted strictly according to the principles of the Declaration of Helsinki. Patients were included into the registry upon having signed the informed consent. The eurIPFreg and eurIPFbank are listed in ClinicalTrials.gov (NCT02951416). EurILDreg is registered in German Clinical Trials Register, DRKS 00028968.

PMID:39879227 | DOI:10.1371/journal.pone.0316484