Eur Respir Rev. 2025 Mar 5;34(175):240201. doi: 10.1183/16000617.0201-2024. Print 2025 Jan.

ABSTRACT

INTRODUCTION: Social determinants of health (SDH), including age, sex, ethnicity, socioeconomic status and rurality, influence health outcomes. Clinical trials investigating antifibrotic agents for people with idiopathic pulmonary fibrosis (IPF) have been conducted in predominantly White and male populations; it is unclear whether other SDH have been considered. This study aimed to investigate active consideration and reporting of SDH in clinical trials of antifibrotic agents for people with IPF.

METHODS: Three registries (ClinicalTrials.gov, ANZCTR and International Standard Randomised Controlled Trial Number (ISRCTN)) plus CENTRAL (Cochrane Central Register of Controlled Trials) were searched for clinical trials investigating antifibrotic agents for people with IPF or various progressive fibrotic ILD variants registered from 1 January 2000 until 3 September 2023. Data were extracted regarding trial phase/status, recruitment strategies and eligibility criteria. If trial results were available, SDH data from demographics and subgroup analyses were extracted.

RESULTS: Of 313 records identified, 70 trials were included. The majority of trials were phase II or III (77%), 56% were completed and 61% had reported results that included eight terminated trials. All 70 trials specified age and sex, but not other SDH, within their eligibility criteria. Of 43 trials reporting results, all reported age and sex and 40 (95%) reported ethnicity. 10 387 participants were described (74% male, 77% White, 16% Asian and <1% Black). Descriptors for ethnicity varied considerably. Five trials (12%) included only White participants and three (7%) included only Asian participants. No other SDH were reported.

CONCLUSIONS: SDH beyond age, sex and ethnicity were neither considered nor reported in antifibrotic IPF trials. Trial populations were predominantly male and White. There is a need to actively consider SDH to ensure diverse and representative clinical trial populations.

PMID:40044188 | DOI:10.1183/16000617.0201-2024

Eur Respir Rev. 2025 Mar 5;34(175):230212. doi: 10.1183/16000617.0212-2023. Print 2025 Jan.

ABSTRACT

BACKGROUND: The role of objective cough monitoring systems for assessments in adults with chronic respiratory diseases (CRDs) is unclear. This systematic review aimed to synthesise current literature on frequency of use and characteristics of these systems.

METHODS: MEDLINE, Embase and CENTRAL were systematically searched to identify relevant literature evaluating cough in adults with CRDs using objective cough monitoring systems. The primary outcomes were utility and characteristics of the systems, with the secondary outcome being usability.

RESULTS: We identified 54 primary studies (4909 patients, with 3364 having idiopathic chronic cough). Included studies were generally of low risk of bias. Objective monitoring systems identified were VitaloJAK (n=19 studies), Leicester Cough Monitor (LCM, n=18), LEOSound (n=2), PulmoTrack (n=2), Hull Automated Cough Counter (HACC, n=1), LifeShirt (n=1), and unnamed devices (n=11). There was limited assessment against manual counting, with low-to-moderate correlation to patient-reported outcome measures for VitaloJAK (p<0.05), LCM (r=0.43-0.78) and unnamed devices (r=0.38-0.40). Test-retest consistency was evaluated in two studies, showing favourable results. There was at least moderate effect size of longitudinal measurement changes to various treatments for VitaloJAK (nine out of 16), LCM (two out of eight), HACC (n=1), LCM and HACC (n=1), PulmoTrack (n=1) and unnamed devices (n=3).

CONCLUSIONS: Few studies evaluated the agreement of objective cough monitoring systems against manual counting. Most studies were conducted in patients with idiopathic chronic cough, with the VitaloJAK and LCM being were the most evaluated objective cough monitoring systems. Further evaluation of objective cough monitoring systems is needed for research and clinic application.

PMID:40044185 | DOI:10.1183/16000617.0212-2023

Tissue Cell. 2025 Mar 1;94:102817. doi: 10.1016/j.tice.2025.102817. Online ahead of print.

