Eur Respir Rev. 2025 Jul 9;34(177):240206. doi: 10.1183/16000617.0206-2024. Print 2025 Jul.

ABSTRACT

INTRODUCTION: Validated and reliable patient-reported outcome measures (PROMs) are recommended to assess the severity and impact of cough in interstitial lung disease (ILD). We systematically reviewed the literature to identify PROMs for cough in ILD, examining their psychometric properties.

METHODS: We searched four databases from inception to 10 January 2025. English-language original articles that described the use of a PROM to measure cough in adults with ILD and addressed the psychometric properties, method of administration or results of usability testing were selected.

RESULTS: 21 PROMs were evaluated in 35 studies, including 14 in idiopathic pulmonary fibrosis (IPF) and seven in other ILDs, eight cough-specific PROMs, and 13 disease-specific PROMs with a domain for cough. No tool had sufficient evidence for more than 5/7 of the psychometric properties evaluated. There was evidence for content validity for four PROMs in IPF (A Tool to Assess Quality of Life in Idiopathic Pulmonary Fibrosis (ATAQ-IPF), the Cough and Sputum Assessment Questionnaire (CASA-Q), Evaluating Respiratory Symptoms: COPD (E-RS™:COPD) and the Living with Idiopathic Pulmonary Fibrosis Questionnaire (L-IPF)). Only one study evaluated convergent validity using objective cough monitoring, demonstrating high validity for the Leicester Cough Questionnaire (LCQ) (r=-0.74- -0.80) and cough visual analogue scale (VAS) (r=0.80). Acceptable internal consistency (α>0.7) was demonstrated for 10 PROMs (ATAQ-IPF, the Cross-Atlantic modification of ATAQ-IPF, the Chinese version of ATAQ-IPF, CASA-Q, E-RS™:COPD, LCQ, L-IPF, the IPF-specific version of St George's Respiratory Questionnaire (SGRQ), the modified version of the Edmonton System Assessment System and SGRQ). The cough VAS demonstrated good predictive validity and L-IPF was responsive to ILD-specific therapies, with effect sizes ranging from 0.32 to 0.44.

CONCLUSION: Evidence supporting the measurement properties of available PROMs for cough in ILD is limited. Further validation of existing instruments and the development of new disease-specific PROMs are needed.

PMID:40633974 | DOI:10.1183/16000617.0206-2024

Semin Respir Crit Care Med. 2025 Jul 9. doi: 10.1055/a-2651-1937. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a rare but devastating diagnosis for patients with only two approved drug therapies. Extensive preclinical studies have identified and characterized novel pathways driving IPF pathogenesis, and researchers have identified several new promising therapeutic targets to help treat IPF. However, translating these preclinical models into viable treatment modalities has proven challenging. This review will address the evolving nature of IPF research, examine the preclinical studies and their target pathways that have advanced to clinical trials, and address the translational gap that has limited success of novel therapeutic trials for IPF.

PMID:40633816 | DOI:10.1055/a-2651-1937

Lung. 2025 Jul 9;203(1):78. doi: 10.1007/s00408-025-00830-6.

ABSTRACT

BACKGROUND: Telomere shortening, a hallmark of cellular aging, is associated with poor outcomes in idiopathic pulmonary fibrosis (IPF). This study aimed to explore the relationships between telomere length (TL), pulmonary function tests, and telomere-related gene (TRG) mutations in a real-world IPF population.

METHODS: We included IPF patients from two Belgian academic hospitals, collecting demographic and clinical data. TL was measured using Flow-FISH and expressed as a percentile. Short TL was defined as below the 10th percentile (P10), and very short TL as below the 1st percentile (P1).

RESULTS: We analysed 143 patients (106 men, 74%), with a median age of 70 years. Thirty patients (21%) met the European Respiratory Society (ERS) criteria for familial pulmonary fibrosis (FPF). Short TL was found in 74 patients (50%), predominantly in men (p < 0.05). Patients with short TL experienced a greater decline in lung function over 24 months compared to those with normal TL (- 4% vs + 3% FVC, p < 0.05; - 7% vs - 3% DLCO, p < 0.05). Patients with very short TL were younger at diagnosis and tended to have a more pronounced FVC decline (- 5% vs - 1%, p = 0.06). TRG variants were identified in 16 individuals, occurring more frequently in those with short (14/27, 52%) or very short TL (10/20, 50%).

