Lancet Respir Med. 2024 Jun 13:S2213-2600(24)00177-2. doi: 10.1016/S2213-2600(24)00177-2. Online ahead of print.

NO ABSTRACT

PMID:38880115 | DOI:10.1016/S2213-2600(24)00177-2

Expert Rev Respir Med. 2024 Jun 15. doi: 10.1080/17476348.2024.2369253. Online ahead of print.

ABSTRACT

BACKGROUND: Previous observational studies have shown that past infection of herpes simplex virus (HSV) is associated with idiopathic pulmonary fibrosis (IPF). The present study aims to identify the causal link between HSV infection (exposure factor) and IPF (outcome factor).

RESEARCH DESIGN AND METHODS: To date, the largest publicly available genome-wide association study (GWAS) for HSV infection (1,595 cases and 211,856 controls from Finnish ancestry) and for IPF (1,028 cases and 196,986 controls from Finnish ancestry) were used to perform this two-sample Mendelian randomization (MR) study.

RESULTS: We found no significant pleiotropy or heterogeneity of all selected nine HSV infection-associated genetic instrumental variants (IVs) in IPF GWAS dataset. Interestingly, we found that as HSV infection genetically increased, IPF risk increased based on an inverse-variance weighted (IVW) analysis (odds ratio [OR] = 1.280, 95% confidence interval [CI]: 1.048-1.563; p = 0.015) and weighted median (OR = 1.321, 95% CI: 1.032-1.692; p = 0.027).

CONCLUSIONS: Our analysis suggests a causal effect of genetically increased HSV infection on IPF risk. Thus, HSV infection may be a potential risk factor for IPF.

PMID:38878268 | DOI:10.1080/17476348.2024.2369253

Sci Rep. 2024 Jun 14;14(1):13774. doi: 10.1038/s41598-024-64548-w.

ABSTRACT

Assessment of lung function is an important clinical tool for the diagnosis and monitoring of chronic lung diseases, including idiopathic pulmonary fibrosis (IPF). In mice, lung function maneuvers use algorithm-based ventilation strategies including forced oscillation technique (FOT), negative pressure-driven forced expiratory (NPFE) and pressure-volume (PV) maneuvers via the FlexiVent system. This lung function test (LFT) is usually performed as end-point measurement only, requiring several mice for each time point to be analyzed. Repetitive lung function maneuvers would allow monitoring of a disease process within the same individual while reducing the numbers of laboratory animals. However, its feasibility in mice and impact on developing lung fibrosis has not been studied so far. Using orotracheal cannulation without surgical exposure of the trachea, we examined the tolerability to repetitive lung function maneuvers (up to four times) in one and the same mouse, both under healthy conditions and in a model of AdTGF-β1 induced lung fibrosis. In essence, we found that repetitive invasive lung function maneuvers were well tolerated and did not accentuate experimental lung fibrosis in mice. This study contributes to the 3R principle aiming to reduce the numbers of experimental animals used in biomedical research.

PMID:38877042 | DOI:10.1038/s41598-024-64548-w

Acta Histochem. 2024 Jun 13:152168. doi: 10.1016/j.acthis.2024.152168. Online ahead of print.

NO ABSTRACT

PMID:38876928 | DOI:10.1016/j.acthis.2024.152168

Acad Radiol. 2024 Jun 13:S1076-6332(24)00286-1. doi: 10.1016/j.acra.2024.05.005. Online ahead of print.

ABSTRACT

RATIONALE AND OBJECTIVES: To establish a quantitative CT threshold for radiological disease progression of progressive pulmonary fibrosis (PPF) and evaluate its feasibility in patients with connective tissue disease-related interstitial lung disease (CTD-ILD).