ABSTRACT

Growth factors and cytokines in the vitreous are critical drivers of proliferative diabetic retinopathy (PDR), a condition in which many patients exhibit resistance to current therapies. PDR is characterized by the formation of fibrovascular membranes on the vitreous side of the retina, which, if untreated, can lead to retinal detachment. Nintedanib, a clinically approved drug for idiopathic pulmonary fibrosis, targets multiple tyrosine kinases, including vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs), and fibroblast growth factor receptors (FGFRs). In this study, we demonstrate that nintedanib effectively inhibits PDR vitreous-induced signaling molecules-namely, phosphorylation of VEGFR2, Akt, and Erk1/2-as well as cellular responses, including proliferation, migration, and tube formation in primary human retinal microvascular endothelial cells, at a non-toxic concentration of 1 μM. These findings suggest that nintedanib holds potential as a novel therapeutic option for the treatment of PDR.

PMID:40043340 | DOI:10.1016/j.tice.2025.102817

Eur J Nucl Med Mol Imaging. 2025 Mar 5. doi: 10.1007/s00259-025-07146-w. Online ahead of print.

NO ABSTRACT

PMID:40042637 | DOI:10.1007/s00259-025-07146-w

ERJ Open Res. 2025 Mar 3;11(2):00823-2024. doi: 10.1183/23120541.00823-2024. eCollection 2025 Mar.

ABSTRACT

BACKGROUND: With the introduction of the antifibrotic drugs targeting progressive pulmonary fibroses, it becomes imperative to provide reliable contemporary estimates of the most common interstitial lung diseases. We aimed to provide contemporary estimates of the incidence and survival of idiopathic pulmonary fibrosis (IPF), hypersensitivity pneumonitis (HP) and connective tissue disease-associated interstitial lung disease (CTD-ILDs), and to compare their survival to that of the general population. To do this we have used data extracted from the Optimum Patient Care Research Database (OPCRD).

METHODS: In this matched cohort study, we extracted incident cases of HP, CTD-ILD and IPF, and age and sex matched controls for each case, for the years 2010-2019. We calculated annual incidence rates and analysed incidence trends over time using segmented regression modelling. We estimated survival for cases and controls using the Kaplan-Meier model.

RESULTS: We extracted data for 18 914 incident cases of interstitial lung diseases between 2010 and 2019 from the OPRCD. Incidence rates varied across the different diseases, with rates of 18.12, 7.96 and 2.63 per 100 000 person-years for IPF, CTD-ILD and HP, respectively. 5-year survival for IPF, CTD-ILD and HP was 40%, 54% and 66%, respectively, and this was generally ∼50% lower than that of the general population.

CONCLUSION: Our population-based study emphasises the considerable burden of interstitial lung diseases, with >20 000 new cases diagnosed each year in the UK, many of whom will be eligible for antifibrotic drugs.

PMID:40040895 | PMC:PMC11874205 | DOI:10.1183/23120541.00823-2024

ERJ Open Res. 2025 Mar 3;11(2):00899-2024. doi: 10.1183/23120541.00899-2024. eCollection 2025 Mar.

ABSTRACT

BACKGROUND: Suspected interstitial lung disease (ILD) patients may be referred to an ILD-specialist centre or a non-ILD-specialist centre for diagnosis and treatment. Early referral and management of patients at ILD-specialist centres has been shown to improve survival and reduce hospitalisations. The COVID-19 pandemic has affected the ILD patient diagnostic pathway and prompted centres to adapt. This study investigates and contrasts ILD patient pathways in ILD-specialist and non-ILD-specialist centres, focusing on referrals, caseloads, diagnostic tools, multi-disciplinary team (MDT) meeting practices and resource accessibility.

METHODS: Conducted as a cross-sectional study, a global self-selecting survey ran from September 2022 to January 2023. Participants included ILD specialists and healthcare professionals (HCPs) from ILD-specialist centres and non-ILD-specialist centres.

RESULTS: Of 363 unique respondents from 64 countries, 259 were from ILD-specialist centres and 104 from non-ILD-specialist centres. ILD centres had better resource availability, exhibiting higher utilisation of diagnostic tests (median: 12 tests) than non-ILD centres (nine tests) and better access to specialist professions attending MDT meetings (median: six professions at meeting) in specialist centres than non-ILD centres (three professions at meeting). Transitioning to virtual MDT meetings allowed HCPs from other locations to join meetings in nearly 90% of all centres, increasing regular participation in 60% of specialist centres and 72% of non-ILD centres. For treatment of patients, specialist centres had better access to antifibrotic drugs (91%) compared to non-ILD centres (60%).

