Spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis

Nature Genetics, Год журнала: 2025, Номер unknown

Опубликована: Фев. 3, 2025

Abstract Large-scale changes in the structure and cellular makeup of distal lung are a hallmark pulmonary fibrosis (PF), but spatial contexts that contribute to disease pathogenesis have remained uncertain. Using image-based transcriptomics, we analyzed gene expression 1.6 million cells from 35 unique lungs. Through complementary cell-based innovative cell-agnostic analyses, characterized localization PF-emergent cell types, established molecular basis classical PF histopathologic features identified diversity distinct molecularly defined niches control machine learning trajectory analysis segment rank airspaces on gradient remodeling severity, compositional associated with progressive pathology, beginning alveolar epithelial dysregulation culminating macrophage polarization. Together, these results provide unique, spatially resolved view establish methods could be applied other transcriptomic studies.

Язык: Английский

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Progressive lung fibrosis: reprogramming a genetically vulnerable bronchoalveolar epithelium

Journal of Clinical Investigation, Год журнала: 2025, Номер 135(1)

Опубликована: Янв. 1, 2025

Idiopathic pulmonary fibrosis (IPF) is etiologically complex, with well-documented genetic and nongenetic origins. In this Review, we speculate that the development of IPF requires two hits: first establishes a vulnerable bronchoalveolar epithelium, second triggers mechanisms reprogram distal epithelia to initiate perpetuate profibrotic phenotype. While vulnerability most often driven by common or rare variants, subsequent injury results in persistent changes cell biology disrupt tissue homeostasis activate fibroblasts. The dynamic can best be contextualized temporally, including stages vulnerability, early disease, progressive lung fibrosis. These dimensions highlight critical adversely epithelial function, fibroblasts, lead remodeling. Together better recognition conceptual approach should novel therapeutics directed at etiologic temporal drivers will ultimately transform care patients from palliative curative.

Язык: Английский

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Gender Differences Are a Leading Factor in 5-Year Survival of Patients with Idiopathic Pulmonary Fibrosis over Antifibrotic Therapy Reduction

Life, Год журнала: 2025, Номер 15(1), С. 106 - 106

Опубликована: Янв. 16, 2025

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with median survival of 3–5 years. Antifibrotic therapies like pirfenidone and nintedanib slow progression, but the outcomes vary. Gender may influence presentation, response to treatment. This study evaluates impact gender on 5-year survival, pharmacological management, clinical patients IPF. Methods: A retrospective cohort 254 IPF was conducted, 164 (131 males:33 females) having complete data. Patients underwent spirometry, DLCO, 6 min walk tests. Data comorbidities, smoking, antifibrotic therapy type, dosage adjustments, adverse events were collected. We used Kaplan–Meier curves logistic regression assess gender-related differences in outcomes. Results: Men had worse function at diagnosis (FVC 74.9 ± 18.5 vs. 87.2 20.1% pred.; p < 0.001) higher smoking prevalence (74% 30%; 0.001). Women better (51.2 40.8 19.2 months; = 0.005) despite more frequent biopsy use (36% 17%; 0.013). tolerated longer (p No found between receiving reduced dosing those full dosing. Conclusions: has significant outcomes, women demonstrating tolerance long-term therapy. In contrast, reducing treatment does not appear significantly affect These findings underscore need for future research gender-specific management approaches.

Язык: Английский

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Human respiratory airway progenitors derived from pluripotent cells generate alveolar epithelial cells and model pulmonary fibrosis

Nature Biotechnology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 24, 2025

Язык: Английский

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Modification of the course of disease progression in idiopathic pulmonary fibrosis by pirfenidone: evidence of the potential for disease reversal

BMJ Case Reports, Год журнала: 2025, Номер 18(3), С. e263966 - e263966

Опубликована: Март 1, 2025

Idiopathic pulmonary fibrosis (IPF) is a fibrosing pneumonia of unknown causation with chronic, progressive course that may be modified by treatment the antifibrotic agents, pirfenidone and nintedanib. Both drugs have been shown to slow disease progression, but, in rare cases, has stabilise even improve lung function. We present case patient whose function pathognomonic features on CT imaging improved significantly commencement pirfenidone. Withholding was associated functional morphological deterioration subsequently reversed stabilised following recommencement this treatment. discuss potential mechanisms might explain response, compare our others described previously consequences restricted prescribing within specified range vital capacity opportunity influence natural history IPF early before irreversible develops.

