Am J Respir Cell Mol Biol. 2025 May 9. doi: 10.1165/rcmb.2025-0030OC. Online ahead of print.

ABSTRACT

Contractile myofibroblasts immersed in stiffened remodelled extracellular matrix (ECM) characterise fibrotic lesions in idiopathic pulmonary fibrosis (IPF). Lipofibroblasts are lipid-droplet containing interstitial fibroblasts that support functional homeostasis of the developing and adult lung. We show that stiff substrates augment myofibroblast differentiation and ECM production in vitro under basal conditions and following transforming growth factor-β1 (TGF-β1) incubation when cultured on tissue culture plastic, whereas culture in soft microenvironments (as spheroids or on soft collagen-coated substrate) redirects myofibroblast to a lipofibroblast-like phenotype (identified by expression of adipose differentiation-related protein (ADRP) and intracellular lipid droplets), with reduced basal alpha-smooth muscle actin (α-SMA), collagen I, vimentin (VIM) and fibronectin (FN1) expression. The fibrogenic effects of TGF-β1 are prevented in fibroblasts cultured in soft settings. Global proteomics showed similar numbers of TGF-β1-induced differentially expressed proteins in stiff and soft settings (271 and 436, respectively). Of these, only 33 were similarly altered by TGF-β1; 200 were exclusively altered by TGF-β1 in stiff setting; 365 in soft setting, while 38 showed opposite responses. Reductions in YAP/TAZ, beta-catenin and SMAD expression and their limited nuclear levels in soft settings may explain the "afibrogenic" characteristic of these lipofibroblasts. Thus, in spheroids of lipofibroblasts TGF-β1 intracellular signalling is redirected and uncoupled from fibrogenesis, including YAP/TAZ, β-catenin and SMAD. Understanding the proximal causal mechano-transduction signalling networks that are differentially active in soft and stiff microenvironments may reveal novel drug targets for fibrosis treatment.

PMID:40343813 | DOI:10.1165/rcmb.2025-0030OC

Eur Radiol. 2025 May 8. doi: 10.1007/s00330-025-11649-3. Online ahead of print.

ABSTRACT

OBJECTIVES: To develop a new high-resolution (HR)CT abnormalities quantification tool (CVILDES) for interstitial lung diseases (ILDs) based on the nnU-Net network structure and to determine whether the quantitative parameters derived from this new software could offer a reliable and precise assessment in a clinical setting that is in line with expert visual evaluation.

METHODS: HRCT scans from 83 cases of ILDs and 20 cases of other diffuse lung diseases were labeled section by section by multiple radiologists and were used as training data for developing a deep learning model based on nnU-Net, employing a supervised learning approach. For clinical validation, a cohort including 51 cases of interstitial pneumonia with autoimmune features (IPAF) and 14 cases of idiopathic pulmonary fibrosis (IPF) had CT parenchymal patterns evaluated quantitatively with CVILDES and by visual evaluation. Subsequently, we assessed the correlation of the two methodologies for ILD features quantification. Furthermore, the correlation between the quantitative results derived from the two methods and pulmonary function parameters (DLCO%, FVC%, and FEV%) was compared.

RESULTS: All CT data were successfully quantified using CVILDES. CVILDES-quantified results (total ILD extent, ground-glass opacity, consolidation, reticular pattern and honeycombing) showed a strong correlation with visual evaluation and were numerically close to the visual evaluation results (r = 0.64-0.89, p < 0.0001), particularly for the extent of fibrosis (r = 0.82, p < 0.0001). As judged by correlation with pulmonary function parameters, CVILDES quantification was comparable or even superior to visual evaluation.

CONCLUSION: nnU-Net-based CVILDES was comparable to visual evaluation for ILD abnormalities quantification.

KEY POINTS: Question Visual assessment of ILD on HRCT is time-consuming and exhibits poor inter-observer agreement, making it challenging to accurately evaluate the therapeutic efficacy. Findings nnU-Net-based Computer vision-based ILD evaluation system (CVILDES) accurately segmented and quantified the HRCT features of ILD, and results were comparable to visual evaluation. Clinical relevance This study developed a new tool that has the potential to be applied in the quantitative assessment of ILD.

PMID:40341974 | DOI:10.1007/s00330-025-11649-3

BMC Pulm Med. 2025 May 8;25(1):221. doi: 10.1186/s12890-025-03689-8.

