J Clin Med. 2025 Jan 23;14(3):731. doi: 10.3390/jcm14030731.

ABSTRACT

Background: Transbronchial lung cryobiopsy (TBLC) has a high incidence of adverse events. This study aimed to investigate the relationship between the occurrence of these events and the condition of the pathology samples or pathological diagnosis in TBLC. Methods: We studied 102 patients who underwent TBLC for the diagnosis of interstitial lung disease. We analyzed the association between the condition or diagnosis of pathology samples and the occurrence of TBLC-related adverse events, including hemorrhage, pneumothorax, and acute exacerbation of interstitial lung disease. Results: The adverse events occurred in 19 patients (18.6%), of which hemorrhage was the most common (14 patients, 13.7%). The patients who experienced adverse events, especially hemorrhage, were less likely to have successful sampling with TBLC and showed lower diagnostic confidence in the pathology results. The diagnostic confidence was level A in 50 cases (49.0%) and level C in 23 cases (22.6%). TBLC-related adverse events, including hemorrhage, were significantly more common in patients with lower pathological confidence levels. Conclusions: TBLC-related adverse events, particularly hemorrhage, can lead to fewer successful samples and lower levels of diagnostic confidence.

PMID:39941401 | DOI:10.3390/jcm14030731

J Clin Med. 2025 Jan 22;14(3):714. doi: 10.3390/jcm14030714.

ABSTRACT

Background: Over the last few years, a few imaging studies have performed conventional transthoracic echocardiography (TTE) implemented with speckle tracking echocardiography (STE) for the assessment of biventricular mechanics in patients with non-advanced idiopathic pulmonary fibrosis (IPF). This systematic review and meta-analysis aimed at evaluating the overall effect of mild-to-moderate IPF on the main indices of biventricular systolic function assessed by TTE and STE. Methods: All imaging studies assessing right ventricular (RV)-global longitudinal strain (GLS), left ventricular (LV)-GLS, tricuspid annular plane systolic excursion (TAPSE), and left ventricular ejection fraction (LVEF) in IPF patients vs. healthy controls, selected from PubMed, Scopus, and EMBASE databases, were included. Continuous data (RV-GLS, LV-GLS, TAPSE, and LVEF) were pooled as standardized mean differences (SMDs) comparing the IPF group with healthy controls. The SMD of RV-GLS was calculated using the random-effect model, whereas the SMDs of LV-GLS, TAPSE, and LVEF were calculated using the fixed-effect model. Results: The full texts of 6 studies with 255 IPF patients and 195 healthy controls were analyzed. Despite preserved TAPSE and LVEF, both RV-GLS and LV-GLS were significantly, although modestly, reduced in the IPF patients vs. the controls. The SMD was large (-1.01, 95% CI -1.47, -0.54, p < 0.001) for RV-GLS, medium (-0.62, 95% CI -0.82, -0.42, p < 0.001) for LV-GLS, small (-0.42, 95% CI -0.61, -0.23, p < 0.001) for TAPSE, and small and not statistically significant (-0.20, 95% CI -0.42, 0.03, p = 0.09) for LVEF assessment. Between-study heterogeneity was high for the studies assessing RV-GLS (I2 = 80.5%), low-to-moderate for those evaluating LV-GLS (I2 = 41.7%), and low for those measuring TAPSE (I2 = 16.4%) and LVEF (I2 = 7.63%). The Egger's test yielded a p-value of 0.60, 0.11, 0.31, and 0.68 for the RV-GLS, LV-GLS, TAPSE, and LVEF assessment, respectively, indicating no publication bias. On meta-regression analysis, none of the moderators was significantly associated with effect modification for RV-GLS (all p > 0.05). The sensitivity analysis supported the robustness of the results. Conclusions: RV-GLS impairment is an early marker of subclinical myocardial dysfunction in mild-to-moderate IPF. STE should be considered for implementation in clinical practice for early detection of RV dysfunction in IPF patients without advanced lung disease.