MATERIALS AND METHODS: Between April 2007 and October 2022, patients diagnosed with CTD-ILD retrospectively evaluated. CT quantification was conducted using a commercial software by summing the percentages of ground-glass opacity, consolidation, reticular opacity, and honeycombing. The quantitative threshold for radiological progression was determined based on the highest discrimination on overall survival (OS). Two thoracic radiologists independently evaluated visual radiological progression, and the senior radiologist's assessment was used as the final result. Cox regression was used to assess prognosis of PPF based on the visual assessment and quantitative threshold.

RESULTS: 97 patients were included and followed up for a median of 30.3 months (range, 4.7-198.1 months). For defining radiological disease progression, the optimal quantitative CT threshold was 4%. Using this threshold, 12 patients were diagnosed with PPF, while 14 patients were diagnosed with PPF based on the visual assessment, with an agreement rate of 97.9% (95/97). Worsening respiratory symptoms (hazard ratio [HR], 12.73; P < .001), PPF based on the visual assessment (HR, 8.86; P = .002) and based on the quantitative threshold (HR, 6.72; P = .009) were independent risk factors for poor OS.

CONCLUSION: The quantitative CT threshold for radiological disease progression (4%) was feasible in defining PPF in terms of its agreement with PPF grouping and prognostic performance when compared to visual assessment.

PMID:38876844 | DOI:10.1016/j.acra.2024.05.005

Biomed Pharmacother. 2024 Jun 13;176:116896. doi: 10.1016/j.biopha.2024.116896. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a severe disability due to progressive lung dysfunction. IPF has long been viewed as a non-immune form of pulmonary fibrosis, but nowadays it is accepted that a chronic inflammatory response can exacerbate fibrotic patterns. IL-1-like cytokines and ATP are highly detected in the lung and broncho-alveolar lavage fluid of IPF patients. Because ATP binds the purinergic receptor P2RX7 involved in the release of IL-1-like cytokines, we aimed to understand the role of P2RX7 in IPF. PBMCs from IPF patients were treated with nintedanib or pirfenidone in the presence of ATP. Under these conditions, PBMCs still released IL-1-like cytokines and the pro-fibrotic TGFβ. Bulk and scRNAseq demonstrated that lung tissues of IPF patients had higher levels of P2RX7, especially on macrophages, which were correlated to T cell activity and inflammatory response with a TGFBI and IL-10 signature. A subcluster of macrophages in IPF lung tissues had 2055 genes that were not in common with the other subclusters, and that were involved in metabolic and PDGF, FGF and VEGF associated pathways. These data confirmed what observed on circulating cells that, although treated with anti-fibrotic agents, nintedanib or pirfenidone, they were still able to release IL-1 cytokines and the fibrogenic TGFβ. In conclusion, these data imply that because nintedanib and pirfenidone do not block ATP-induced IL-1-like cytokines and TGFβ induced during P2RX7 activation, it is plausible to consider P2RX7 on circulating cells and/or tissue biopsies as potential pharmacological tool for IPF patients.

PMID:38876049 | DOI:10.1016/j.biopha.2024.116896

Fibrosis (Hong Kong). 2023 Dec;1(2):10007. doi: 10.35534/fibrosis.2023.10007. Epub 2023 Nov 28.

ABSTRACT

The composition of extracellular matrix (ECM) is altered during pathologic scarring in damaged organs including the lung. One major change in the ECM involves the cross-linking of collagen, which promotes fibroblast to myofibroblast differentiation. We examined the role of lysyl oxidase (LOX)-like 2 in lung progenitors and fibroblasts cultured from normal or IPF lung samples and in a humanized mouse model of IPF using a monoclonal antibody (Simtuzumab). Primary lung fibroblasts from normal donor lungs and IPF lung explants were examined for expression of LOXL2. Targeting LOXL2 with Simtuzumab on normal and IPF fibroblasts was examined both in vitro and in vivo for synthetic, functional, and profibrotic properties. LOXL2 was increased at transcript and protein level in IPF compared with normal lung samples. In a dose-dependent manner, Simtuzumab enhanced differentiation of fibroblasts into myofibroblasts. Inhibition of LOXL2 also enhanced fibroblast invasion and accelerated the outgrowth of fibroblasts from dissociated human lung cell preparations. Finally, preventative or delayed delivery of Simtuzumab enhanced lung fibrosis in a humanized mouse model of pulmonary fibrosis. Consistent with its failure in a Phase 2 clinical trial, Simtuzumab exhibited no therapeutic efficacy in translational in vitro and in vivo assays.