CONCLUSION: Short TL is common in both sporadic and familial IPF and serves as a predictive biomarker for accelerated lung function decline. Additionally, the presence of short TL is indicative of an underlying TRG mutation.

PMID:40632247 | DOI:10.1007/s00408-025-00830-6

Monaldi Arch Chest Dis. 2025 Jul 8. doi: 10.4081/monaldi.2025.3349. Online ahead of print.

ABSTRACT

Gastroesophageal reflux disease (GERD) and idiopathic pulmonary fibrosis (IPF) frequently coexist, with GERD potentially exacerbating IPF progression through microaspiration and pulmonary inflammation. This systematic review and meta-analysis assessed the impact of anti-reflux therapy, including proton pump inhibitors and H2-receptor antagonists, on mortality outcomes in IPF patients with concurrent GERD. A systematic search identified six eligible studies, including 2874 patients, for quantitative synthesis. Results indicate that anti-reflux therapy may reduce IPF-related mortality, with a pooled relative risk (RR) of 0.79 [95% confidence interval (CI): 0.55-1.33], although this finding was not statistically significant. However, no significant effect was observed on overall mortality (pooled RR: 0.97, 95% CI: 0.74-1.25). Study heterogeneity was moderate (I²=60%), reflecting variability in study designs, populations, and therapeutic regimens. The observational nature of most studies highlights the need for randomized controlled trials to better understand anti-reflux therapy's role in IPF management. While anti-reflux therapy was associated with a potential reduction in IPF-related mortality (RR: 0.79, 95% CI: 0.55-1.33), no significant effect on overall mortality was observed (RR: 0.97, 95% CI: 0.74-1.25). Future research should also evaluate the long-term safety of anti-reflux therapy, given concerns about complications such as infections and renal impairment. This analysis underscores the importance of tailored treatment approaches in IPF patients with GERD to optimize clinical outcomes.

PMID:40631927 | DOI:10.4081/monaldi.2025.3349

bioRxiv [Preprint]. 2025 Jul 3:2025.06.30.662456. doi: 10.1101/2025.06.30.662456.

ABSTRACT

Alveolar type II (AT2) progenitor cell exhaustion and impaired regenerative capacity are key pathogenic hallmarks in idiopathic pulmonary fibrosis (IPF). Nicotinamide adenine dinucleotide (NAD + ) functions as a central regulator of cellular energy metabolism. We have reported that downregulation of NAD + -dependent sirtuin signaling contributes to the impaired progenitor function of IPF AT2s. In this study, we identified that a key NAD + biosynthesis enzyme, nicotinamide phosphoribosyltransferase (NAMPT), is significantly downregulated in IPF AT2s. NAMPT deficiency impairs AT2 renewal and enhances lung fibrosis through downregulation of SIRT7 and SOD2, which results in increased oxidative stress, mitochondrial dysfunction, induction of pathological transitional gene expression and impaired regenerative capacity to generate alveolar type I (AT1) cell required for gas exchange. Mice with deletion of Nampt in AT2s showed severely impaired AT2 renewal and increased susceptibility to bleomycin lung injury and spontaneous fibrois. Activation of NAMPT by small molecule activators promoted AT2 renewal, restored homeostasis, and reversed lung fibrosis. NAMPT activation could be a therapeutic strategy for restoring AT2 progenitor function and halting or reversing progressive pulmonary fibrosis.

PMID:40631208 | PMC:PMC12236712 | DOI:10.1101/2025.06.30.662456

bioRxiv [Preprint]. 2025 Jul 4:2025.07.01.662364. doi: 10.1101/2025.07.01.662364.

ABSTRACT

Characterizing senescent cells and identifying corresponding senescence-associated genes within complex tissues is critical for our understanding of aging and age-related diseases. We present DeepSAS, an intrinsic-hoc framework for elucidating the heterogeneity encoded in senescent cells and their associated genes from single-cell RNA-seq data using deep graph representation learning. Applied to both healthy eye cell atlas and in-house idiopathic pulmonary fibrosis datasets with Xenium spatial transcriptomics validation, DeepSAS reveals robust and biologically grounded senotypes and demonstrates superior benchmarking performance compared with existing methods.