PMID:39941384 | DOI:10.3390/jcm14030714

Int J Mol Sci. 2025 Feb 6;26(3):1378. doi: 10.3390/ijms26031378.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) has been associated with mitochondrial dysfunction. We investigated whether mitochondrial DNA variants in peripheral blood leukocytes (PBLs), which affect proteins of the respiratory chain and mitochondrial function, could be associated with an increased risk and poor prognosis of IPF. From 2020 to 2022, we recruited 36 patients (age: 75.3 ± 8.5; female: 19%) with IPF, and 80 control subjects (age: 72.3 ± 9.0; female: 27%). The mitochondrial genome of peripheral blood leukocytes was determined using next-generation sequencing. During a 45-month follow-up, 10 (28%) patients with IPF remained stable and the other 26 (72%) progressed, with 12 (33%) mortalities. IPF patients had more non-synonymous (NS) variants (substitution/deletion/insertion) in mitochondrial COX3 gene (coding for subunit 3 of complex IV of the respiratory chain), and more mitochondrial tRNA variants located in the anticodon (AC) stem, AC loop, variable loop, T-arm, and T-loop of the tRNA clover-leaf structure in PBLs than the control group. The succumbed IPF patients were older, had lower initial diffusion capacity, and higher initial fibrosis score on high-resolution computerized tomography (HRCT) than the alive group. NS variants in mitochondrial COX3 gene and tRNA variants in PBLs were associated with shorter survival. Our study shows that (1) leukocyte mitochondrial COX3 NS variants are associated with risk and prognosis of IPF; (2) leukocyte mitochondrial tRNA variants located in the AC stem, AC loop, variable loop, T-arm, and T-loop of the tRNA clover-leaf structure are associated with risk, and the presence of tRNA variants is associated with poor prognosis of IPF.

PMID:39941146 | DOI:10.3390/ijms26031378

ACS Appl Mater Interfaces. 2025 Feb 12. doi: 10.1021/acsami.4c21657. Online ahead of print.

ABSTRACT

Biodegradable poly(β-amino) esters (PBAEs) have been a focus of interest for delivering therapeutic siRNA for several years. While no approved therapies are on the market yet, our study aims to advance PBAE-based treatments for currently "undruggable" diseases. The PBAEs used in this study are based on a recently reported step-growth copolymerization, which results in polymers with a unique balance of lipophilicity and positive charge, thereby showcasing diverse properties. Upon incubation with siRNA, these PBAEs form a unique structure and topology, which we classify as a subtype of classical polyplex, termed "micelle-embedded polyplexes" (mPolyplexes). The impact of different nebulizers on the physicochemical performance of these nanoparticles was investigated, and it was found that various mPolyplexes can be nebulized using vibrating-mesh nebulizers without the loss of gene silencing activity nor a change in physicochemical properties, setting them apart from other nanoparticles such as marketed LNPs. Finally, their therapeutic application was tested ex vivo in human precision-cut lung slices from patients with lung fibrosis. mPolyplexes mediated 52% gene silencing of matrix metalloprotease 7 (MMP7) and a downstream effect on collagen I (Col I) with 33% downregulation as determined via qPCR.

PMID:39938880 | DOI:10.1021/acsami.4c21657

J Proteomics. 2025 Feb 10:105400. doi: 10.1016/j.jprot.2025.105400. Online ahead of print.

NO ABSTRACT

PMID:39938635 | DOI:10.1016/j.jprot.2025.105400

Respir Investig. 2025 Feb 11;63(3):241-246. doi: 10.1016/j.resinv.2025.01.008. Online ahead of print.

ABSTRACT

BACKGROUND: The 6-min walk test (6MWT), used to monitor disease progression or exacerbation in interstitial lung disease, faces challenges such as requiring a 30-m walking path and difficulty assessing patients with gait disturbance. The 1-min sit-to-stand test (1STST) offers a convenient alternative, potentially addressing these issues. Despite its advantages, the effectiveness of the 1STST in patients with idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) still needs to be explored. We assessed 1STST's ability to detect exercise-induced desaturation in a randomized, crossover trial involving patients with IPF or PPF.