PMID:38873180 | PMC:PMC11175361 | DOI:10.35534/fibrosis.2023.10007

J Cell Mol Med. 2024 Jun;28(11):e18414. doi: 10.1111/jcmm.18414.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a debilitating interstitial lung disease characterized by progressive fibrosis and poor prognosis. Despite advancements in treatment, the pathophysiological mechanisms of IPF remain elusive. Herein, we conducted an integrated bioinformatics analysis combining clinical data and carried out experimental validations to unveil the intricate molecular mechanism of IPF. Leveraging three IPF datasets, we identified 817 upregulated and 560 downregulated differentially expressed genes (DEGs). Of these, 14 DEGs associated with copper metabolism were identified, shedding light on the potential involvement of disrupted copper metabolism in IPF progression. Immune infiltration analysis revealed dysregulated immune cell infiltration in IPF, with a notable correlation between copper metabolism-related genes and immune cells. Weighted gene co-expression network analysis (WGCNA) identified a central module correlated with IPF-associated genes, among which STEAP2 emerged as a key hub gene. Subsequent in vivo and in vitro studies confirmed the upregulation of STEAP2 in IPF model. Knockdown of STEAP2 using siRNA alleviated fibrosis in vitro, suggesting potential pathway related to copper metabolism in the pathophysiological progression of IPF. Our study established a novel link between immune cell infiltration and dysregulated copper metabolism. The revelation of intracellular copper overload and upregulated STEAP2 unravelled a potential therapeutic option. These findings offer valuable insights for future research and therapeutic interventions targeting STEAP2 and associated pathways in IPF.

PMID:38872435 | DOI:10.1111/jcmm.18414

Thorax. 2024 Jun 13:thorax-2024-221398. doi: 10.1136/thorax-2024-221398. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease for which there are no reliable biomarkers or disease-modifying drugs. Here, we integrated human genomics and proteomics to investigate the causal associations between 2769 plasma proteins and IPF. Our Mendelian randomisation analysis identified nine proteins associated with IPF, of which three (FUT3, ADAM15 and USP28) were colocalised. ADAM15 emerged as the top candidate, supported by expression quantitative trait locus analysis in both blood and lung tissue. These findings provide novel insights into the aetiology of IPF and offer translational opportunities in response to the clinical challenges of this devastating disease.

PMID:38871465 | DOI:10.1136/thorax-2024-221398

Eur Respir J. 2024 Jun 13:2302080. doi: 10.1183/13993003.02080-2023. Online ahead of print.

ABSTRACT

INTRODUCTION: Previous research has suggested that the incidence of idiopathic pulmonary fibrosis (IPF) is increasing in the United Kingdom (UK) and elsewhere. The aim of this study is to provide contemporary estimates of IPF mortality rates across 24 European Countries from 2013 to 2018, using death certificates data from the European Statistics Institution (EUROSTAT) database.

METHODS: We extracted country data for IPF (International Classification of Diseases 10th Edition, ICD-10, code "J84.1") mortality from the EUROSTAT dataset. We calculated country- age- and sex-specific death registration rates between 2013 and 2018. We used direct standardisation to compare rates between countries. We calculated annual trends in mortality rate ratios using a segmented regression model.

RESULTS: The overall standardised mortality rate in EU Countries during this period was 3.90 per 10 0000 person-years (95%, CI 3.80-3.90), with the rate raising from 3.70 in the 2013 to 4.00 in the 2018 (average annual percent change: 1.74%, 95% CI 0.91-2.59). We observed substantial inter-country differences, with the highest rates detected in Ireland, the UK, and Finland, the lowest rate in Bulgaria, and middle rates in Germany, Greece, Italy, the Netherlands, Portugal, and Slovenia.