PMID:40631080 | PMC:PMC12236723 | DOI:10.1101/2025.07.01.662364

Front Med (Lausanne). 2025 Jun 24;12:1569590. doi: 10.3389/fmed.2025.1569590. eCollection 2025.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening lung disease with limited treatment efficacy. Salvia miltiorrhiza (SM), a traditional Chinese medicine (TCM), is widely used in Chinese hospitals due to its antithrombotic, anti-inflammatory, and antioxidant properties. SM has also demonstrated potential as an anti-fibrotic agent. This study aims to investigate the therapeutic effects and mechanisms of SM injection in treating IPF.

METHODS: Active components and targets of SM were acquired from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, while IPF-associated genes were obtained from the DisGeNET database. Venn analysis was applied to intersect SM targets with IPF-associated genes, identifying potential therapeutic targets. A protein-protein interaction (PPI) network of these targets was constructed using the STRING database and visualized with Cytoscape software, where the CytoHubba plug-in was utilized to determine core therapeutic targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the core targets were conducted via R language, and molecular docking was performed to predict the binding affinities of active compounds to the core targets. The core targets were further validated through qRT-PCR, Western blot (WB), and ELISA experiments.

RESULTS: 70 potential target genes of SM injection for the treatment of IPF were identified, with MMP9, IL-6, and TNF-α as the core targets. These core targets were linked to pathways involving inflammation, oxidative stress, and extracellular matrix (ECM) remodeling. In vitro experiments indicated that SM injection alleviated pulmonary fibrosis by downregulating MMP9, IL-6, and TNF-α.

CONCLUSION: SM injection may effectively reduce pulmonary fibrosis through multi-target mechanisms, providing a new therapeutic strategy for IPF from the perspective of TCM.

PMID:40630478 | PMC:PMC12235086 | DOI:10.3389/fmed.2025.1569590

Front Genet. 2025 Jun 24;16:1544864. doi: 10.3389/fgene.2025.1544864. eCollection 2025.

ABSTRACT

BACKGROUND AND OBJECTIVE: Idiopathic Pulmonary Fibrosis (IPF) is an interstitial lung disease that causes irreversible alterations in the architecture of the lung parenchyma, leading to impaired ventilation. Both environmental factors and genetic predisposition play significant roles in the development of IPF. A single nucleotide polymorphism (SNP) (rs35705950) within the promoter of the mucin 5B gene (MUC5B) has been reported to be associated with the disease; however, no data is available from Lebanon or the Middle East. This study aims to identify the frequency of the MUC5B promoter variant among a cohort of Lebanese IPF patients, compare it to the general population and assess its association with the risk of developing the disease.

METHODS: A total of 55 patients diagnosed with IPF, according to the ATS/ERS criteria, and 94 healthy controls were included in the study. DNA samples were extracted and genotyped for the MUC5B promoter polymorphism by Sanger sequencing. Descriptive statistics were performed on clinical characteristics. Pearson's chi-squared and T-student tests were performed to determine statistical significance. Odds ratios quantified genetic variant associations with IPF.

RESULTS: The MUC5B SNP rs35705950 was significantly more frequent in IPF patients compared to the control group, in both heterozygous and homozygous forms. Additionally, a significant association was found between the variant and susceptibility to IPF.

CONCLUSION: This study shows that the MUC5B polymorphism rs35705950 is significantly more frequent in the Lebanese IPF population compared to the control group and is associated with an increased risk of developing IPF.

PMID:40630118 | PMC:PMC12234449 | DOI:10.3389/fgene.2025.1544864

ARP Rheumatol. 2025 Apr-Jun;4(2):106-114.

ABSTRACT

BACKGROUND: In the context of the COVID-19 pandemic, understanding the influence of pre-existing Interstitial Lung Disease (ILD) on patient outcomes is crucial. This study aimed to compare the impact of COVID-19 on patients with Idiopathic Interstitial Pneumonia (IIP) versus Connective Tissue Disease-related ILD (CTD-ILD) in terms of mortality, length of hospital stay (LOS) and Intensive Care Unit (ICU) admission.

METHODS: The National Inpatient Sample (NIS) database for 2019-2020 identified adult patients hospitalized with COVID-19 and either IP or CTD-ILD. Patient demographics, comorbidities, and outcomes were analyzed.

RESULTS: Among 1,010,030 COVID-19 hospitalizations, 11,030 had ILD, with 1,105 associated with CTD. Although both IL and CTD-ILD groups had higher mortality rates than non-ILD patients, there was no significant difference in mortality between CTD-ILD and ILI groups. The odds ratio for mortality was 0.78 (95% CI 0.50-1.2, p = 0.3) for CTD-ILD compared to ILP patients and 1.54 (95% CI 1.03-2.31, p = 0.03) for CTD-ILD compared to non-ILD patients.