METHODS: Participants were divided into group A (6MWT to 1STST) and B (1STST to 6MWT), with a 30-min rest period between the tests. The primary endpoint was the difference in nadir oxygen saturation (SpO2) between the groups throughout the study. Secondary endpoints included the percentage of participants with a nadir SpO₂ <88% during the tests, a decline of ≥4% in SpO2, and the variation in Borg scores post-tests.

RESULTS: Twenty-three participants (91.3% male; mean age ± standard deviation: 77.2 ± 7.4 years) diagnosed with IPF and PPF were enrolled in this study. The difference in nadir SpO2 between the 1STST and 6MWT was 1.14% (95% confidence interval: -0.18, 2.48), with the 95% confidence intervals falling within the predefined equivalence range. No significant differences were observed in the secondary endpoints.

CONCLUSIONS: The results suggest that the 1STST is as effective as the 6MWT in detecting desaturation in patients with IPF and PPF.

TRIAL REGISTRATION: This study was registered on the website of the Japan Registry of Clinical Trials (jRCT1032230037; URL: https://jrct.niph.go.jp/).

PMID:39938407 | DOI:10.1016/j.resinv.2025.01.008

Ann Am Thorac Soc. 2025 Feb 12. doi: 10.1513/AnnalsATS.202501-130ED. Online ahead of print.

NO ABSTRACT

PMID:39938064 | DOI:10.1513/AnnalsATS.202501-130ED

J Surg Res. 2025 Jan;305:295-303. doi: 10.1016/j.jss.2024.11.002. Epub 2024 Dec 27.

ABSTRACT

INTRODUCTION: Due to parenchymal fibrosis and chest wall contraction in idiopathic pulmonary fibrosis (IPF), donor lung allografts are generally undersized to accommodate smaller diseased chest cavities. We hypothesized that transplanting oversized allografts (OAs) in recipients with IPF would be associated with thoracic cavity expansion.

METHODS: A single center retrospective study of IPF patients who underwent lung transplant between 2014 and 2022 was conducted. Size matching was determined by comparing donor and recipient lung height on chest radiographs, measured from lung apex to middiaphragm on donor and recipient inspiratory anterior to posterior chest radiographs. Allografts that were ≥10% larger on chest radiograph compared to corresponding recipient lungs were deemed OAs, or not oversized allografts. Allograft lung height and pulmonary function tests were collected at 1, 6, and 12 mo and a comparative analysis was performed.

RESULTS: The OA group had a significant increase in change of height in the left lung at 1 mo and both lungs at 6 mo (P < 0.05). There were no significant differences in change of forced expiratory volume in 1 s at 1, 6, 12 mo between the two groups. The change in forced vital capacity was significantly increased in the OA group at 6 mo (P < 0.05). The degree of donor to recipient allograft size mismatch and resultant recipient pleural cavity expansion was significantly correlated at 1 and 6 mo (P < 0.05).

CONCLUSIONS: Transplanting larger allografts into IPF patients was associated with pleural cavity expansion, without an associated change in pulmonary function tests. Thus, larger allografts potentially can be used in IPF patients, thereby increasing donor availability for these patients.

PMID:39937562 | DOI:10.1016/j.jss.2024.11.002

Cells. 2025 Feb 5;14(3):222. doi: 10.3390/cells14030222.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is an epithelial-driven interstitial lung disease of unknown etiology characterized by the excessive proliferation of fibroblast populations that synthesize large amounts of extracellular matrix. In this devastating disorder, all aging hallmarks appear prematurely or are altered. This review highlights key findings about IPF characteristics recently recognized as hallmarks of aging, including mechanical alterations, inflammaging, dysbiosis, alternative splicing, and disabled macroautophagy. It also revisits the classic hallmarks of aging, which encompass stem cell exhaustion, cellular senescence, and altered intercellular communication. Enhancing our understanding of the fundamental processes that underlie the altered hallmarks of aging in IPF may facilitate the development of innovative experimental strategies to improve therapeutic outcomes.