Язык: Английский

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Genetic Testing Utilization in the U.S. Registry for Childhood Interstitial and Diffuse Lung Diseases

Pediatric Pulmonology, Год журнала: 2025, Номер 60(4)

Опубликована: Апрель 1, 2025

ABSTRACT Introduction Childhood interstitial and diffuse lung diseases (chILD) comprise a diverse group of rare disorders. Identifying the underlying cause is crucial for treatment, prognosis, estimating recurrence risk. The objective this study was to assess utilization genetic testing subjects enrolled in United States National Registry ChILD, multicenter observational study. Methods Genetic data from participating sites were reviewed analyzed relationship clinical characteristics. Results Of 609 children 22 centers, performed 55.5% ( n = 338). results positive (diagnostic) 22.8% 77), negative 60.7% 205), uncertain 16.6% 56). Most through gene panels (55.9%), followed by exome sequencing (ES) or whole genome (WGS) (26.9%), single (24.6%), and/or chromosomal microarray (11.8%). For participants with results, majority diagnosed panel (33.8%; 26) (32.5%; 25). most common diagnosis confirmed SFTPC ‐associated surfactant metabolism dysfunction. 59 unclassified ILD, only 22% 13) had undergone ES WGS, 61% 36) received testing, 27% 16) did not have any reported. Conclusion has been variable infants ChILD Registry. Additional efforts are needed develop recommendations suspected ILD. Furthermore, there opportunity broader ES/WGS discovery disease unclear etiology.

Язык: Английский

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Interstitial Lung Disease Epidemiology in the Past Three Decades: A Narrative Review

Journal of Clinical Medicine, Год журнала: 2024, Номер 13(23), С. 7350 - 7350

Опубликована: Дек. 2, 2024

Current epidemiological data on interstitial lung disease (ILD) are still poor. The principal cause of the discordant is associated with a heterogeneous group respiratory diseases that includes large number, about 200 families, low frequency, distinct and sometimes unknown etiology, different progression. In fact, some conditions spontaneously resolve, whereas others, such as IPF most non-IPF ILDs, progress to failure death despite treatment. Furthermore, limited. scope narrative review report ILD incidence prevalence in registries from countries last three decades. We identified 20 (17 prospective 3 retrospective) major Europe (n = 10), Asia 7), North America 2), Oceania 1). Significant discrepancies subtype among reported registries. These could be determined by ethnicities socioeconomic well updates diagnosis classification. progressively ameliorating through better adherence updated guidelines classification codes. An accurate definite compilation will useful for more precise monitoring progression Future research identify populations highest risk factors, including genetic molecular studies, implementation scores needed improve clinical assessment.

Язык: Английский

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Genetic evidence reveals a causal relationship between rheumatoid arthritis and interstitial lung disease

Frontiers in Genetics, Год журнала: 2024, Номер 15

Опубликована: Май 14, 2024

Background/purpose: Previous epidemiological studies have associated interstitial lung disease (ILD) with rheumatoid arthritis (RA), yet the causality of this relationship remains uncertain. This study aimed to investigate genetic causal link between ILD and RA. Methods: Genome-wide association (GWAS) statistics for RA were collected from public datasets. Relevant single-nucleotide polymorphisms (SNPs) selected by executing quality control steps GWAS summary results. A two-sample bidirectional Mendelian randomization (MR) analysis was performed assess two conditions. The MR primarily used inverse variance weighting (IVW), weighted median (WM), MR-Egger regression methods. Sensitivity analyses, including MR-Egger, leave-one-out, Pleiotropy RESidual Sum Outlier (MR-PRESSO), conducted evaluate heterogeneity pleiotropy. Replication analyses using Asian datasets also enhance robustness our findings. Results: In European population, found increase risk 9.6% (OR: 1.096, 95% CI: 1.023–1.174, p = 0.009). Conversely, a 12.8% increased 1.128, 1.013–1.256, 0.029). further supported these findings, particularly attributable 1.33, 1.18–1.49, -value &lt;0.001). Conclusion: Our findings underscore clinical importance screening in patients suggest that effective management could significantly benefit patients. potential applicability novel treatments warrants exploration. Additionally, racial disparities manifestation diseases should not be overlooked, as they may offer new perspectives targeted therapies diverse populations.

Язык: Английский

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Biomarker-defined endotypes of pulmonary fibrosis

The Lancet Respiratory Medicine, Год журнала: 2024, Номер 12(9), С. 657 - 659

Опубликована: Июль 15, 2024

Язык: Английский

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