ABSTRACT

BACKGROUND: The antifibrotic therapies, pirfenidone and nintedanib, have been approved since 2014 for idiopathic pulmonary fibrosis (IPF), but in the United States only a quarter of people living with IPF have ever been exposed to an antifibrotic. Understanding the burden and consequences of the disease and its treatment from the perspective of people living with IPF may facilitate improved education and outreach for them and their providers.

METHODS: Qualitative interviews with people living with IPF explored perspectives on the diagnosis and management of IPF. Transcripts were analyzed to derive themes and topics, and illustrative quotes were selected for presentation. Data were developed into a 74-item on-line survey taken by additional people living with IPF. Quantitative survey data were analyzed with 95% confidence intervals and Z tests.

RESULTS: Sixteen people living with IPF underwent qualitative interviews. Direct quotes were used to derive and support themes, and survey stimuli are presented. Ninety additional people living with IPF responded to the on-line survey. 52% of survey participants were male, 54% used supplemental oxygen, and 34% had never been exposed to an antifibrotic. Top sources of information about their IPF diagnosis were their healthcare provider, the internet, and support groups. Most participants had one or more of shortness of breath, fatigue, or cough and over 40% described these symptoms as very burdensome. The most common reason for not starting an antifibrotic was, "I am waiting to start treatment until my symptoms worsen." For those treated with antifibrotics, (78%) agreed with a statement that their antifibrotic gives them hope even though around 90% had at least one side effect.

CONCLUSIONS: Most individuals living with IPF experienced significant challenges due to their disease and its treatment, that substantially impacted their quality of life. A better understanding of these challenges can facilitate patient-centered and shared decision-making, ultimately enhancing outcomes and satisfaction for people living with IPF.

PMID:40340670 | DOI:10.1186/s12890-025-03689-8

ERJ Open Res. 2025 May 6;11(3):00784-2024. doi: 10.1183/23120541.00784-2024. eCollection 2025 May.

ABSTRACT

BACKGROUND: Interstitial lung disease (ILD) represents a heterogenous group of diseases that have substantial morbidity and mortality. The Envisia Genomic Classifier (EGC) is a test that analyses RNA derived from transbronchial biopsy (TBBx) samples to make a positive or negative genomic usual interstitial pneumonitis (UIP) designation. Our study assesses the ability for the EGC to predict progression of disease, with a longer duration of follow-up than previous studies.

METHODS: Patients referred for cryobiopsy for outpatient workup of ILD concurrently had TBBx and EGC testing performed. We performed a retrospective analysis to assess differences in progression of disease between EGC-positive and negative patients, applying Kaplan-Meier survival analysis and log-rank tests. Confidence in ILD diagnosis before and after the EGC result was also noted, and the difference in confidence levels was assessed by a Wilcoxon signed-rank test.

RESULTS: 82 patient cases were analysed. EGC-positive patients had a shorter progression-free survival (PFS) than EGC-negative patients, (p<0.0001), with 622 versus 1487 median PFS days respectively. EGC-positive patients also had worse progression in the subsets of patients with "indeterminate for UIP" computed tomography (CT) (p=0.0052), "alternative diagnosis" CT (p=0.0144) and non-idiopathic pulmonary fibrosis ILD diagnosis (p=0.0157). Additionally, EGC increased the diagnostic confidence level (p<0.0001).

CONCLUSION: EGC positivity predicts worse ILD progression over a sustained follow-up period. The ability to predict worse prediction early in the ILD course without the need for surgical biopsy would have significant clinical impact.

PMID:40337340 | PMC:PMC12053734 | DOI:10.1183/23120541.00784-2024

Int J Mol Sci. 2025 Apr 18;26(8):3850. doi: 10.3390/ijms26083850.