PMID:39937013 | DOI:10.3390/cells14030222

Front Genet. 2025 Jan 22;15:1464471. doi: 10.3389/fgene.2024.1464471. eCollection 2024.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a severe chronic respiratory disease characterized by treatment challenges and poor prognosis. Identifying relevant biomarkers for effective early-stage risk prediction is therefore of critical importance.

METHODS: In this study, we obtained gene expression profiles and corresponding clinical data of IPF patients from the GEO database. GO enrichment and KEGG pathway analyses were performed using R software. To construct an IPF risk prediction model, we employed LASSO-Cox regression analysis and the SVM-RFE algorithm. PODNL1 and PIGA were identified as potential biomarkers associated with IPF onset, and their predictive accuracy was confirmed using ROC curve analysis in the test set. Furthermore, GSEA revealed enrichment in multiple pathways, while immune function analysis demonstrated a significant correlation between IPF onset and immune cell infiltration. Finally, the roles of PODNL1 and PIGA as biomarkers were validated through in vivo and in vitro experiments using qRT-PCR, Western blotting, and immunohistochemistry.

RESULTS: These findings suggest that PODNL1 and PIGA may serve as critical biomarkers for IPF onset and contribute to its pathogenesis.

DISCUSSION: This study highlights their potential for early biomarker discovery and risk prediction in IPF, offering insights into disease mechanisms and diagnostic strategies.

PMID:39935693 | PMC:PMC11811625 | DOI:10.3389/fgene.2024.1464471

J Inflamm Res. 2025 Feb 7;18:1899-1910. doi: 10.2147/JIR.S499029. eCollection 2025.

ABSTRACT

While TRIM proteins are extensively studied in the context of lung tumors, their roles in non-tumor chronic lung diseases remain underexplored. This review delves into the emerging significance of TRIM family proteins in the pathogenesis of idiopathic pulmonary fibrosis (IPF), asthma, chronic obstructive pulmonary disease (COPD), and pulmonary hypertension (PH). TRIM proteins modulate key pathological processes, including inflammation, fibrosis, and cellular remodeling, contributing to disease progression. We highlight their potential as biomarkers and therapeutic targets, offering promising avenues for drug development in these debilitating respiratory disorders. However, the translation of these findings into clinical applications faces significant challenges. These include the dual functional nature of TRIM proteins, their context-dependent roles, the complexity of their downstream signaling networks, and the limitations of current therapeutic strategies in achieving tissue-specific targeting with minimal off-target effects. Addressing these challenges will require innovative approaches and interdisciplinary efforts to unlock the therapeutic potential of TRIM proteins in non-tumor chronic lung diseases.

PMID:39935527 | PMC:PMC11812559 | DOI:10.2147/JIR.S499029

Biomed Rep. 2025 Jan 23;22(3):52. doi: 10.3892/br.2025.1930. eCollection 2025 Mar.