CONCLUSIONS: Diagnostic pathways for ILD patients diverged between specialist centres and non-ILD centres. Disparities in resource and specialist availability existed between centres.

PMID:40040894 | PMC:PMC11874298 | DOI:10.1183/23120541.00899-2024

Biochem Genet. 2025 Mar 4. doi: 10.1007/s10528-025-11071-w. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease linked to aging. Mitochondrial dysfunction in circulating T cells, often caused by disruption of mitochondrial DNA (mtDNA), may play a role in age-related conditions like IPF. In our previous study, we found high mtDNA mutational loads in blood lymphocytes from IPF patients, especially in regions critical for mtDNA expression. Since Complex I of the electron transport chain, partly encoded by mtDNA, is essential for energy production, we conducted a preliminary study on its activity. We found significantly reduced Complex I activity (p < 0.001) in lymphocytes from 40 IPF patients compared to 40 controls, which was positively correlated with lung function decline, specifically in functional vital capacity and diffusing capacity for carbon monoxide. These findings indicate that T cell mitochondrial dysfunction is associated with disease progression in IPF. Future work will explore the mechanisms linking T cell mitochondrial disruption with fibrosis, potentially uncovering new therapeutic targets.

PMID:40038177 | DOI:10.1007/s10528-025-11071-w

Intern Emerg Med. 2025 Mar 4. doi: 10.1007/s11739-025-03908-4. Online ahead of print.

ABSTRACT

Aortitis and periaortitis refer to the inflammation of the aortic wall and the surrounding tissues. Both conditions are associated with various diseases and express nonspecific manifestations. Early diagnosis and treatment are crucial to improve the prognosis of the disease. This study aimed to assess the causes and main clinical features of aortitis and periaortitis in patients from a single centre in Spain. Observational, retrospective study of patients diagnosed with aortitis or periaortitis at a Spanish referral center over the last decade. 134 patients (87 female; mean age of 55.1 ± 9.1 years) were recruited, 132 of which had aortitis and two periaortitis. Aortitis was associated with giant cell arteritis (n = 102), Takayasu's arteritis (n = 6), IgG4-related disease (n = 6), infectious diseases (n = 3), malignancy (n = 1), drugs (n = 1), isolated aortitis (n = 1), and other immune-mediated inflammatory diseases (IMIDs) (n = 12). IMIDs included were Sjögren's syndrome (n = 2), sarcoidosis (n = 2), rheumatoid arthritis (n = 2), axial spondyloarthritis (n = 2), inflammatory bowel disease (n = 1), primary biliary cirrhosis (n = 1), idiopathic pulmonary fibrosis (n = 1), and polyarteritis nodosa (n = 1). Periaortitis was due to idiopathic retroperitoneal fibrosis in both cases. Imaging techniques used for diagnosis included 18F-FDG PET/CT scan (n = 133), CT-angiography (n = 44), and/or MRI-angiography (n = 33). Polymyalgia rheumatica (52.2%) and asthenia (53.7%) were the most common manifestations, followed by limb claudication (23.9%) and inflammatory back pain (26.9%). Acute-phase reactants were typically increased. Aortitis is a common condition and may be associated with multiple non-infectious diseases. Its clinical presentation is often unspecific, requiring a high level of suspicion to get an early diagnosis and treatment.

PMID:40038164 | DOI:10.1007/s11739-025-03908-4

J Ethnopharmacol. 2025 Mar 2:119568. doi: 10.1016/j.jep.2025.119568. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Maimendong decoction (MMDD) originates from the ancient Chinese medical text Synopsis of the Golden Chamber and is a well-established remedy for treating lung diseases. It has demonstrated efficacy in the long-term clinical management of idiopathic pulmonary fibrosis (IPF); however, its underlying mechanisms remain unclear.

AIM OF THE STUDY: This study investigates whether MMDD alleviates IPF by reducing type 2 alveolar epithelial cell (AEC2) senescence and enhancing mitochondrial autophagy. It also explores whether these effects are mediated through the PTEN-induced putative kinase 1 (PINK1)/Parkinson juvenile disease protein 2 (Parkin) pathway.