ABSTRACT

The resolution of the recent COVID-19 pandemic still requires attention, since the consequences of having suffered the infection, even in mild cases, are associated with several acute and chronic pathological conditions referred to as post-COVID syndrome (PCS). PCS often manifests with pulmonary disease and, in up to 9% of cases, a more serious complication known as post-COVID-19 pulmonary fibrosis (PC19-PF), which has a similar clinical course as idiopathic pulmonary fibrosis (IPF). Generating knowledge to provide robust evidence about the clinical benefits of different therapeutic strategies to treat the pulmonary effects of PCS can provide new insights to amplify therapeutic options for these patients. We present evidence found after a scoping review, following extended PRIMSA guidelines, for the use of immunomodulators in pulmonary PCS. We start with a brief description of the immunomodulatory properties of the relevant drugs, their clinically proven efficacy for viral infections and chronic inflammatory conditions, and their use during the COVID-19 pandemic. We emphasize the need for well-designed clinical trials to improve our understanding the physiopathology of pulmonary PCS and PC19-PF and also to determine the efficacy and safety of candidate treatments.

PMID:40332501 | DOI:10.3390/ijms26083850

Exp Cell Res. 2025 May 4:114584. doi: 10.1016/j.yexcr.2025.114584. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis is a chronic fibrotic lung disease with limited treatment options, making the development of new therapies crucial. We previously demonstrated that γδ T cells, a subset of immune effector cells, exhibit antifibrotic properties. We have also shown that natural killer (NK) cells, another class of immune effectors, can be efficiently expanded in culture using interleukin-2 (IL-2) and interleukin-18 (IL-18). This study examined the effects of interleukin-12 (IL-12)-stimulated NK cells, expanded with IL-2 and IL-18, on type I collagen and α-smooth muscle actin (αSMA) expression in pulmonary fibroblasts. IL-12-stimulated human NK cells exhibited reduced cytotoxicity toward pulmonary fibroblasts while retaining their proliferative capacity. Co-culture of IL-12-stimulated NK cells with fibroblasts significantly suppressed type I collagen and αSMA expression, even without direct cell contact, indicating the involvement of soluble factors. Supernatants from IL-12-stimulated NK cells partially inhibited the expression of these antifibrotic factors, suggesting a dual mechanism: direct cell-cell interaction and soluble factor secretion. Interferon-γ (IFN-γ) in the supernatant significantly increased, and neutralizing anti-IFN-γ monoclonal antibody partially reversed type I collagen and αSMA suppression. Similarly, IL-12-stimulated murine NK cells suppressed type I collagen in mouse pulmonary fibroblasts. These findings suggest that IL-12-stimulated NK cells inhibit the expression of fibrosis-associated molecules via contact-dependent and -independent mechanisms, supporting their potential for adoptive cell therapy in pulmonary fibrosis.

PMID:40328414 | DOI:10.1016/j.yexcr.2025.114584

Gen Physiol Biophys. 2025 May;44(3):187-200. doi: 10.4149/gpb_2025008.

ABSTRACT

The abnormal proliferation and activation of fibroblasts have been implicated in idiopathic pulmonary fibrosis. Herein, the present research explored the impacts of the relationship between hydroxysafflor yellow A (HSYA) and a disintegrin and metalloproteinase 17 (ADAM17) on fibroblast activation, which can provide novel insight into the treatment and management of idiopathic pulmonary fibrosis. MRC-5 fibroblasts were firstly activated with TGF-β1, followed by measurement of ADAM17 expression through qRT-PCR and Western blot. Fibrosis-related gene and protein expression levels, cell viability, proliferation, migration, and fibroblast-to-myofibroblast transdifferentiation were determined by qRT-PCR and Western blot, MTS, EdU, Transwell, and immunofluorescence assays, respectively. Moreover, the regulatory relationships among HSYA, ADAM17, and the NF-κB/STAT3 pathway in MRC-5 cells were analyzed by bioinformatics analysis, qRT-PCR, and Western blot. The results show that HSYA treatment could diminish the fibrosis-related gene and protein expression patterns, proliferation, migration, and fibroblast-to-myofibroblast transdifferentiation in TGF-β1-stimulated MRC-5 cells. Moreover, HSYA could repress the TGF-β1-triggered ADAM17 up-regulation, thereby suppressing the NF-κB/STAT3 pathway. Furthermore, over-expression of ADAM17 negated the inhibitory effect of HSYA on fibroblast activation induced by TGF-β1. The findings revealed that HSYA blocked the NF-κB/STAT3 pathway activation by down-regulating ADAM17, thereby inhibiting TGF-β1-induced fibroblast activation.