CONCLUSION: In summary, the IPF mortality rate is increasing across Europe. There are currently more than 17 000 deaths recorded from IPF each year in Europe but the marked geographical differences we observed suggest that this figure may underestimate the true rate considerably.

PMID:38871377 | DOI:10.1183/13993003.02080-2023

Phytomedicine. 2024 Apr 20;132:155664. doi: 10.1016/j.phymed.2024.155664. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a refractory respiratory disease mainly attributed to multiple pathological factors such as oxidative stress, infectious inflammation, and idiopathic fibrosis for decades. The medicinal plant Glycyrrhiza uralensis extract (ULE) was widely used to control respiratory diseases in China. However, the regulatory mechanism of scientific evidence to support the therapeutic benefits of ULE in the management of COPD is greatly limited.

PURPOSE: This study aims to discover the potential protection mechanism of ULE on COPD via a muti-targets strategy.

STUDY DESIGN AND METHODS: The present study set out to determine the potential protective effects of ULE on COPD through a multi-target strategy. In vivo and in vitro models of COPD were established using cigarette smoke and lipopolysaccharide to assess the protective effects of ULE. It was evaluated by measuring inflammatory cytokines and assessing pulmonary pathological changes. HPLC was used to verify the active compounds of the potential compounds that were collected and screened using HERB, works of literature, and ADME tools. The mechanisms of ULE in the treatment of COPD were explored using transcriptomics, connectivity-map, and network pharmacology approaches. The relevant targets were further investigated using RT-PCR, western blot, and immunohistochemistry. The HCK inhibitor (iHCK-37) was used to evaluate the potential mechanism of ULE's active compounds in the prevention of COPD.

RESULTS: ULE effectively protected the lungs of COPD mice from oxidative stress, inflammation, and fibrosis damage. After screening and verification using ADME properties and HPLC, 4 active compounds were identified in ULE: liquiritin (LQ), licochalcone B (LCB), licochalcone A (LCA), and echinatin (ET). Network pharmacology integrated with transcriptomics analysis showed that ULE mitigated oxidative stress, inflammation, and fibrosis in COPD by suppressing HCK. The combination of LCB and LQ was optimized for anti-inflammation, antioxidation, and anti-fibrosis activities. The iHCK-37 further validated the preventive treatment of LCB and LQ on COPD by inhibiting HCK to exert antioxidant, anti-inflammatory, and anti-fibrotic effects. The combination of LCB and LQ, in a 1:1 ratio, exerted synergistic antioxidative, anti-inflammatory, and anti-fibrotic effects in the treatment of COPD by downregulating HCK.

CONCLUSION: The combination of LCB and LQ performed a significant anti-COPD effect via downregulating HCK.

PMID:38870751 | DOI:10.1016/j.phymed.2024.155664

Respir Res. 2024 Jun 13;25(1):241. doi: 10.1186/s12931-024-02845-8.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic disease of unknown etiology that lacks a specific treatment. In IPF, macrophages play a key regulatory role as a major component of the lung immune system, especially during inflammation and fibrosis. However, our understanding of the cellular heterogeneity and molecular characterization of macrophages in IPF, as well as their relevance in the clinical setting, is relatively limited. In this study, we analyzed in-depth single-cell transcriptome sequencing (scRNA-seq) data from lung tissues of IPF patients, identified macrophage subpopulations in IPF, and probed their molecular characteristics and biological functions. hdWGCNA identified co-expressed gene modules of a subpopulation of IPF-associated macrophages (IPF-MΦ), and probed the IPF-MΦ by a machine-learning approach. hdWGCNA identified a subpopulation of IPF-associated macrophage subpopulations and probed the IPF-MΦ signature gene (IRMG) for its prognostic value, and a prediction model was developed on this basis. In addition, IPF-MΦ was obtained after recluster analysis of macrophages in IPF lung tissues. Coexpressed gene modules of IPF-MΦ were identified by hdWGCNA. Then, a machine learning approach was utilized to reveal the characteristic genes of IPF-MΦ, and a prediction model was built on this basis. In addition, we discovered a type of macrophage unique to IPF lung tissue named ATP5-MΦ. Its characteristic gene encodes a subunit of the mitochondrial ATP synthase complex, which is closely related to oxidative phosphorylation and proton transmembrane transport, suggesting that ATP5-MΦ may have higher ATP synthesis capacity in IPF lung tissue. This study provides new insights into the pathogenesis of IPF and provides a basis for evaluating disease prognosis and predictive medicine in IPF patients.

