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

Respir Res. 2025 Feb 28;26(1):80. doi: 10.1186/s12931-025-03139-3.

ABSTRACT

BACKGROUND: Supplemental oxygen therapy is commonly prescribed in clinical practice for patients with fibrosing interstitial lung disease (ILD) to reduce breathlessness and increase physical capacity. Only a few studies have evaluated the incidence of oxygen therapy use, with evidence lacking in its use among fibrosing ILD subtypes including patients with idiopathic pulmonary fibrosis (IPF) and non-IPF ILD. This study aimed to estimate incidence of oxygen therapy and factors associated with oxygen therapy initiation.

METHODS: This non-interventional study used US administrative claims and electronic health record data from 01 October 2015 to 30 June 2022. Patients aged ≥ 18 years with newly diagnosed fibrosing ILD (≥ 2 fibrosing ILD diagnoses in any position on different dates of service within 365 days) were included; the index date was the first date with ILD diagnosis. Patients were followed until the earlier of health plan disenrollment, death, or end of study period. Oxygen therapy use was evaluated among patients without evidence of oxygen therapy before the index date, stratified by the underlying fibrosing disease (i.e., IPF vs. non-IPF ILD). Factors associated with oxygen therapy use were evaluated using Cox proportional hazards regression.

RESULTS: A total of 114,921 patients (IPF n = 5,555; non-IPF ILD n = 109,366) newly diagnosed with fibrosing ILD were included in the study. The mean (standard deviation) age of patients with ILD was 66.9 (14.2) years, and 47.2% were male. Patients were followed for a mean of 24 months after ILD diagnosis, during which 38% of fibrosing ILD patients initiated oxygen therapy; a higher proportion of patients with IPF initiated oxygen therapy compared to those with non-IPF ILD (68% and 36%, respectively). Factors associated with oxygen therapy initiation included IPF, higher Charlson comorbidity scores, and comorbidities that impair respiratory capacity.

CONCLUSIONS: The study findings demonstrate a substantial proportion of patients with fibrosing ILD initiated oxygen therapy following initial ILD diagnosis, with higher rates of oxygen therapy initiation observed among patients with IPF compared with non-IPF ILD. Respiratory comorbidities were key factors associated with increased initiation of oxygen therapy.

PMID:40022082 | DOI:10.1186/s12931-025-03139-3

Respir Res. 2025 Feb 28;26(1):73. doi: 10.1186/s12931-025-03136-6.

ABSTRACT

BACKGROUND: The prognostic value of patterns and quantitative measures of lung fibrosis on high-resolution computed tomography (HRCT) in patients identified as having progressive pulmonary fibrosis (PPF) has not been established. We investigated whether HRCT patterns and quantitative scores were associated with risk of progression in patients with PPF.

METHODS: Patients enrolled in the ILD-PRO Registry had an interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis, reticular abnormality and traction bronchiectasis, and met criteria for ILD progression. HRCT images taken between 24 months prior to enrollment and 90 days after enrollment were analyzed using a machine learning algorithm to derive quantitative scores. Associations were assessed between HRCT pattern (usual interstitial pneumonia [UIP]-like versus other patterns) and tertiles of quantitative scores and measures of disease severity at enrollment, and between these patterns/tertiles at enrollment and ILD progression (relative decline in forced vital capacity [FVC] % predicted ≥ 10%, lung transplant, or death) over a median follow-up of 17.3 months.

RESULTS: Among 395 patients, 178 (45.1%) had a UIP-like pattern on HRCT. A UIP-like pattern did not associate with worse disease severity at enrollment or an increased risk of ILD progression (HR 1.01 [95% CI: 0.71, 1.44]). The highest quantitative lung fibrosis (QLF) score tertile (≥ 20.5%) was associated with worse disease severity. In unadjusted analyses, patients with QLF scores in the highest tertile had a significantly increased risk of ILD progression versus the middle tertile (HR [95% CI] 1.63 [1.07, 2.49] and a numerically increased risk versus the lowest tertile (HR 1.46 [0.97, 2.18]); however, after adjustment for sex, age, FVC % predicted and oxygen use at enrollment, there were no significant differences. There were no significant associations between tertiles of quantitative ILD score, quantitative ground glass score, or quantitative honeycomb cysts score and risk of ILD progression in unadjusted or adjusted analyses.

CONCLUSIONS: In a real-world cohort of patients with PPF, QLF score associated with subsequent risk of ILD progression, while HRCT pattern did not. The QLF score did not provide additional prognostic information beyond clinical variables.

TRIAL REGISTRATION: ClinicalTrials.gov; No: NCT01915511; registered August 5, 2013; URL: www.

CLINICALTRIALS: gov .

PMID:40022059 | DOI:10.1186/s12931-025-03136-6

BMC Pulm Med. 2025 Feb 28;25(1):98. doi: 10.1186/s12890-025-03555-7.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, irreversible, and fatal disease characterized by progressive interstitial lung fibrosis. Given its insidious onset and poor outcome, there is an urgent need to elucidate the molecular mechanisms underlying IPF and identify effective therapeutic targets and diagnosis and prognosis biomarkers. Ferroptosis is an iron-dependent form of programmed cell death that occurs as lipid peroxides accumulate. Growing evidence suggests that ferroptosis is important in IPF.