PMID:40326971 | DOI:10.4149/gpb_2025008

Pulm Ther. 2025 May 5. doi: 10.1007/s41030-025-00296-0. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) represents a clinical and therapeutic challenge characterized by progressive fibrosis and destruction of the lung architecture. The pathogenesis of IPF has been long debated; while it is generally believed that repeated lung injury and abnormal wound repair are the main pathogenetic mechanisms, clear understanding of disease development and efficacious treatment remain important unmet needs. Indeed, current standard of care (i.e., the antifibrotic drugs pirfenidone and nintedanib) can slow down lung function decline and disease progression without halting the disease. In the last 2 decades, several clinical trials in IPF have been completed mostly with negative results. Yet, unprecedented numbers of clinical trials of pharmacological interventions are currently being conducted. In this review, we summarize and critically discuss the current and future treatment landscape of IPF, with emphasis on the most promising developmental molecules.

PMID:40323570 | DOI:10.1007/s41030-025-00296-0

Mol Clin Oncol. 2025 Apr 23;22(6):59. doi: 10.3892/mco.2025.2854. eCollection 2025 Jun.

ABSTRACT

Although nintedanib, an anti-fibrotic drug, relieves the chronological worsening of pulmonary function and prevents acute exacerbations of interstitial pneumonia, the perioperative safety and efficacy of nintedanib remains to be elucidated. The present study aimed to examine the safety and efficacy of nintedanib in patients with interstitial pneumonia. This study included 12 patients who underwent lung resection, including bilobectomy (n=2), lobectomy (n=7), segmentectomy (n=2) and wedge resection (n=1) between January 2020 and August 2023 at Juntendo University Nerima Hospital (Tokyo, Japan). Nintedanib was administered preoperatively to 10 male and two female patients with idiopathic pulmonary fibrosis and stage I to III lung cancer. The nintedanib dosing period ranged from 14 to 43 days. None of the patients canceled or postponed surgery because of side effects of nintedanib. Although prolonged air leak (n=3), surgical site infection (n=2), pyothorax (n=1), heart failure (n=1) and pleurisy (n=1) were observed postoperatively, the 30-day mortality rate was 0, with no acute exacerbation of interstitial pneumonia. These results encourage further investigation into the potential of nintedanib treatment in a larger patient cohort through prospective verification.

PMID:40322548 | PMC:PMC12046624 | DOI:10.3892/mco.2025.2854

Sci Rep. 2025 May 2;15(1):15453. doi: 10.1038/s41598-025-99857-1.

ABSTRACT

The contribution of forced oscillation technique (FOT), also called oscillometry, in diagnosis and follow-up of progressive pulmonary fibrosis (PPF) is not yet established. The aims of this monocentric retrospective study were to compare the FOT profile between patients suffering from PPF and stable non-idiopathic pulmonary fibrosis (IPF) interstitial lung diseases (ILDs), to look for a correlation between oscillometry and conventional function tests currently used for PPF follow-up and functional definition (forced vital capacity (FVC) and diffusing lung capacity (DLCO)) and correlation with ILD severity according to FVC. Compared to non-IPF stable ILDs (n = 96), PPF patients (n = 45) showed lower median resistance at 5Hz (Xrs5) values (during inspiratory phase: 0.31 versus -0.39 cmH2O/(L/sec), p = 0.019595). Xrs5 also showed moderate correlation with FVC and DLCO. Finally, among all ILDs (n = 160), Xrs5 showed correlation with disease severity according to FVC. These results suggest that, in conjunction with conventional pulmonary function tests, FOT could be an interesting tool to predict progressive course of fibrosing non-IPF ILDs. Its exact contribution to PPF diagnosis and follow-up needs to be determined by a prospective approach.

PMID:40316670 | DOI:10.1038/s41598-025-99857-1

Med Image Anal. 2025 Apr 26;103:103604. doi: 10.1016/j.media.2025.103604. Online ahead of print.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is a progressive lung disease that continuously scars and thickens lung tissue, leading to respiratory difficulties. Timely assessment of IPF progression is essential for developing treatment plans and improving patient survival rates. However, current clinical standards require multiple (usually two) CT scans at certain intervals to assess disease progression. This presents a dilemma: the disease progression is identified only after the disease has already progressed. To address this issue, a feasible solution is to generate the follow-up CT image from the patient's initial CT image to achieve early prediction of IPF. To this end, we propose a lung structure and function information-guided residual diffusion model. The key components of our model include (1) using a 2.5D generation strategy to reduce computational cost of generating 3D images with the diffusion model; (2) designing structural attention to mitigate negative impact of spatial misalignment between the two CT images on generation performance; (3) employing residual diffusion to accelerate model training and inference while focusing more on differences between the two CT images (i.e., the lesion areas); and (4) developing a CLIP-based text extraction module to extract lung function test information and further using such extracted information to guide the generation. Extensive experiments demonstrate that our method can effectively predict IPF progression and achieve superior generation performance compared to state-of-the-art methods.