ABSTRACT

Metabolic disorders are a significant feature of fibrotic diseases. Nevertheless, the lack of sufficient proof regarding the cause-and-effect association between circulating metabolites and the promotion or prevention of idiopathic pulmonary fibrosis (IPF) persists. To assess the causal association between IPF and genetic proxies of 486 blood metabolites, a dual sample Mendelian randomization (MR) analysis was performed. Therefore, the two-sample MR technique and genome-wide association study data were employed to assess the association between 486 serum metabolites and IPF. To produce the primary outcomes, the inverse variance weighted (IVW) technique was applied, while to assess the stability and dependability of the outcomes, sensitivity analysis using MR-Egger analysis was performed. Additionally, weighted median, Cochran's Q-test, Egger intercept test and the leave-one-out method were used. The results of the present study revealed a total of 21 metabolites in blood circulation that could affect the risk of IPF (PIVW<0.05). Among them, 10 compounds were already known, namely cotinine [odds ratio (OR)=1.206; 95% confidence interval (CI), 1.002-1.452; P=0.047], hypoxanthine (OR=0.225; 95% CI, 0.056-0.899; P=0.034), aspartyl phenylalanine (OR=4.309; 95% CI, 1.084-17.131; P=0.038), acetyl-carnitine (OR=5.767; 95% CI, 1.398-23.789; P=0.015), 2-aminobutyrate (OR=0.155; 95% CI, 0.033-0.713; P=0.016), Docosapentaenoic acid (PubChem ID: 5497182; OR=0.214; 95% CI, 0.055-0.833; P=0.026), octanoyl-carnitine (PubChem ID: 177508; OR=3.398; 95% CI, 1.179-9.794; P=0.023), alpha-hydroxy-isovalerate (PubChem ID: 857803-94-2; OR=0.324; 95% CI, 0.112-0.931; P=0.036), 1,7-dimethylurate (PubChem ID: 91611; OR=0.401; 95% CI, 0.172-0.931; P=0.033) and 1-linoleoyl-glycerophosphocholine (PubChem ID: 657272; OR=6.559; 95% CI, 1.060-40.557; P=0.043). Additionally, the study also identified 11 currently unknown chemical structures. The results of Cochran's Q-test indicated that there was no significant heterogeneity, while MR-Egger's intercept analysis verified the lack of horizontal pleiotropy. The retention of one method for plotting also supported the reliability of the MR analysis. Overall, the results of the current study supported the cause-and-effect association between IPF and 21 blood metabolites, including 10 with already known chemical composition and 11 which are still awaiting determination. These findings could provide novel insights for the further investigation of the mechanism underlying the development of IPF.

PMID:39931651 | PMC:PMC11808644 | DOI:10.3892/br.2025.1930

F1000Res. 2024 Mar 22;13:216. doi: 10.12688/f1000research.142513.1. eCollection 2024.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a disease with high mortality, and there are only two specific drugs available for therapeutic management with limitations. The study aims to identify comprehensive therapeutic mechanisms of Zingiber zerumbet rhizomes (ZZR) to treat IPF by using network pharmacology followed battery of in silico studies.

METHODS: The protein-protein interaction network was developed using Cytoscape to obtain core disease targets involved in IPF and their interactive molecules of ZZR. Based on the pharmacophore properties of phytomolecules from ZZR, the drug targets in IPF were explored. Protein-protein interaction network was built in Cytoscape to screen potential targets and components of ZZR. Molecular docking and dynamics were conducted as an empirical study to investigate the mechanism explored through network pharmacology in relation to the hub targets.

RESULTS: The network analysis conferred kaempferol derivatives that had demonstrated a promising therapeutic effect on the perturbed, robust network hubs of TGF-β1, EGFR, TNF-α, MMP2 & MMP9 reported to alter the biological process of mesenchymal transition, myofibroblast proliferation, and cellular matrix deposition in pulmonary fibrosis. The phytomolecules of ZZR act on two major significant pathways, namely the TGF-β-signaling pathway and the FOXO-signaling pathway, to inhibit IPF. Confirmational molecular docking and dynamics simulation studies possessed good stability and interactions of the protein-ligand complexes by RMSD, RMSF, rGyr, SASA, and principal component analysis (PCA). Validated molecular docking and dynamics simulations provided new insight into exploring the mechanism and multi-target effect of ZZR to treat pulmonary fibrosis by restoring the alveolar phenotype through cellular networking.

CONCLUSIONS: Network pharmacology and in silico studies confirm the multitargeted activity of ZZR in the treatment of IPF. Further in vitro and in vivo studies are to be conducted to validate these findings.

PMID:39931327 | PMC:PMC11809647 | DOI:10.12688/f1000research.142513.1

Med Adv. 2024 Dec;2(4):336-348. doi: 10.1002/med4.86. Epub 2024 Dec 17.