MATERIALS AND METHODS: An IPF mouse model was established with bleomycin (BLM). Mice were administered MMDD, pirfenidone (PFD), or saline for 7 or 28 days. Body weight, lung coefficient, and lung appearance were monitored, and lung tissue pathology was assessed. The expression levels of p53, p21, p16, SA-β-gal activity, and senescence-associated secretory phenotype (SASP) markers were measured. Ultrastructural changes in AEC2 mitochondria were analyzed using transmission electron microscopy. Protein levels of autophagy markers sequestosome-1 and light chain 3 were assessed. The protein levels of PINK1, Parkin, and phosphorylated Parkin were further assessed using network pharmacology analysis and molecular docking technology.

RESULTS: MMDD alleviated BLM-induced IPF by improving body weight, lung appearance, and histopathological features. It reduced AEC2 senescence markers, including p53, p21, p16, SA-β-gal, and SASP, while enhancing mitochondrial autophagy and repairing mitochondrial damage. Network pharmacology and molecular docking identified PINK1 as a major target, and Western blot (WB) analysis confirmed that MMDD regulates the PINK1/Parkin signaling pathway in the treatment of IPF.

CONCLUSIONS: MMDD regulates the PINK1/Parkin signaling pathway, alleviates AEC2 senescence, and enhances mitochondrial autophagy, providing significant therapeutic potential for IPF treatment.

PMID:40037475 | DOI:10.1016/j.jep.2025.119568

Elife. 2025 Mar 4;13:RP102451. doi: 10.7554/eLife.102451.

ABSTRACT

BACKGROUND: In idiopathic pulmonary fibrosis (IPF) patients, alveolar architectures are lost and gas transfer function would decline, which cannot be rescued by conventional anti-fibrotic therapy. P63+ lung basal progenitor cells are reported to have potential to repair damaged lung epithelium in animal models, which need further investigation in clinical trials.

METHODS: We cloned and expanded P63+ progenitor cells from IPF patients to manufacture cell product REGEND001, which were further characterized by morphology and single-cell transcriptomic analysis. Subsequently, an open-label, dose-escalation autologous progenitor cell transplantation clinical trial was conducted. We treated 12 patients with ascending doses of cells: 0.6x, 1x, 2x and 3.3x106 cells/kg bodyweight. The primary outcome was the incidence and severity of cell therapy-related adverse events (AEs); secondary outcome included other safety and efficacy evaluations.

RESULTS: P63+ basal progenitor cell was safe and tolerated at all doses, with no dose-limiting toxicity or cell therapy-related severe adverse events observed. Patients in three higher dose groups showed significant improvement of lung gas transfer function as well as exercise ability. Resolution of honeycomb lesion was observed in patients of higher dose groups.

CONCLUSIONS: REGEND001 has high safety profile and meanwhile encourages further efficacy exploration in IPF patients.

FUNDING: National High Level Hospital Clinical Research Funding (2022-PUMCH-B-108), National Key Research and Development Plan (2024YFA1108900, 2024YFA1108500), Jiangsu Province Science and Technology Special Project Funding (BE2023727), National Biopharmaceutical Technology Research Project Funding (NCTIB2023XB01011), Non-profit Central Research Institute Fund of Chinese Academy of Medical Science (2020-PT320-005), and Regend Therapeutics.

CLINICAL TRIAL NUMBER: Chinese clinical trial registry: CTR20210349.

PMID:40036154 | DOI:10.7554/eLife.102451

Cureus. 2025 Jan 31;17(1):e78319. doi: 10.7759/cureus.78319. eCollection 2025 Jan.