CONCLUSION: This study underscores the importance of considering ILD subtypes in predicting COVID-19 outcomes. Despite demographic and comorbidity differences, mortality rates were comparable between CTD-ILD and IIP patients. Further research is needed to explore underlying mechanisms contributing to mortality in different ILD subtypes and the impact of specific rheumatological diseases and treatments on COVID-19 outcomes.

PMID:40629819

JCI Insight. 2025 Jul 8:e182050. doi: 10.1172/jci.insight.182050. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a severe diffuse progressive fibrosing interstitial disease leading to respiratory failure and death in the absence of organ transplantation. Substantial evidence has confirmed the pivotal role of fibroblasts in the progression of IPF, yet effective therapeutic options are scarce. Single-cell transcriptomics profiling revealed that among the diverse fibroblast subsets, FAP1+ alveolar fibroblasts (AFs) are pivotal for the progression of IPF. On the basis of these findings, we developed FAP1-targeting chimeric antigen receptor cytotoxic effector regulatory T (CAR-cTregs) cells, which leverage the targeted killing advantage of the currently trending CAR-based immunotherapy for tumors and incorporate the immunosuppressive functions of Tregs to mitigate the inflammation caused by both the disease itself and CAR-T-cell infusion. Accordingly, CAR-cTregs were constructed to effectively eliminate FAP1+ fibroblasts in vitro. This cytotoxic effect can be abrogated by inhibitors of the granzyme-perforin pathway. In the bleomycin-induced PF model, CAR-cTregs were found to reverse fibrosis characterized by diminished recruitment of fibrocytes and improved remodeling of epithelial cells. Together, our results demonstrate that CAR-cTregs can serve as a promising therapeutic option for IPF and provide a novel strategy for treating multiple chronic inflammatory diseases by inducing both cytotoxicity and immunosuppression.

PMID:40627450 | DOI:10.1172/jci.insight.182050

Lung. 2025 Jul 8;203(1):77. doi: 10.1007/s00408-025-00832-4.

ABSTRACT

PURPOSE: Pulmonary fibrosis is defined as progressive based on the combination of radiological, clinical, and functional criteria. Nintedanib can reduce the rate of lung function decline, but no data are available on its effectiveness to hamper disease progression evaluated by these criteria. The primary aim of the study was to assess the number of patients with progressive pulmonary fibrosis (PPF) who no longer meet progression criteria after one year of treatment with nintedanib.

METHODS: A retrospective, observational, multicenter study was carried out in Italy.

RESULTS: 172 patients (91 (52.9%) males) with PPF were recruited, and 135 (78.5%) completed one year of treatment. After one year, 87 (64.4%) patients no longer met INBUILD progression criteria, while 107 (79.3%) did not meet 2022 ATS/ERS/JRS/ALAT guidelines criteria. Nintedanib hampered progression regardless of inclusion criteria, radiological pattern, and etiological diagnosis. Forced vital capacity (FVC) decline was significantly higher in the 12 months before than in those of treatment (mean, SD): 2512.3 (863.2) ml vs. 2313.6 (821.9) ml; p < 0.0001; 2313.6 (821.9) vs. 2335.7 (865.1); p = 0.82). FVC decline was significantly higher in the year before than in the year of treatment regardless of radiological pattern, etiological subtypes, and respiratory function. Diarrhea (mostly mild) was the most frequent adverse event (51.7%). A permanent discontinuation of the drug was recorded in 15 (9%) patients.

CONCLUSION: Nintedanib is effective and safe in patients with PPF. Besides slowing lung function decline, it hampers progression regardless of etiological diagnosis, radiological pattern, respiratory function, and baseline inclusion criteria.

PMID:40627063 | DOI:10.1007/s00408-025-00832-4

Angew Chem Int Ed Engl. 2025 Jul 8:e202505077. doi: 10.1002/anie.202505077. Online ahead of print.