ABSTRACT

BACKGROUND: Accurate staging systems are essential for assessing the severity of idiopathic pulmonary fibrosis (IPF) and guiding clinical management. This study aimed to evaluate the prognostic value of pulmonary comorbidities and body mass index (BMI) in IPF, develop a nomogram predicting overall survival (OS), and create a nomogram-based survival prediction model.

METHODS: Patients with IPF were identified from electronic medical records of the West Virginia hospital system. Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression analysis was used for variable selection, and a nomogram was constructed. Risk groups were defined based on the nomogram's probability tertiles. The performance of the nomogram-based model was evaluated using Harrell's concordance index (C-index) and the Hosmer-Lemeshow test.

RESULTS: The study included 152 patients with IPF. The majority of the patients were elderly, male, and had a BMI above 24 kg/m2. The median survival duration was 7.6 years. The survival rates were 91% at 1 year, 78% at 3 years, and 68% at 5 years. LASSO regression selected carbon monoxide lung diffusion capacity percentage predicted (DLco%), BMI, pulmonary hypertension, pulmonary embolism, and sleep apnea as independent predictive variables. The nomogram demonstrated good discrimination (C-index = 0.71) and calibration.

CONCLUSIONS: Pulmonary comorbidities and BMI have significant prognostic value in IPF, emphasizing the necessity for consistent screening, assessment, and management of these factors in IPF care. Furthermore, the nomogram-based staging system showed promising performance in predicting OS and represents an actionable staging system that could potentially improve clinical management in IPF. Further validation of the nomogram is warranted to confirm its utility in clinical practice.

PMID:39931115 | PMC:PMC11809524 | DOI:10.1002/med4.86

J Cell Mol Med. 2025 Feb;29(3):e70402. doi: 10.1111/jcmm.70402.

ABSTRACT

The cell populations, particularly subpopulations, involved in the onset and progression of idiopathic pulmonary fibrosis (IPF) remain incompletely understood. This study employed single-cell RNA-seq to identify cell populations and subpopulations with significantly altered proportions in the lungs of patients with IPF. In IPF lungs, endothelial cell proportions were significantly increased, while alveolar epithelial cell proportions were markedly decreased. Among the three identified fibroblast subpopulations, the proportion of myofibroblasts was significantly increased, while the proportions of the other two fibroblast subtypes were reduced. Similarly, within the three macrophage subpopulations, the macrophage_SPP1 subpopulation, localised to fibroblastic foci, showed a significant increase in proportion, while the alveolar macrophage subpopulation was significantly reduced. Trajectory analysis revealed that fibroblasts in IPF lungs could differentiate into myofibroblasts, and alveolar macrophages could transition into the macrophage_SPP1 subpopulation. Among T-cell subpopulations, only the CD4 T_FOXP3 subpopulation exhibited a significant change, whereas all four B-cell subpopulations showed significant proportional shifts. These findings provide a comprehensive view of the cellular alterations contributing to IPF pathogenesis. Extensive interactions among various cell populations and subpopulations were identified. The proportions of various cell populations and subpopulations in IPF lungs, including endothelial cells, fibroblasts, macrophages and B cells, were significantly altered. Further in-depth investigation into the roles of cell subpopulations with significantly altered proportions in the onset and progression of IPF will provide valuable insights into the pathological mechanisms underlying the disease. This understanding could facilitate the development of novel therapeutic strategies and medications for IPF treatment.

PMID:39928535 | DOI:10.1111/jcmm.70402

Am J Respir Crit Care Med. 2025 Feb 10. doi: 10.1164/rccm.202411-2157OC. Online ahead of print.

ABSTRACT

RATIONALE: Pulmonary hypertension (PH) commonly complicates idiopathic pulmonary fibrosis (IPF). However, the rate of change in pulmonary hemodynamics in IPF remains poorly defined.

OBJECTIVES: To examine the rate of change in pulmonary hemodynamics among patients with IPF.