PMID:38872139 | DOI:10.1186/s12931-024-02845-8

Biochem Genet. 2024 Jun 13. doi: 10.1007/s10528-024-10853-y. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive form of pulmonary fibrosis of unknown etiology. Despite ongoing research, there is currently no cure for this disease. Recent studies have highlighted the significance of competitive endogenous RNA (ceRNA) regulatory networks in IPF development. Therefore, this study investigated the ceRNA network associated with IPF pathogenesis. We obtained gene expression datasets (GSE32538, GSE32537, GSE47460, and GSE24206) from the Gene Expression Omnibus (GEO) database and analyzed them using bioinformatics tools to identify differentially expressed messenger RNAs (DEmRNAs), microRNAs (DEmiRNAs), and long non-coding RNAs (DElncRNA). For DEmRNAs, we conducted an enrichment analysis, constructed protein-protein interaction networks, and identified hub genes. Additionally, we predicted the target genes of differentially expressed mRNAs and their interacting long non-coding RNAs using various databases. Subsequently, we screened RNA molecules with ceRNA regulatory relations in the lncACTdb database based on the screening results. Furthermore, we performed disease and functional enrichment analyses and pathway prediction for miRNAs in the ceRNA network. We also validated the expression levels of candidate DEmRNAs through quantitative real-time reverse transcriptase polymerase chain reaction and analyzed the correlation between the expression of these candidate DEmRNAs and the percent predicted pre-bronchodilator forced vital capacity [%predicted FVC (pre-bd)]. We found that three ceRNA regulatory axes, specifically KCNQ1OT1/XIST/NEAT1-miR-20a-5p-ITGB8, XIST-miR-146b-5p/miR-31-5p- MMP16, and NEAT1-miR-31-5p-MMP16, have the potential to significantly affect IPF progression. Further examination of the underlying regulatory mechanisms within this network enhances our understanding of IPF pathogenesis and may aid in the identification of diagnostic biomarkers and therapeutic targets.

PMID:38871957 | DOI:10.1007/s10528-024-10853-y

J Physiother. 2024 Jun 12:S1836-9553(24)00043-2. doi: 10.1016/j.jphys.2024.05.004. Online ahead of print.

NO ABSTRACT

PMID:38871591 | DOI:10.1016/j.jphys.2024.05.004

J Physiother. 2024 Jun 12:S1836-9553(24)00044-4. doi: 10.1016/j.jphys.2024.05.005. Online ahead of print.

NO ABSTRACT

PMID:38871587 | DOI:10.1016/j.jphys.2024.05.005

PLoS One. 2024 Jun 13;19(6):e0305429. doi: 10.1371/journal.pone.0305429. eCollection 2024.

ABSTRACT

BACKGROUND: In real-world studies, the rate of discontinuation of nintedanib (NT) varies from 4% to 53%. Switching anti-fibrotic treatment in patients with idiopathic pulmonary fibrosis (IPF) has not been adequately investigated, and data on the tolerability and efficacy of changes in anti-fibrotic treatment is limited in clinical practice.

OBJECTIVE: To identify factors associated with poor continuation of NT, efficacy and predictors of deterioration after switching from NT to pirfenidone (PFD) in patients with IPF.

SUBJECTS AND METHODS: One hundred and seventy patients with IPF in whom NT was introduced between April 2017 and March 2022 were included to investigate NT continuation status and the effect of switching to PFD.