PMID:40315576 | DOI:10.1016/j.media.2025.103604

Cell Signal. 2025 Apr 29:111830. doi: 10.1016/j.cellsig.2025.111830. Online ahead of print.

ABSTRACT

Senescence of alveolar epithelial cells (AEC) is a key event in the onset and progression of Idiopathic pulmonary fibrosis (IPF). The pathogenic mechanisms that underlie the effects of AEC senescence remain largely unexplained. Some age-related diseases have an etiology linked to mitochondrial dysfunction induced by excessive lysine succinylation (Ksucc). SIRT5 can remove excessive Ksucc levels to maintain mitochondrial homeostasis. Therefore, this study aimed to determine the effects of SIRT5-mediated de-Ksucc on mitochondrial function and pulmonary fibrosis after AEC senescence. We found AEC in the lungs derived from IPF patients exhibit a marked accumulation of dysmorphic and dysfunctional mitochondria and excessive Ksucc levels. These mitochondrial abnormalities in AEC of normal mice with advancing age were associated with the downregulation of SIRT5. Increased SIRT5 expression by LV-SIRT5pcDNA in senescent AEC sustains mitochondrial integrity and reduces fibrotic effects of AEC senescence in established bleomycin (BLM)-aging mouse model. The level of ITGB1 K238 was upregulation in senescent AEC, LV-SIRT5pcDNA down-regulates the Ksucc level of ITGB1 K238 blocking the activation of ITGB1/STAT3 signaling pathway associated pulmonary fibrosis. Collectively, our findings indicate excessive lysine succinylation (hyperKsucc) is a fundamental basis for mitochondrial dysfunction in pulmonary fibrosis induced by the AEC senescence and SIRT5 alleviates AEC senescence by stabilizing the mitochondrial function.

PMID:40311988 | DOI:10.1016/j.cellsig.2025.111830

Pharmacol Res. 2025 Apr 29:107756. doi: 10.1016/j.phrs.2025.107756. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is one of the most common interstitial lung diseases with a high mortality rate. Calcaratarin D (CalD), a labdane diterpenoid, has been shown to possess anti-inflammatory properties. The present study evaluated the therapeutic potential of CalD in pulmonary fibrosis. A single dose of bleomycin (BLM, 2.5mg/kg) was instilled intratracheally in mice for up to 21 days to develop lung fibrosis. Oral CalD (50mg/kg) reduced BLM-induced inflammatory cell infiltration, especially pro-fibrotic Arg1-expressing interstitial macrophages in the bronchoalveolar lavage fluid. During the late fibrotic phase, CalD decreased BLM-induced mortality and body weight loss. In addition, CalD ameliorated lung histopathology, reduced collagen deposition and mucus hypersecretion, and improved lung functions in BLM-exposed mice. Furthermore, CalD modulated the levels of pro-inflammatory cytokines, chemokines, and growth factors in BAL fluid and lung tissues. In mouse lungs, BLM selectively upregulated Wnt10A level and promoted β-catenin nuclear translocation. CalD not only blocked Wnt10A/β-catenin signaling pathway but also reduced pro-fibrotic markers such as collagens, α-SMA and FHL2. In normal human lung fibroblasts, CalD inhibited TGF-β1-stimulated pro-fibrotic markers and Wnt/β-catenin signaling pathway by reducing Wnt10A production, upregulating endogenous Wnt antagonist DKK1 level, dephosphorylating Wnt ligand co-receptor LRP6, and preventing β-catenin and YAP/TAZ nuclear translocation. The antifibrotic action of CalD was shown to be dependent on its α,β-unsaturated γ-butyrolactone structure that is essential for CalD to form covalent interaction with cellular protein targets. Our results imply that CalD could be a novel antifibrotic agent for IPF, acting through blockade of the Wnt/β-catenin signaling pathway.