ABSTRACT

Pentraxin-2 (PTX-2), also known as Serum Amyloid P component, functions as an immunoregulatory glycoprotein and plays a crucial role in fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). Desialylation of PTX-2 has recently been associated with reduced bioactivity and diminished inhibition of fibrocyte differentiation in IPF patients. Each monomer in the naturally assembled pentameric complex is N-glycosylated, predominantly featuring terminal sialic acids on biantennary glycans. However, the influence of these glycoforms on PTX-2's mechanism of action (MoA) and conformational properties has not been comprehensively investigated. In this study, we demonstrate the combined application of surface-induced dissociation (SID) and ion-mobility mass spectrometry (IM-MS) to assess the impact of specific glyco-engineered PTX-2 variants on the stability of its pentameric and decameric complexes. We further explore the effect of individual monomer glycosylation on complex stability. Our results reveal that high levels of terminal sialylation significantly enhance complex stability, whereas desialylation and mannosylation reduce the stability of both pentameric and decameric PTX-2 forms. Regarding the stability of single PTX-2 monomers ejected from the pentamer, in contrast, we found that desialylated and highly mannosylated glycans contribute the individual monomer stability.

PMID:40626977 | DOI:10.1002/anie.202505077

Front Immunol. 2025 Jun 23;16:1598306. doi: 10.3389/fimmu.2025.1598306. eCollection 2025.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis is a progressive lung disease with a poor prognosis. Alveolar macrophages (AMs) are essential for maintaining lung homeostasis and play a significant role in the development of lung fibrosis. Tissue-Resident Alveolar Macrophages (TR-AMs), which originate from embryonic progenitors, can self-renew locally in a steady state, independent of hematopoiesis. During fibrogenesis, circulating monocytes rapidly migrate into the lungs and differentiate into monocyte-derived AMs (Mo-AMs). MicroRNAs (miRNAs), small non-coding RNAs, are critical for regulating gene expression. Our recent study found that the loss of miRNAs in embryonic progenitors significantly decreased the number of TR-AMs in late-stage embryos, indicating that miRNAs are necessary for TR-AM development. However, the role of miRNAs in the postnatal maintenance of TR-AMs and Mo-AMs, as well as their function in pulmonary fibrosis, remains unclear.

METHODS AND RESULTS: Here, we demonstrate that deleting miRNAs after birth severely disrupts TR-AM homeostasis and Mo-AM repopulation from the bone marrow following irradiation. The deficiency of miRNAs in TR-AMs and Mo-AMs was linked to diminished bleomycin-induced experimental lung fibrosis. Mechanistically, the absence of miRNAs increased TR-AM apoptosis under both normal and fibrotic conditions. RNA sequencing (RNA-seq) analysis revealed distinct transcriptomic and pathway changes in miRNA-deficient AM subgroups after lung injury. The integration of RNA-seq and miRNA array analyses identified miRNA-mRNA networks in TR-AMs and Mo-AMs in response to bleomycin injury. Ingenuity Pathway Analysis further predicted let-7a, miR-155, and miR-125 as unique upstream regulators of Mo-AM responses to lung fibrosis.

CONCLUSIONS: Our findings suggest that miRNAs are key epigenetic mediators that differentially regulate the maintenance and function of TR-AMs and Mo-AMs in the pathogenesis of pulmonary fibrosis.

PMID:40625745 | PMC:PMC12231002 | DOI:10.3389/fimmu.2025.1598306

J Vis Exp. 2025 Jun 17;(220). doi: 10.3791/68484.

ABSTRACT

Animal models play a crucial role in understanding disease mechanisms and testing potential therapeutic approaches. However, traditional murine models of idiopathic pulmonary fibrosis (IPF) that rely on a single-dose bleomycin injection fail to accurately replicate the complex pathological features observed in IPF patients. This study introduces an improved method using two successive oropharyngeal administrations of bleomycin in mice, which more effectively mimics the progression of IPF. This novel protocol induces key pathological changes, such as the formation of honeycomb-like cysts, fibroblastic foci, and bronchiolization of the alveolar epithelium, closely resembling the histopathology seen in human IPF. By utilizing this model, we are able to capture the progressive fibrotic changes over a longer time frame, which provides more reliable insights into the pathogenesis of IPF. Furthermore, this two-dose approach offers several advantages over conventional single-dose models, including better reproducibility and a more robust representation of the disease's development. This method enhances our ability to study the mechanisms underlying IPF and evaluate potential therapeutic interventions. The proposed protocol offers significant advancement in preclinical research and provides a valuable tool for investigating both the biology of pulmonary fibrosis and the efficacy of novel treatments.

PMID:40622990 | DOI:10.3791/68484

J Ethnopharmacol. 2025 Jul 4:120233. doi: 10.1016/j.jep.2025.120233. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Codonopsis radix (CR), an herbal medicine, has been officially named and used since Wu Yiluo's "Bentushu Letter" in the Qing Dynasty. It has the effect of invigorating the spleen and lung, nourishing blood, and benefiting body fluid. However, there are few reports on the impact of CR on idiopathic pulmonary fibrosis (IPF).