ABSTRACT

Introduction Inflammatory cells play a role in several idiopathic pulmonary fibrosis (IPF) pathogenesis steps. We aimed to evaluate the predictive value of peripheral blood cell (PBC) counts and inflammation indexes in the prognosis and mortality of IPF. Materials and methods A total of 155 patients with IPF followed between 1 January 2016 and 1 January 2023 were evaluated retrospectively. The baseline values and annual changes for pulmonary function tests and the PBC counts, ratios, and inflammation indexes (leukocyte, neutrophil, platelet, monocyte, lymphocyte, red cell distribution width (RDW), neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), Systemic Immune Inflammation (SII) index, Systemic Inflammation Response Index (SIRI), the Aggregate Index of Systemic Inflammation (AISI)) were recorded. The relation between PBC, ratios, and inflammatory indexes with functional parameters (forced vital capacity (FVC), diffusing capacity of the lung for carbon monoxide (DLCO), 6-minute walking test (6MWT), Gender, Age, and Physiology (GAP) index, GAP stage) and mortality were examined. Results It was found that baseline RDW and neutrophil count were negatively correlated with survival time. The prognosis was worse in patients who had an RDW>13.6% and a neutrophil count>5.26×109/L (p = 0.0005 and p = 0.037, respectively). Significant correlations were observed between baseline peripheral blood cell counts, ratios, and index values (leukocyte, monocyte, neutrophil, platelet, monocyte, lymphocyte, NLR, PLR, MLR, SII, SIRI, AISI) and functional parameters (FVC, DLCO, 6MWT, GAP index, GAP stage). However, there was no significant correlation between the yearly changes. Conclusions Increased neutrophils and RDW may be related to the poor prognosis in IPF. Peripheral blood cell counts and inflammatory indices may provide useful information in identifying patients with worse functional status.

PMID:40034886 | PMC:PMC11873667 | DOI:10.7759/cureus.78319

Front Mol Biosci. 2025 Feb 17;12:1507163. doi: 10.3389/fmolb.2025.1507163. eCollection 2025.

ABSTRACT

BACKGROUND: The idiopathic pulmonary fibrosis (IPF) is a progressive and lethal interstitial lung disease with high morbidity and mortality. IPF is characterized by excessive extracellular matrix accumulation (ECM) and epithelial-mesenchymal transformation (EMT). To date, few anti-fibrotic therapeutics are available to reverse the progression of pulmonary fibrosis, and it is important to explore new profibrotic molecular regulators mediating EMT and pulmonary fibrosis.

METHODS: Based on our model of TGF-β1-induced EMT in BEAS-2B cells, we performed the genome-wide CRISPR/Cas9 knockout (GeCKO) screening technique, pathway and functional enrichment analysis, loss-of-function experiment, as well as other experimental techniques to comprehensively investigate profibrotic regulators contributing to EMT and the pathogenesis of pulmonary fibrosis.

RESULTS: Utilizing the GeCKO library screening, we identified 76 top molecular regulators. Ten candidate genes were subsequently confirmed by integrating the high-throughput data with findings from pathway and functional enrichment analysis. Among the candidate genes, knockout of COL20A1 and COL27A1 led to decreased mRNA expression of ECM components (Fibronectin and Collagen-I), as well as an increased rate of cell apoptosis. The mRNA expression of Collagen-I, together with the cell viability and migration, were inhibited when knocking out the WNT11. In addition, a decrease in the protein deposition of ECM components was observed by suppressing the expression of COL20A1, COL27A1, and WNT11.

CONCLUSION: Our study demonstrates that the COL20A1, COL27A1, and WNT11 serve as key profibrotic regulators of EMT. Gaining understanding and insights into these key profibrotic regulators of EMT paves the way for the discovery of new therapeutic targets against the onset and progression of IPF.

PMID:40034336 | PMC:PMC11872725 | DOI:10.3389/fmolb.2025.1507163

Br J Pharmacol. 2025 Mar 4. doi: 10.1111/bph.17470. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by fibroblast activation and abnormal accumulation of extracellular matrix in the lungs. We previously demonstrated the importance of the heat shock protein αB-crystallin (HSPB5) in TGF-β1 profibrotic signalling, which suggests that HSPB5 could be a new therapeutic target for the treatment of IPF. The purpose of this study was thus to develop antisense oligonucleotides targeting HSPB5 and to study their effects on the development of experimental pulmonary fibrosis.

EXPERIMENTAL APPROACH: Specific antisense oligonucleotides (ASO) were designed and screened in vitro, based on their ability to inhibit human and murine HSPB5 expression. The selected ASO22 was characterized in vitro in human fibroblast CCD-19Lu cells and A549 epithelial pulmonary cells, as well as in vivo using a mouse model of bleomycin-induced pulmonary fibrosis.