PMID:40311955 | DOI:10.1016/j.phrs.2025.107756

Am J Pathol. 2025 Apr 29:S0002-9440(25)00140-3. doi: 10.1016/j.ajpath.2025.03.013. Online ahead of print.

ABSTRACT

Collagen VII is an essential anchoring protein in the basement membrane zone, maintaining the attachment of stratified and pseudostratified epithelia to the underlying interstitial matrix. However, collagen VII is largely unexplored in normal lungs and idiopathic pulmonary fibrosis (IPF), a disease characterized by excessive accumulation of extracellular matrix (ECM) and aberrant re-epithelialization of fibrotic lung parenchyma. Analysis of collagen VII mRNA and protein in IPF distal lungs demonstrated elevated levels compared to normal lungs. To investigate its cellular source and spatial distribution in lung tissue, immunohistochemistry, RNAscope in situ hybridization, and cell culture experiments in combination with analysis of public transcriptomic datasets were performed. In IPF lungs, collagen VII was abundant in pathological remodeled airways and honeycomb cysts, associated with increased basal cell populations. In contrast, in the control lungs, collagen VII was mainly localized in larger airways. RNA sequencing data revealed that epithelial basal cells and KRT5-/KRT17+ aberrant basaloid cells are the primary sources of COL7A1 expression. Furthermore, COL7A1 expression was found in mesenchymal subsets and both collagen VII mRNA and protein were observed in fibroblast foci, another histopathological feature of IPF. In vitro, COL7A1 expression was found to be increased in normal human lung fibroblasts treated with TGF-β1. These findings suggest that collagen VII could be involved in the process of abnormal re-epithelialization in lung fibrosis.

PMID:40311757 | DOI:10.1016/j.ajpath.2025.03.013

Lancet Respir Med. 2025 Apr 28:S2213-2600(25)00116-X. doi: 10.1016/S2213-2600(25)00116-X. Online ahead of print.

NO ABSTRACT

PMID:40311651 | DOI:10.1016/S2213-2600(25)00116-X

Lancet Respir Med. 2025 Apr 28:S2213-2600(25)00045-1. doi: 10.1016/S2213-2600(25)00045-1. Online ahead of print.

ABSTRACT

BACKGROUND: Rare pathogenic variants in telomere-related genes are associated with poorer clinical outcomes in idiopathic pulmonary fibrosis (IPF). We aimed to assess whether rare qualifying variants in monogenic adult-onset pulmonary fibrosis genes are associated with IPF survival. Using polygenic risk scores (PRS), we also evaluated the influence of common IPF risk variants in patients carrying the qualifying variants.

METHODS: We identified qualifying variants in telomere and non-telomere genes using whole-genome sequences from individuals clinically diagnosed with IPF and enrolled in the Pulmonary Fibrosis Foundation Patient Registry (PFFPR), a large multicentre, observational cohort study (March 29, 2016 to June 15, 2018, n=888). We also derived a PRS for IPF (PRS-IPF) from known common sentinel IPF variants. The primary outcome was the association between qualifying variants and survival. The secondary outcome was the association between qualifying variants and PRS-IPF. We used logistic regression models adjusted for sex, age at diagnosis, and principal components of genetic heterogeneity to examine the mutual relationship of qualifying variants and PRS-IPF. The association between qualifying variants and PRS-IPF with survival was tested using Cox proportional hazard models adjusted for baseline confounders. Validation of the results was sought in data from an independent multicentre, prospective, observational cohort study of IPF in the UK (PROFILE, May 17, 2010 to Sept 5, 2017, n=472), and results were meta-analysed under a fixed-effects model.

FINDINGS: We included 888 patients from PFFPR and 472 from PROFILE, totalling 1360 participants. In the PFFPR, carriers of qualifying variants in monogenic adult-onset pulmonary fibrosis genes were associated with lower PRS-IPF (odds ratio 1·79 [95% CI 1·15-2·81]; p=0·010) and shorter survival (hazard ratio 1·53 [1·12-2·10]; p=7·33 × 10-3). Individuals with the lowest PRS-IPF also had worse survival (1·61 [1·25-2·07]; p=1·87 × 10-4). These findings were validated in PROFILE and the meta-analysis of the results showed a consistent direction of effect across both cohorts.