AIM OF THE STUDY: This study evaluated the therapeutic effects of CR on IPF through in vivo and in vitro experiments and explored possible mechanisms. Specifically, we aimed to clarify whether the main pharmacodynamic components in CR exert synergistic regulatory effects and to reveal the underlying synergistic mechanism.

MATERIALS AND METHODS: The water extract group (CWE), polysaccharide group (CP), and small molecules group (CS) were successfully extracted from CR, the CS components were purified, and the CWE and CP components were preliminarily characterized. Next, based on the activation of lung fibroblasts by transforming growth factor-β1 (TGF-β1), Compusyn software was used to analyze the combination index (CI) of CS and CP. The effects of CR components on fibroblast differentiation, proliferation, apoptosis and related signaling pathways were studied. Based on the bleomycin (BLM) induced IPF model in rats, the effects of CR on histopathologic manifestations and fibrotic marker expression levels were observed. Histological analysis, immunofluorescence, and western blot were used to observe changes in CR effective components after intervention. The synergies of CS and CP components in CR and their effects on related signaling pathways were evaluated to identity potential anti-IPF mechanisms.

RESULTS: In vitro experiments confirmed a synergistic effect when the CS to CP ratio was 1:8. The effective components of CR reversed TGF-β1-induced proliferation, migration, and extracellular matrix (ECM) deposition in MRC-5 cells while promoting cell apoptosis. CP and CS components exhibited a synergistic effect. Additionally, results showed that CR effective components inhibited fibroblast differentiation into myofibroblasts. In vivo pharmacodynamic evaluation and mechanism demonstrated that CR effective components improved the severity of BLM-induced IPF in rats, as evidenced by histopathological manifestations and fibrosis marker expression levels. The synergistic anti-IPF mechanism of CS and CP components in CR was linked to interference with the TGF-β1/Smad signaling pathway.

CONCLUSIONS: This study for the first time revealed that the main anti-IPF pharmacological active components of CR derived from CS and CP components, with an optimal CS:CP ratio of 1:8. They inhibit fibroblast proliferation by suppressing TGF-β1/Smad-mediated expression of proliferative proteins (PCNA, Survivin) and promote Bcl-2/Bax-regulated fibroblast apoptosis, thereby reducing ECM deposition proteins (FN, α-SMA, Col-I). By inhibiting the transformation of fibroblasts into myofibroblasts, they exert a synergistic anti-fibrotic effect. These findings suggest that effective components in CR may represent a new approach for IPF treatment.

PMID:40619039 | DOI:10.1016/j.jep.2025.120233

J Control Release. 2025 Jul 4:114005. doi: 10.1016/j.jconrel.2025.114005. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal chronic disease. One of the Food and Drug Administration (FDA)-approved therapies for IPF, oral pirfenidone (PFD), has limited clinical applications owing to its systemic side effects. In contrast to oral administration, inhaled therapy offers enhanced therapeutic efficacy at the target organ while minimizing systemic side effects. However, its application has challenges, such as limited drug delivery to the distal lung region and rapid clearance. In this study, we developed pulmonary surfactant (PS)-based PFD-loaded nanovesicles (PFD-PSNVs) for targeted delivery to the lung area and prolonged retention and examined their safety, stability, and antifibrotic efficacy. PFD-PSNVs were prepared using the thin-film hydration and extrusion method. The mean size and zeta potential of PFD-PSNVs were 149.7 ± 10.1 nm and - 31.3 ± 2.3 mV, respectively. An in vitro antifibrotic study showed that PFD-PSNVs inhibited the expression of fibrotic factors such as p-ERK, p-SMAD2/3, and α-SMA proteins on fibroblasts activated by transforming growth factor-β1. When inhaled in mice using a nebulizer, the PFD-PSNVs remained in lung tissues for 24 h, whereas Arikayce, an FDA-approved liposomal formulation for inhalation, was eliminated within 6 h. In a bleomycin sulfate-induced IPF mouse model, inhalation treatment with PFD-PSNVs significantly reduced collagen deposition (76.2 ± 4.1 %, p < 0.01) and α-SMA expression (60.8 ± 3.7 %, p < 0.05) compared with inhalation treatment with the PFD-loaded CtrlNV (PFD-CNVs) formulation and oral administration of PFD. These results indicate that PSNVs have great potential as an inhaled drug delivery system for the treatment of IPF.