METHODS: The rate of change in mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) was examined in patients with IPF listed for lung transplantation. The 5th and 7th World Symposium on Pulmonary Hypertension definitions for precapillary PH were employed in this analysis.

MEASUREMENTS AND MAIN RESULTS: There were 496 patients with IPF that had at least two right heart catheterizations (RHCs) while listed for lung transplantation. The median time between repeated RHCs was 9 months (interquartile range [IQR]: 6-14). PH was present in 25.8% and 46.8% at the first RHC, while 42.9% and 64.3% had PH by the two definitions respectively, at the time of the final RHC. The median rate of change in the mPAP and PVR were 3.8 mmHg/year (IQR: -0.9-11.8) and 0.8 Wood Units/year (IQR: -0.2-2.4), respectively. The rate of PVR change was slower for those with established PH compared with those without PH. 28.6% of the patients had accelerated progression of their hemodynamics, arbitrarily defined as an increase in PVR of ≥ 2 Wood Units/year.

CONCLUSIONS: PH associated with IPF tends to progress in an unpredictable fashion, with some patients demonstrating an accelerated phenotype. Among patients with RHC hemodynamics below the threshold for therapy, close vigilance is warranted with consideration for an early repeat RHC. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PMID:39928362 | DOI:10.1164/rccm.202411-2157OC

Brief Bioinform. 2024 Nov 22;26(1):bbaf033. doi: 10.1093/bib/bbaf033.

ABSTRACT

In single-cell studies, cells can be characterized with multiple sources of heterogeneity (SOH) such as cell type, developmental stage, cell cycle phase, activation state, and so on. In some studies, many nuisance SOH are of no interest, but may confound the identification of the SOH of interest, and thus affect the accurate annotate the corresponding cell subpopulations. In this paper, we develop B-Lightning, a novel and robust method designed to identify marker genes and cell subpopulations corresponding to an SOH (e.g. cell activation status), isolating it from other SOH (e.g. cell type, cell cycle phase). B-Lightning uses an iterative approach to enrich a small set of trustworthy marker genes to more reliable marker genes and boost the signals of the SOH of interest. Multiple numerical and experimental studies showed that B-Lightning outperforms existing methods in terms of sensitivity and robustness in identifying marker genes. Moreover, it increases the power to differentiate cell subpopulations of interest from other heterogeneous cohorts. B-Lightning successfully identified new senescence markers in ciliated cells from human idiopathic pulmonary fibrosis lung tissues, new T-cell memory and effector markers in the context of SARS-COV-2 infections, and their synchronized patterns that were previously neglected, new AD markers that can better differentiate AD severity, and new dendritic cell functioning markers with differential transcriptomics profiles across breast cancer subtypes. This paper highlights B-Lightning's potential as a powerful tool for single-cell data analysis, particularly in complex data sets where SOH of interest are entangled with numerous nuisance factors.

PMID:39927857 | DOI:10.1093/bib/bbaf033

JCI Insight. 2025 Feb 10;10(3):e165837. doi: 10.1172/jci.insight.165837.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an age-related interstitial lung disease, characterized by inadequate alveolar regeneration and ectopic bronchiolization. While some molecular pathways regulating lung progenitor cells have been described, the role of metabolic pathways in alveolar regeneration is poorly understood. We report that expression of fatty acid oxidation (FAO) genes is significantly diminished in alveolar epithelial cells of IPF lungs by single-cell RNA sequencing and tissue staining. Genetic and pharmacological inhibition in AT2 cells of carnitine palmitoyltransferase 1a (CPT1a), the rate-limiting enzyme of FAO, promoted mitochondrial dysfunction and acquisition of aberrant intermediate states expressing basaloid, and airway secretory cell markers SCGB1A1 and SCGB3A2. Furthermore, mice with deficiency of CPT1a in AT2 cells show enhanced susceptibility to developing lung fibrosis with an accumulation of epithelial cells expressing markers of intermediate cells, airway secretory cells, and senescence. We found that deficiency of CPT1a causes a decrease in SMAD7 protein levels and TGF-β signaling pathway activation. These findings suggest that the mitochondrial FAO metabolic pathway contributes to the regulation of lung progenitor cell repair responses and deficiency of FAO contributes to aberrant lung repair and the development of lung fibrosis.