KEY RESULTS: ASO22 was selected for its capacity to inhibit TGF-β1-induced expression of HSPB5 and additional key markers of fibrosis such as plasminogen activator inhibitor-1, collagen, fibronectin and α-smooth muscle actin in fibroblastic human CCD-19Lu cells as well as plasminogen activator inhibitor-1 and α-smooth muscle actin in pulmonary epithelial A549 cells. Intra-tracheal or intravenous administration of ASO22 in bleomycin-induced pulmonary fibrotic mice decreased HSPB5 expression and reduced fibrosis, as demonstrated by decreased pulmonary remodelling, collagen accumulation and Acta2 and Col1a1 expression.

CONCLUSION AND IMPLICATIONS: Our results suggest that an antisense oligonucleotide strategy targeting HSPB5 could be of interest for the treatment of IPF.

PMID:40033950 | DOI:10.1111/bph.17470

BMJ Case Rep. 2025 Mar 3;18(3):e263966. doi: 10.1136/bcr-2024-263966.

ABSTRACT

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

PMID:40032576 | DOI:10.1136/bcr-2024-263966

bioRxiv [Preprint]. 2025 Feb 17:2025.02.12.637970. doi: 10.1101/2025.02.12.637970.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable lung disease characterized by tissue scarring that disrupts gas exchange. Epithelial cell dysfunction, fibroblast activation, and excessive extracellular matrix deposition drive this pathology that ultimately leads to respiratory failure. Mechanistic studies have shown that repeated injury to alveolar epithelial cells initiates an aberrant wound-healing response in surrounding fibroblasts through secretion of mediators like transforming growth factor-β, yet the precise biological pathways contributing to disease progression are not fully understood. To better study these interactions there is a critical need for lung models that replicate the cellular heterogeneity, geometry, and biomechanics of the distal lung microenvironment. In this study, induced pluripotent stem cell-derived alveolar epithelial type II (iATII) cells and human pulmonary fibroblasts were arranged to replicate human lung micro-architecture and embedded in soft or stiff poly(ethylene glycol) norbornene (PEG-NB) hydrogels that recapitulated the mechanical properties of healthy and fibrotic lung tissue, respectively. The co-cultured cells were then exposed to pro-fibrotic biochemical cues, including inflammatory cytokines and growth factors. iATIIs and fibroblasts exhibited differentiation pathways and gene expression patterns consistent with trends observed during IPF progression in vivo . A design of experiments statistical analysis identified stiff hydrogels combined with pro-fibrotic biochemical cue exposure as the most effective condition for modeling fibrosis in vitro . Finally, treatment with Nintedanib, one of only two Food and Drug Administration (FDA)-approved drugs for IPF, was assessed. Treatment reduced fibroblast activation, as indicated by downregulation of key activation genes, and upregulated several epithelial genes. These findings demonstrate that human 3D co-culture models hold tremendous potential for advancing our understanding of IPF and identifying novel therapeutic targets.

STATEMENT OF SIGNIFICANCE: This study leverages advanced biomaterials and biofabrication techniques to engineer physiologically relevant, patient-specific, and sex-matched models of pulmonary fibrosis, addressing the critical need for pre-clinical therapeutic drug screening platforms. These human 3D lung models successfully replicated key features of fibrotic lung tissue. Tuning microenvironmental stiffness of 3D PEG-NB hydrogels to match fibrotic lung values and exposing human iATII cells and fibroblasts to pro-inflammatory biochemical cues recreated hallmark characteristics of in vivo fibrosis pathogenesis, including epithelial differentiation and loss, as well as fibroblast activation. The utility of these models was further validated by demonstrating responsiveness to Nintedanib, a clinically available treatment for IPF. These findings highlight the transformative potential of well-defined biomaterial-based 3D models for elucidating complex disease mechanisms and accelerating therapeutic drug discovery for chronic pulmonary diseases like idiopathic pulmonary fibrosis.

PMID:40027659 | PMC:PMC11870410 | DOI:10.1101/2025.02.12.637970

SLAS Discov. 2025 Feb 28:100223. doi: 10.1016/j.slasd.2025.100223. Online ahead of print.