PMID:40618852 | DOI:10.1016/j.jconrel.2025.114005

Health Technol Assess. 2025 Jul 2:1-33. doi: 10.3310/TWKS4194. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis is a devastating condition of unknown cause that results in progressive, irreversible scarring of the lung, manifesting as breathlessness and dry cough. Idiopathic pulmonary fibrosis is thought to be responsible for as many as 1 in 100 deaths in the United Kingdom, killing 5300 people a year. Ambulatory oxygen therapy is commonly used in idiopathic pulmonary fibrosis to relieve exertional breathlessness, although evidence to support this strategy is lacking. This pragmatic randomised controlled trial was planned to test whether use of ambulatory oxygen therapy is beneficial in people with idiopathic pulmonary fibrosis.

METHODS: We planned a randomised controlled trial in 260 patients with idiopathic pulmonary fibrosis who are breathless on exertion and do not meet criteria for long-term oxygen therapy, randomising in a 1 : 1 ratio between ambulatory oxygen therapy and best supportive care. Primary outcome was a quality-of-life questionnaire validated in pulmonary fibrosis, the King's Brief Interstitial Lung Disease questionnaire, measured at 6 months. We calculated our sample size based on the minimum clinically important difference of four units and standard deviation equal to 8.85 in King's Brief Interstitial Lung Disease questionnaire; assuming power of 90% and 5% two-sided significance level, thus required 130 per arm, after accounting for 20% dropout. The trials unit's web-based randomisation algorithm minimises on factors potentially influencing response to ambulatory oxygen therapy, such as severity of idiopathic pulmonary fibrosis, desaturation to < 88% present on walking, current or recent (within 6 months) pulmonary rehabilitation, and recruitment centre. Secondary outcomes included symptoms, exercise capacity and cost-effectiveness. A process evaluation included assessment of trial fidelity and acceptability of the intervention with use of qualitative research methods and arts approaches with patients and staff. Qualitative interviews were conducted with patients from the Ambulatory Oxygen for Pulmonary Fibrosis trial and the idiopathic pulmonary fibrosis patient support group Action for Pulmonary Fibrosis, and stakeholders: healthcare professionals and policy-makers. Interviews were audio-recorded, transcribed clean verbatim. Photovoice methodology was conducted with patients. A workshop prior to data collection informed and guided data collection and analysis. Traditional qualitative analysis and arts-based coproduction analysis approaches were used to produce a short film. An economic model was planned but could not occur due to early termination.

RESULTS: The trial was stopped prematurely due to low recruitment. This was due to a combination of the impact of COVID-19 on research infrastructure, financial issues for sites with the payment structure for the trial and lack of equipoise which limited site recruitment. Seven out of 25 eligible, interested patients were randomised after pre-screening, implying a lack of interest among patients in the study. Baseline characteristics indicated that patients were elderly (mean age 81) and predominantly male. Qualitative work with 11 patients and 23 other stakeholders concluded that ambulatory oxygen therapy is desirable, acceptable and widely commissioned in the United Kingdom, such that further trials are not likely to be feasible.

CONCLUSION: Although we are not able to formally address our objectives of assessing efficacy and cost-effectiveness of ambulatory oxygen therapy in idiopathic pulmonary fibrosis, it is unlikely that conducting a randomised controlled trial is feasible due to lack of equipoise.

FUNDING: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR131149.

PMID:40613728 | DOI:10.3310/TWKS4194

Ann Hum Genet. 2025 Jul 4:e12605. doi: 10.1111/ahg.12605. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF), the predominant idiopathic interstitial pneumonia, is marked by progressive, irreversible lung damage with a 3-year median survival rate in the elderly. Cardiovascular disease (CVD) is the most common disease in the elderly population and its incidence is increasing all the time, especially in the Asia-Pacific region, coinciding with the rise in global mortality. Despite clinical indications of a link between IPF and CVD, the mechanisms are not well understood. This study applies a bidirectional two-sample Mendelian randomization (MR) approach to explore potential causalities between IPF and CVD.

METHODS: Summary data from public genome-wide association study (GWAS) databases for IPF (27,449 participants) and CVD were utilized. Single nucleotide polymorphisms (SNPs) served as instrumental variables in MR analysis, employing inverse variance-weighted (IVW), weighted median (WM), and MR-Egger methods. Heterogeneity was assessed with Cochran's Q test, and sensitivity analyses were conducted using MR-PRESSO.