RESULTS: A total of 123 patients (72.4%) continued NT for 1 year and had a significantly higher %forced vital capacity (FVC) at NT introduction than those who discontinued within 1 year (80.9% ± 16.3% vs. 71.9% ± 22.1%, P = 0.004). The determinant of poor NT continuation was the high GAP stage. On the other hand, 28 of 36 patients who discontinued NT because of disease progression switched to PFD. Consequently, FVC decline was suppressed before and after the change. The predictor of deterioration after the switch was a lower body mass index.

CONCLUSIONS: In patients with IPF, early NT introduction increased continuation rates, and switching to PFD was effective when patients deteriorated despite initial NT treatment.

PMID:38870246 | DOI:10.1371/journal.pone.0305429

Multidiscip Respir Med. 2024 Jun 13;19. doi: 10.5826/mrm.2024.982.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) represents a fibrotic interstitial lung disease characterized by uncertain etiology and poor prognosis. Over the years, the path to effective treatments has been marked by a series of advances and setbacks. The introduction of approved antifibrotic drugs, pirfenidone and nintedanib, marked a pivotal moment in the management of IPF. However, despite these advances, these drugs are not curative, although they can slow the natural progression of the disease. The history of drug therapy for IPF goes together with the increased understanding of the pathogenic mechanisms underlying the disease. Based on that, current research efforts continue to explore new therapies, possible personalized treatment strategies, drug combinations, and potential biomarkers for diagnosis and prognosis. In this review, we outline the route that led to the discover of the first effective therapies, ongoing clinical trials, and future directions in the search for more effective treatments.

PMID:38869027 | DOI:10.5826/mrm.2024.982

Heart Lung. 2024 Jun 11;68:9-17. doi: 10.1016/j.hrtlng.2024.06.003. Online ahead of print.

ABSTRACT

BACKGROUND: A key component of idiopathic pulmonary fibrosis (IPF) is the involvement of immune cells. However, the causal interaction between different immune cell signatures and IPF remain inconclusive.

OBJECTIVES: Based on publicly accessible data, our study utilized the Mendelian randomization (MR) approach to determine the causative relevance of complex immune cell phenotypes in IPF.

METHODS: We deployed a two-sample Mendelian randomization approach to evaluate the causal interaction between immune cell markers and IPF. All data regarding 731 immune signatures and IPF were acquired from two genome-wide association studies (GWAS) that are accessible to the public. The original study adopted the inverse variance weighted (IVW) method, followed by sensitivity analyses aimed at eliminating heterogeneity and pleiotropy. Additionally, Multivariate Mendelian randomization (MVMR) was utilized to identify the independent risk factors in our study.

RESULTS: The summary dataset for IPF was accessed from the Finnish Genetic Consortium R9, comprising 2018 patients and 373,064 controls. And the dataset for immune signatures was conducted in 3,757 Sardinian individuals. By conducting IVW and extensive sensitivity analyses, univariate Mendelian randomization (UVMR) identified one immunophenotype that remained causally associated with IPF after false discovery rate (FDR) correction: CD39 on CD39+ CD8+T cells (odd ratio [OR] = 0.850, 95 % confidence interval [CI] = 0.787-0.918, P = 3.68 × 10-5). The causal association with IPF was further validated using MVMR.

CONCLUSIONS: Based on rigorous MR analysis methods and FDR correction, our study demonstrated that CD39 on CD39+ CD8+T cells showed a protective effect against IPF, providing effective insights for preventing and diagnosing pulmonary fibrosis.

PMID:38865855 | DOI:10.1016/j.hrtlng.2024.06.003

Respir Res. 2024 Jun 12;25(1):239. doi: 10.1186/s12931-024-02864-5.

ABSTRACT

BACKGROUND: In familial pulmonary fibrosis (FPF) at least two biological relatives are affected. Patients with FPF have diverse clinical features.