INTERPRETATION: We found non-additive effects between qualifying variants and common risk variants in IPF survival, suggesting distinct disease subtypes and raising the possibility of using PRS to guide sequencing prioritisation. Assessing the carrier status for qualifying variants and modelling PRS-IPF promises to further contribute to predicting disease progression among patients with IPF.

FUNDING: Instituto de Salud Carlos III; Instituto Tecnológico y de Eenergías Renovables; Cabildo Insular de Tenerife; Fundación DISA; National Heart, Lung, and Blood Institute of the US National Institutes of Health; and UK Medical Research Council.

PMID:40311650 | DOI:10.1016/S2213-2600(25)00045-1

Front Pharmacol. 2025 Apr 16;16:1552251. doi: 10.3389/fphar.2025.1552251. eCollection 2025.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) has a higher morbidity and poor prognosis. Gui-Zhi-Fu-Ling-Wan (GFW) is a traditional Chinese herbal formula which exerts anti-inflammatory and anti-oxidative effects. The goal was to determine the protective effect of GFW on bleomycin (BLM)-induced pulmonary fibrosis.

METHODS: One hundred and twenty-four mice were randomly divided into eight groups, and orally supplemented with GFW (1 g/kg) in 1 week ago and continuing to 1 week later of single BLM intratracheal injection (5.0 mg/kg). Lung tissues were collected in 7 days and 21 days after BLM injection. BEAS-2B cells were pretreated with GFW (100 μg/mL) for three consecutive days before BLM (10 μg/mL) exposure. Cells were harvested in 12 or 24 h after BLM co-culture.

RESULTS: GFW supplementation alleviated BLM-induced alveolar structure destruction and inflammatory cell infiltration in mice lungs. BLM-incurred collagen deposition was attenuated by GFW. In addition, GFW pretreatment repressed BLM-evoked downregulation of E-cadherin, and elevation of N-cadherin and Vimentin in mouse lungs. Besides, BLM-excited GPX4 reduction, ferritin increases, lipid peroxidation, and free iron overload were significantly relieved by GFW pretreatment in mouse lungs and BEAS-2B cells. Notably, BLM-provoked mitochondrial reactive oxygen species (mtROS) excessive production, elevation of mitochondrial stress markers, such as HSP70 and CLPP, and mitochondrial injury, were all abolished in mouse lungs and BEAS-2B cells by GFW pretreatment.

CONCLUSION: GFW supplementation attenuated BLM-evoked lung injury and pulmonary fibrosis partially through repressing EMT and mtROS-mediated ferroptosis in pulmonary epithelial cells.

PMID:40308766 | PMC:PMC12041222 | DOI:10.3389/fphar.2025.1552251

J Nat Med. 2025 Apr 30. doi: 10.1007/s11418-025-01896-5. Online ahead of print.

ABSTRACT

This study aimed to investigate the effects of astragaloside IV(AS-IV) and quercetin (QCT) on autophagic activity, pyroptosis, and epithelial-mesenchymal transdifferentiation (EMT) in the context of idiopathic pulmonary fibrosis (IPF), utilizing both in vivo and in vitro models. In the in vivo component of the research, C57BL/6 J mice were subjected to bleomycin (BLM) modeling, followed by AS-IV + QCT intervention at low, medium, and high doses for 14 and 28 days. Pathological changes in lung tissue were assessed through HE and Masson staining. Additionally, the expression levels of autophagy and pyroptosis-related proteins in serum and bronchoalveolar lavage fluid were examined via Western blot analysis. In the in vitro experiment, RAW264.7 macrophage cells were co-cultured with MLE-12 alveolar epithelial cells (3:1 ratio), implementing BLM and NLR family pyrin domain-containing protein (NLRP3) + BLM models to induce IPF. The effects of AS-IV and QCT on these cells were evaluated by electron microscopy to observe structural changes, while Western blot and ELISA were used to measure the expression of autophagy and pyroptosis-related proteins. Results showed that AS-IV and QCT significantly enhanced autophagic activity, evidenced by increased levels of LC3II and beclin-1 and decreased levels of P62. Additionally, both compounds reduced the expression of pyroptosis-related proteins (NLRP3, Caspase-1, IL-1β, and IL-18) and slowed the progression of EMT in alveolar epithelial cells. These findings propose that AS-IV and QCT inhibit the EMT process in IPF by activating autophagic mechanisms while suppressing pyroptosis, thereby underscoring their potential as innovative therapeutic strategies for IPF and highlighting the promising implications of herbal compounds in its prevention and treatment.