RESULTS: The IVW analysis revealed no significant associations between genetically predicted IPF and CVD, except for a significant negative association with large artery atherosclerosis stroke and IPF. The WM method supported this inverse relationship. MR-Egger intercept indicated pleiotropy in the link between IPF and heart failure, with no outliers detected by MR-PRESSO. Cochran's Q test showed no significant heterogeneity for the relationships.

CONCLUSION: The bidirectional MR study suggests a potential negative influence of large artery atherosclerosis stroke on IPF, hinting at a protective role of IPF in stroke incidence. The absence of significant associations with other CVDs and IPF implies a more complex relationship than previously considered. Further research is needed to clarify the intricate connections between IPF and CVD.

PMID:40613241 | DOI:10.1111/ahg.12605

Front Immunol. 2025 Jun 19;16:1514439. doi: 10.3389/fimmu.2025.1514439. eCollection 2025.

ABSTRACT

OBJECTIVE: The term progressive pulmonary fibrosis (PPF) refers to a specific disorder that becomes worse despite optimal treatment. The pathogenic explanation of this progressive worsening is still to be found. In this study, we explored whether any histological, molecular, radiological, or clinical features could predict a progressive phenotype in patients with fibrotic interstitial lung diseases.

METHODS: Two hundred and fifteen patients with PPF other than idiopathic pulmonary fibrosis (IPF) and connective tissue disease-associated ILD (CTD-ILD) were followed in our ILD clinic between January 2016 and May 2023. Based on tissue block availability, 48 patients were definitively enrolled. Progression was defined according to the most recent guidelines. Clinical, radiological, and functional data were also collected retrospectively and correlated with tissue morphological and molecular cytokine profiles.

RESULTS: Fifteen patients were classified as progressors (PPF) and 33 as non-progressors (nPPF) with similar age at diagnosis and gender. PPF showed a higher prevalence of traction bronchiectasis (80% vs. 27%; p=<0.001) at CT scan and lower functional parameters [FVC: 2.42 L vs. 3.37 L; p=0.004; TLC: 3.83 L vs. 4.65 L; p=0.027] at diagnosis. Lung specimens revealed a significant overexpression of IL9 in the PPF compared to the nPPF group (p=0.049). Boruta algorithm analysis showed that lymphoid aggregates and traction bronchiectasis at diagnosis are the most important variables in determining the PPF status.

CONCLUSIONS: The present results increase the understanding of the pathological mechanisms of PPF, offering potential avenues for improved prognostication and therapeutic intervention.

PMID:40612945 | PMC:PMC12221905 | DOI:10.3389/fimmu.2025.1514439

Eur Respir J. 2025 Jul 3:2402565. doi: 10.1183/13993003.02565-2024. Online ahead of print.

ABSTRACT

BACKGROUND: The six minute walk test (6 MWT) provides an assessment of patient function and has been employed in interstitial lung disease clinical trials as an endpoint. The ISABELA studies were two replicate randomised controlled trials of IPF that included a regimented 6 MWT protocol. The goal of this study was to combine 6 MWT components into a pragmatic, easy to apply, composite clinical prediction score.

METHODS: 6 MWT parameters associated with time to death or respiratory hospitalisation in the ISABELA studies were integrated into a single composite score. This score was then validated in an external cohort.

RESULTS: There were 1251 patients in the derivation set with 83 respiratory-related hospitalisations and 21 deaths observed after 48 weeks. After multivariable analysis, four parameters were independently predictive of outcomes: Borg dyspnoea score, oxygen flow rate, oxygen saturation nadir and the 6 MWT distance. A pragmatic model, termed the ODDS (oxygen, distance, dyspnoea, saturation) was then developed. This performed better than the individual parameters alone with an area under the curve (AUC) of 0.797, 0.781 and 0.766 for events at 12, 24, and 48 weeks, respectively. The ODDS model was similarly accurate when applied to the external validation set (N=295) at 48 weeks (AUC: 0.758; 95% CI: 0.688-0.825).

CONCLUSION: The 6 MWT imparts important prognostic information which is best captured by combining constituent variables in a composite score system. The ODDS model might find utility in the clinical setting as well as in IPF studies where it can be used to risk stratify patients for outcomes.

PMID:40610052 | DOI:10.1183/13993003.02565-2024