RESEARCH QUESTION: We aimed to characterize demographic and clinical features, re-evaluate high-resolution computed tomography (HRCT) scans and histopathology of surgical lung biopsies, assess survival and investigate the suitability of risk prediction models for FPF patients.

STUDY DESIGN: A retrospective cohort study.

METHODS: FPF data (n = 68) were collected from the medical records of Oulu University Hospital (OUH) and Oulaskangas District Hospital between 1 Jan 2000 and 11 Jan 2023. The inclusion criterion was pulmonary fibrosis (PF) (ICD 10-code J84.X) and at least one self-reported relative with PF. Clinical information was gathered from hospital medical records. HRCT scans and histology were re-evaluated.

RESULTS: Thirty-seven (54.4%) of the patients were men, and 31 (45.6%) were women. The mean ages of the women and men were 68.6 and 61.7 years, respectively (p = 0.003). Thirty-seven (54.4%) patients were nonsmokers. The most common radiological patterns were usual interstitial pneumonia (UIP) (51/75.0%), unclassifiable (8/11.8%) and nonspecific interstitial pneumonia (NSIP) (3/4.4%). Pleuroparenchymal fibroelastosis (PPFE) was observed as a single or combined pattern in 13.2% of the patients. According to the 2022 guidelines for idiopathic pulmonary fibrosis (IPF), the patients were categorized as UIP (31/45.6%), probable UIP (20/29.4%), indeterminate for UIP (7/10.3%) or alternative diagnosis (10/14.7%). The histopathological patterns were UIP (7/41.2%), probable UIP (1/5.9%), indeterminate for UIP (8/47.2%) and alternative diagnosis (1/5.9%). Rare genetic variants were found in 9 patients; these included telomerase reverse transcriptase (TERT, n = 6), telomerase RNA component (TERC, n = 2) and regulator of telomere elongation helicase 1 (RTEL1, n = 1). Half of the patients died (n = 29) or underwent lung transplantation (n = 5), with a median survival of 39.9 months. The risk prediction models composite physiology index (CPI), hazard ratio (HR) 1.07 (95.0% CI 1.04-1.10), and gender-age-physiology index (GAP) stage I predicted survival statistically significantly (p<0.001) compared to combined stages II and III.

CONCLUSIONS: This study confirmed the results of earlier studies showing that FPF patients' radiological and histopathological patterns are diverse. Moreover, radiological and histological features revealed unusual patterns and their combinations.

PMID:38867203 | DOI:10.1186/s12931-024-02864-5

Sci Adv. 2024 Jun 14;10(24):eado4791. doi: 10.1126/sciadv.ado4791. Epub 2024 Jun 12.

ABSTRACT

The stemness loss-associated dysregeneration of impaired alveolar type 2 epithelial (AT2) cells abolishes the reversible therapy of idiopathic pulmonary fibrosis (IPF). We here report an inhalable mucus-penetrating lipid nanoparticle (LNP) for codelivering dual mRNAs, promoting realveolarization via restoring AT2 stemness for IPF treatment. Inhalable LNPs were first formulated with dipalmitoylphosphatidylcholine and our in-house-made ionizable lipids for high-efficiency pulmonary mucus penetration and codelivery of dual messenger RNAs (mRNAs), encoding cytochrome b5 reductase 3 and bone morphogenetic protein 4, respectively. After being inhaled in a bleomycin model, LNPs reverses the mitochondrial dysfunction through ameliorating nicotinamide adenine dinucleotide biosynthesis, which inhibits the accelerated senescence of AT2 cells. Concurrently, pathological epithelial remodeling and fibroblast activation induced by impaired AT2 cells are terminated, ultimately prompting alveolar regeneration. Our data demonstrated that the mRNA-LNP system exhibited high protein expression in lung epithelial cells, which markedly extricated the alveolar collapse and prolonged the survival of fibrosis mice, providing a clinically viable strategy against IPF.

PMID:38865465 | DOI:10.1126/sciadv.ado4791