METHODS: Human ferroptosis PCR array was performed on IPF and control lung tissue. The differentially expressed ferroptosis-related genes (DE-FRGs) were identified, underwent functional enrichment analyses, protein-protein interaction network construction, and potential drug target prediction. The DE-FRGs were validated and their value as diagnostic and prognostic blood biomarkers were evaluated using the Gene Expression Omnibus dataset GSE28042.

RESULTS: The array identified 13 DE-FRGs. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that the DE-FRGs were mainly related to iron ion transport, blood microparticles, and oxidoreductase activity, and were involved in porphyrin metabolism, necroptosis, and the p53 signaling pathway in addition to ferroptosis. The 13 DE-FRGs were analyzed using the Drug-Gene Interaction Database to explore novel IPF therapeutic agents, yielding 42 potential drugs. Four DE-FRGs (BBC3, STEAP3, EPRS, SLC39A8) in the peripheral blood of IPF patients from the GSE28042 dataset demonstrated the same expression pattern as that observed in the lung tissue array. The receiver operating characteristic analysis demonstrated that the area under the curve of STEAP3 and EPRS were > 0.75. The survival analysis demonstrated that STEAP3 and EPRS were significantly different between the IPF and control groups.

CONCLUSIONS: The FRG expression profiles in IPF and control lung tissue were characterized. The findings provided valuable ideas to elucidate the role of ferroptosis in IPF and aided the identification of novel IPF therapeutic targets and biomarkers.

PMID:40022042 | DOI:10.1186/s12890-025-03555-7

Chest. 2025 Feb 26:S0012-3692(25)00267-3. doi: 10.1016/j.chest.2025.02.018. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease associated with lung function decline and high mortality.

RESEARCH QUESTION: What are the associations between thresholds of lung function decline and the risk of mortality in patients with IPF?

STUDY DESIGN AND METHODS: The Idiopathic Pulmonary Fibrosis-Prospective Outcomes Registry enrolled patients with IPF that was diagnosed or confirmed at the enrolling center within the prior 6 months. Associations between time to first decline in FVC or diffusing capacity of the lungs for carbon monoxide (Dlco) of ≥ 2% predicted, ≥ 5% predicted, and ≥ 10% predicted (and ≥ 15% predicted for Dlco) and risk of subsequent death or lung transplant was assessed using Cox proportional hazards models with a time-dependent covariate. Models were unadjusted or adjusted for FVC and Dlco % predicted, age, sex, smoking status, BMI, antifibrotic treatment (yes or no), and oxygen use at enrollment.

RESULTS: Among 1,001 patients, median follow-up time was 38.4 months. Significant associations were observed between all thresholds of decline in FVC and Dlco % predicted and the risk of death or lung transplant in unadjusted and adjusted analyses. In adjusted analyses, absolute declines in FVC of ≥ 2% predicted, ≥ 5% predicted, and ≥ 10% predicted were associated with 1.8-fold, 2.3-fold, and 2.7-fold increases in the risk of subsequent death or lung transplant, whereas absolute declines in Dlco of ≥ 2% predicted, ≥ 5% predicted, ≥ 10% predicted, and ≥ 15% predicted were associated with 2.0-fold, 1.4-fold, 1.5-fold, and 1.9-fold increases in the risk of subsequent death or lung transplantation, respectively. For Dlco, but not FVC, the increase in risk generally was greater for patients meeting a threshold based on a relative rather than an absolute decline.

INTERPRETATION: Even small declines in FVC and Dlco % predicted inform prognosis in patients with IPF.

PMID:40020995 | DOI:10.1016/j.chest.2025.02.018

Chem Biomed Imaging. 2025 Jan 17;3(2):85-94. doi: 10.1021/cbmi.4c00065. eCollection 2025 Feb 24.

ABSTRACT

Disease-recapitulating animal models are valuable tools in preclinical development for the study of compounds. In the case of fibrotic pulmonary diseases such as idiopathic pulmonary fibrosis (IPF), the bleomycin model of lung injury in the mouse is widely used. To evaluate bleomycin-induced changes in the lung, we employed a quantitative, multimodal approach. Using in vivo microcomputed tomography (μCT), we demonstrated radiographic changes associated with disease progression in aeration levels of the lung parenchyma. There exists an unmet need for a quantitative, high-resolution imaging probe to detect pulmonary fibrosis, particularly that can differentiate between inflammatory and fibrotic components of the disease. Matrix remodeling and overexpression of extracellular matrix (ECM) proteins such as collagen and fibronectin are hallmarks of organ fibrosis. A splice variant of fibronectin containing extra domain A (FnEDA) is of particular interest in fibrosis due to its high level of expression in diseased tissue, which is confirmed here using immunohistochemistry (IHC) in mouse and human lungs. An antibody against FnEDA was evaluated for use as an imaging tool, particularly by using in vivo single-photon emission computed tomography (SPECT) and ex vivo near-infrared (NIR) fluorescence imaging. These data were further corroborated with histological tissue staining and fibrosis quantitation based on a Modified Ashcroft (MA) score and a digital image analysis of whole slide lung tissue sections. The fusion of these different approaches represents a robust integrated workflow combining anatomical and molecular imaging technologies to enable the visualization and quantitation of disease activity and treatment response with an inhibitor of the TGFβ signaling pathway.

PMID:40018646 | PMC:PMC11863149 | DOI:10.1021/cbmi.4c00065