PMID:40307659 | DOI:10.1007/s11418-025-01896-5

Sci Rep. 2025 Apr 30;15(1):15255. doi: 10.1038/s41598-025-98569-w.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal fibrosis disease. Due to the limited understanding of its pathogenesis and the fact that its detection largely depends on the operator's technical level and the accuracy of the equipment, the diagnosis and treatment of the disease have significant limitations. In this research, bleomycin was used to establish IPF models of C57/BL6N mice with different injury degrees, and proteomics technology extracted interstitial fluid of lung tissue to analyze the mechanism of fibrosis at different stages. Compared with the normal group, the alveolar area, collagen deposition, tidal volume, and respiratory rate of the experimental group decreased at all periods, and the difference was most significant on the 14th day of modeling. Proteomic techniques, including gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, showed that the progression of pulmonary fibrosis was related to different pathways: glucose metabolism, lipid transport, glycoprotein metabolism, synthesis of sulfur compounds, and other energy metabolism, calcium ion transport were dominant in the early stage of fibrosis and the acute inflammatory stage. The endoplasmic reticulum stress pathway was dominant in the extreme stage of fibrosis, and blood flow shear stress, Extracellular matrix (ECM) receptor activation, and other extracellular matrix-related pathways were dominant in the late stage of fibrosis. Moreover, western bolt validation experiments also confirmed that C/EBP-homologous protein (CHOP), Heat Shock Protein 60 (HSP60), and Alpha smooth muscle actin(α-SMA) proteins were increased in expression related to this pathway at the extreme stage of fibrosis, suggesting that the disruption of ion balance in the endoplasmic reticulum induced by endoplasmic reticulum stress or the disturbance of protein processing and transportation were involved in the occurrence and development of pulmonary fibrosis in mice. The above results are expected to provide ideas for clinical interpretation of the mechanism of pulmonary fibrosis and provide vital data support for its accurate diagnosis and effective treatment.

PMID:40307370 | DOI:10.1038/s41598-025-98569-w

Eur Respir Rev. 2025 Apr 30;34(176):240194. doi: 10.1183/16000617.0194-2024. Print 2025 Apr.

ABSTRACT

BACKGROUND: The unpredictable trajectory and heterogeneity of interstitial lung disease (ILDs) make prognostication challenging. Current prognostic indices and outcome measures have several limitations. Quantitative computed tomography (qCT) provides automated numerical assessment of CT imaging and has shown promise when applied to the prognostication and disease monitoring of ILD. This systematic review aims to highlight the current evidence underpinning the prognostic value of qCT in predicting outcomes in ILD.

METHODS: A comprehensive search of four databases (Medline, EMCare, Embase and CINAHL (Cumulative Index to Nursing and Allied Health Literature)) was conducted for studies published up to and including 22 November 2024. A modified CHARMS (CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies) checklist was used for data extraction. The risk of bias was assessed using a Quality in Prognostic Studies template.

RESULTS: The search identified 1134 unique studies, of which 185 studies met inclusion and exclusion criteria. Commonly studied ILD subtypes included idiopathic pulmonary fibrosis (41%, n=75), mixed subtypes (26%, n=48) and systemic sclerosis ILD (16%, n=30). Numerous studies showed significant prognostic signals, even when adjusted for common covariates and/or significant correlation between serial qCT biomarkers and conventional outcome measures. Heterogenous and nonstandardised reporting methods meant that direct comparison or meta-analysis of studies was not possible. Studies were limited by the use of retrospective methodology without prospective validation and significant study attrition.

DISCUSSION: qCT has shown efficacy in the prognostication and disease monitoring of a range of ILDs. Hurdles exist to widespread adoption including governance concerns, appropriate algorithm anchoring and standardisation of image acquisition. International collaboration is underway to address these hurdles, paving the way for regulatory approval and ultimately patient benefit.

PMID:40306954 | DOI:10.1183/16000617.0194-2024