ABSTRACT

Senescent cells contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF), a disease with significant unmet need and therefore, there is an interest in discovering new drug targets that regulate this process. We design and perform a phenotypic screen with a secreted protein library in primary human lung fibroblasts to identify modulators of cell senescence. We identify FGF9 as a suppressor of several senescence phenotypes reducing stimulated p21 expression, enlarged morphology, DNA damage and SASP secretion, which is consistent with both DNA-damage and ROS induced senescence. We also show that FGF9 reduces fibroblast activation in both healthy and IPF fibroblasts shown by a reduction in pro-fibrotic markers such as α-smooth muscle actin and COL1A1 mRNA. Our findings identify FGF9 as a suppressor of both senescence and fibrotic features in lung fibroblasts and therefore could be targeted as a new therapeutic strategy for respiratory diseases such as IPF.

PMID:40024445 | DOI:10.1016/j.slasd.2025.100223

Int J Biol Macromol. 2025 Feb 28:141602. doi: 10.1016/j.ijbiomac.2025.141602. Online ahead of print.

ABSTRACT

BACKGROUND: SARS-CoV-2 disrupts lung vascular endothelial integrity, contributing to severe COVID-19 complications. However, the molecular mechanisms driving endothelial dysfunction remain underexplored, and targeted therapeutic strategies are lacking.

OBJECTIVE: This study investigates Naringenin-7-O-glucoside (N7G) as a multi-target therapeutic candidate for modulating vascular integrity and immune response by inhibiting MMP1, MMP7, and SERPINE1-key regulators of extracellular matrix (ECM) remodeling and inflammation.

METHODS & RESULTS: RNA-set analysis of COVID-19 lung tissues identified 17 upregulated N7G targets, including MMP1, MMP7, and SERPINE1, with the latter exhibiting the highest expression. PPI network analysis linked these targets to ECM degradation, IL-17, HIF-1, and AGE-RAGE signaling pathways, and endothelial dysfunction. Disease enrichment associated these genes with idiopathic pulmonary fibrosis and asthma. Molecular docking, 200 ns MD simulations (triplicate), and MMGBSA calculations confirmed N7G's stable binding affinity to MMP1, MMP7, and SERPINE1. Immune profiling revealed increased neutrophils and activated CD4+ T cells, alongside reduced mast cells, NK cells, and naïve B cells, indicating immune dysregulation. Correlation analysis linked MMP1, MMP7, and SERPINE1 to distinct immune cell populations, supporting N7G's immunomodulatory role.

CONCLUSION: These findings suggest that N7G exhibits multi-target therapeutic potential by modulating vascular integrity, ECM remodeling, and immune dysregulation, positioning it as a promising candidate for mitigating COVID-19-associated endothelial dysfunction.

PMID:40024412 | DOI:10.1016/j.ijbiomac.2025.141602

Phytomedicine. 2025 Mar 1;140:156545. doi: 10.1016/j.phymed.2025.156545. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an irreversible lung disease for which there is a lack of effective and safe therapeutic drugs. 13-Methylpalmatine (13-Me-PLT) is an active compound from Coptis chinensis, and no study has yet been reported on its pharmacological effects in pulmonary fibrotic diseases. The group has previously demonstrated the antimyocardial fibrosis efficacy of 13-Me-PLT but its effect on pulmonary fibrosis and its potential mechanism has not yet been investigated.

PURPOSE: The present research is designed to clarify the therapeutic potential and mechanism of action of 13-Me-PLT in IPF using a bleomycin (BLM)-induced mouse model of IPF.

METHODS: In vivo, mice were administrated with BLM to establish the IPF model, and IPF mice were treated with 13-Me-PLT (5, 10, and 20 mg/kg) and pirfenidone (PFD, 300 mg/kg) by gavage. In vitro, we employed TGF-β1 (10 ng/ml)-induced MRC5 cells, which were then treated with 13-Me-PLT (5, 10, 20 μM) and PFD (500 μM). High-throughput transcriptome sequencing, molecular dynamics simulations, molecular docking and Surface plasmon resonance (SPR) were employed to elucidate the underlying mechanisms of 13-Me-PLT in mitigating IPF.