PMID:39927460 | DOI:10.1172/jci.insight.165837

Health Sci Rep. 2025 Feb 6;8(2):e70328. doi: 10.1002/hsr2.70328. eCollection 2025 Feb.

ABSTRACT

BACKGROUND AND AIMS: Interactions between the lung microbiome and pulmonary epithelium plays a pivotal role in shaping immunity in the lung. Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung disease (ILD). Some patients with IPF develop episodic acute exacerbations often associated with microbial dysbiosis in the lungs. This study aimed to investigate etiologic agents as well as the lung microbiome in patients with ILDs and sarcoidosis.

METHODS: This study analyzed 31 patients divided into the IPF (IPF-stable, n = 12), acute exacerbation of ILDs (AE-ILDs, n = 6), and sarcoidosis (n = 13) groups. Bronchoalveolar lavage fluid (BALF) samples were analyzed by RNA-based metagenomic next-generation sequencing (NGS) on an Illumina platform.

RESULTS: In total, 87 pathogens were detected using metagenomic NGS at the genus level. Prevotella, Streptococcus, and Veillonella dominated the BALF microbial communities, and sequence reads of these bacteria were abundant, especially in the sarcoidosis group. Conversely, only a small number of bacterial reads were detected in the AE-ILDs group, and the overall proportion of microbial composition differed from that of the other groups. No significant difference was found in community diversity (α-diversity) among the groups, whereas the structural similarity of the microflora (β-diversity) differed significantly between the AE-ILDs and sarcoidosis groups.

CONCLUSIONS: Bacterial sequence reads in BALF were smaller in both the IPF-stable and AE-ILD groups than in the sarcoidosis group. Dysbiosis in the lung microbiome has been observed in patients with AE-ILD and may be related to the progression of inflammation.

PMID:39927182 | PMC:PMC11803077 | DOI:10.1002/hsr2.70328

Respir Med. 2025 Feb 5:107986. doi: 10.1016/j.rmed.2025.107986. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pleuroparenchymal fibroelastosis (iPPFE) is a distinctive chronic interstitial lung disease characterized by upper lobe-dominant elastofibrosis. Deepening of the suprasternal notch is a notable physical feature in patients with iPPFE. However, the anatomical explanation and clinical significance of iPPFE have not yet been studied in detail.

METHODS: We retrospectively examined 84 patients with iPPFE, 59 with idiopathic pulmonary fibrosis (IPF), 32 with chronic hypersensitivity pneumonitis (CHP), and 91 non-interstitial lung disease (ILD) controls. The depth of the suprasternal notch assessed on axial chest computed tomography and its association with clinical, radiological, and physiological parameters, and patient outcomes were investigated.

RESULTS: The depth of the suprasternal notch was anatomically correlated with the thickness of the pre-tracheal soft tissue and posterior or right deviation of the trachea in patients with iPPFE. The depth of the suprasternal notch effectively discriminated patients with iPPFE from those with IPF (sensitivity, 75%; specificity, 86.4%), CHP (sensitivity, 75%; specificity, 84.4%), and non-ILD controls (sensitivity, 75%; specificity, 83.5%), with a cutoff value of 9.5 mm. A log-rank test showed that patients with iPPFE with a deep suprasternal notch had significantly shorter survival than those without a deep suprasternal notch. In addition, a multivariate Cox regression analysis adjusted for age, sex, and %forced vital capacity showed that the depth of the suprasternal notch was an independent risk factor for mortality.

CONCLUSION: The suprasternal notch is a simple and useful indicator with diagnostic and prognostic implications for patients with iPPFE.

PMID:39921067 | DOI:10.1016/j.rmed.2025.107986