RESULT: In vivo experiments showed that 13-Me-PLT significantly ameliorated BLM-induced lung fibrosis in mice. In vitro studies, 13-Me-PLT showed good antifibrotic potential by inhibiting fibroblast differentiation. Transcriptomic analysis of mouse lung tissues identified ITGA5 and TGF-β/Smad signaling pathways as key targets for the antifibrotic effects of 13-Me-PLT. Molecular docking and kinetic analyses further supported these findings. Functional studies involving ITGA5 silencing and overexpression confirmed that 13-Me-PLT down-regulated ITGA5 expression and inhibited the activation of the TGF-β/Smad signaling pathway, confirming its mechanism of action.

CONCLUSION: To our best knowledge, these results provide the first insight that 13-Me-PLT is protective against BLM-induced IPF in mice. Unlike existing antifibrotic drugs, 13-Me-PLT specifically targets the ITGA5/TGF-β/Smad signaling pathway, offering a novel and potentially more effective therapeutic approach. This study not only validates the antifibrotic efficacy of 13-Me-PLT but also elucidates its unique mechanism of action, these findings may provide an opportunity to develop new drugs to treat IPF.

PMID:40023972 | DOI:10.1016/j.phymed.2025.156545

Rev Mal Respir. 2025 Feb 28:S0761-8425(25)00050-6. doi: 10.1016/j.rmr.2025.02.007. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a rare, progressive and fatal disease without pharmacologic curative treatments for the patients. TGF-β is a crucial cytokine in the fibrotic process, and its intracellular signaling pathways are complex and rely on the activation of its receptor. This review summarizes our knowledge on the regulatory checkpoints of the TGF-β signaling. In addition, the main strategies and key potential therapeutic targets identified over recent years are presented, with particular emphasis laid on how they can be used to develop new treatments for pulmonary fibrosis.

PMID:40023715 | DOI:10.1016/j.rmr.2025.02.007

Respir Res. 2025 Feb 28;26(1):81. doi: 10.1186/s12931-025-03146-4.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) are interstitial lung diseases (ILD) that carry a high burden and mortality. IPF/PPF experts and patients call for standardized care, outcome harmonization and holistic management in these complex and devastating diseases, with a focus on person-centeredness. In this cross-sectional international survey study, we aimed to gather information on the person-centred health outcomes European healthcare professionals (HCPs) already use or deem important for use in routine care for IPF/PPF. This work is part of the COCOS-IPF project on developing a Core Outcome Set (COS) for and with patients with IPF/PPF.

METHODS: With the input of IPF/PPF experts, psychologists and patients, we developed an online survey for European multidisciplinary HCPs with IPF/PPF expertise. The survey was programmed in QualtricsXM, piloted and distributed via the networks of the COCOS-IPF consortium. We used content analysis to create an overall list of outcome domains mentioned in the survey, classified these according to the COMET (Core Outcome Measures in Effectiveness Trials) taxonomy and calculated the frequency of all outcomes mentioned.

RESULTS: A total of 149 experts, mainly pulmonologists (n = 120, 81%) working in ILD expert centres, from 31 European countries participated. Of the 40 different outcome domains mentioned, the majority referred to `physiological/clinical` (n = 773, 81%) and `life impact` (n = 138, 14%) outcome domains. Of these, `lung function' (n = 280, 29%), 'exercise capacity' (n = 123, 13%) and `quality of life` (n = 103, 11%) were reported as most frequently used person-centred health outcomes. Survey respondents deemed the same three outcome domains the most important for use in the routine clinical IPF/PPF care, supplemented by chest symptoms. Pulmonologists reported mainly about routine use of `lung function` (n = 252, 26%), while allied HCPs put more focus on outcomes related to physical condition and whole body status.

CONCLUSIONS: HCPs have identified 40 different outcomes domains in a European multidisciplinary survey on person-centred health outcomes in IPF/PPF. Lung function, exercise capacity, quality of life and chest symptoms were rated as the most relevant health outcomes to be assessed routinely in clinical care. These insights can help to support the development of a COS for IPF/PPF clinical care.

PMID:40022111 | DOI:10.1186/s12931-025-03146-4