J Clin Invest. 2025 Jun 3:e191107. doi: 10.1172/JCI191107. Online ahead of print.

ABSTRACT

BACKGROUND: Telomere biology disorders (TBDs) exhibit incomplete penetrance and variable expressivity, even among individuals harboring the same pathogenic variant. We assessed whether common genetic variants associated with telomere length combine with large-effect variants to impact penetrance and expressivity in TBDs.

METHODS: We constructed polygenic scores (PGS) for telomere length in the UK Biobank to quantify common variant burden, and assessed the PGS distribution across patient cohorts and biobanks to determine whether individuals with severe TBD presentations have increased polygenic burden causing short telomeres. We also characterized rare TBD variant carriers in the UK Biobank.

RESULTS: Individuals with TBDs in cohorts enriched for severe pediatric presentations have polygenic scores predictive of short telomeres. In the UK Biobank, we identify carriers of pathogenic TBD variants who are enriched for adult-onset manifestations of TBDs. Unlike individuals in disease cohorts, the PGS of adult carriers do not show a common variant burden for shorter telomeres, consistent with the absence of childhood-onset disease. Notably, TBD variant carriers are enriched for idiopathic pulmonary fibrosis diagnoses, and telomere length PGS stratifies pulmonary fibrosis risk. Finally, common variants affecting telomere length were enriched in enhancers regulating known TBD genes.

CONCLUSION: Common genetic variants combine with large-effect causal variants to impact clinical manifestations in rare TBDs. These findings offer a framework for understanding phenotypic variability in other presumed monogenic disorders.

FUNDING: This work was supported by National Institutes of Health grants R01DK103794, R01HL146500, R01CA265726, R01CA292941, and the Howard Hughes Medical Institute.

PMID:40459934 | DOI:10.1172/JCI191107

Mol Imaging Radionucl Ther. 2025 Jun 3;34(2):143-145. doi: 10.4274/mirt.galenos.2024.60320.

ABSTRACT

Integrins play crucial roles in the migration of tumor cells during angiogenesis and metastasis. Consequently, αvβ6-integrin-targeted positron emission tomography (PET) radiopharmaceuticals have been developed and tested in humans, with clinical trials highlighting their applications in idiopathic pulmonary fibrosis and carcinomas. However, data on integrins are limited, and the role of [68Ga]Ga-Trivehexin tomography/computed tomography (CT) PET/CT is not well-established. Some studies have suggested that [68Ga]Ga-Trivehexin PET/CT is more specific than 18F-fluorodeoxyglucose (18F-FDG) PET/CT, which can yield false-positive results. It has been shown to be more efficient in evaluating pancreatic lesions and head and neck tumors. The role of [68Ga]Ga Trivehexin PET/CT in neuroendocrine tumors is not yet clearly defined. In our case, integrin was negative in the pancreatic neuroendocrine tumor but positive in the breast lobular tumor. Additionally, we observed that the lobular carcinoma lesion in the right breast is somatostatin receptor+positive on [68Ga]Ga-DOTATATE PET/CT.

PMID:40458979 | DOI:10.4274/mirt.galenos.2024.60320

Int J Pharm. 2025 May 31:125750. doi: 10.1016/j.ijpharm.2025.125750. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is characterized by symptoms such as shortness of breath, persistent dry cough, and hypoxemia. The disease can progress rapidly, often leading to respiratory failure. Given its complex and multifactorial nature, pulmonary fibrosis involves multiple pathological progress, such as inflammation, oxidative stress, and fibroblast activation. A single drug cannot effectively address pulmonary fibrosis through multiple mechanisms, but combining drugs maybe create a synergistic effect, target different aspects of the pathological process and improve treatment efficacy. In our previous study, bergenin can improve pulmonary fibrosis. Vitexin is reported to have anti-inflammatory, antioxidant, and anticancer properties, which maybe influence pathways associated with pulmonary fibrosis. Therefore, bergenin and vitexin were chosen for the combined treatment of pulmonary fibrosis. To improve the targeting ability and the affinity of lung fibroblasts, mouse lung fibroblasts-derived exosomes are used as the carriers for drugs. In this study, exosomes loaded with bergenin and vitexin (Exo-Ber + Vit) were successfully prepared using ultracentrifugation and ultrasonication, with an average particle size of approximately 180 nm. Wound-healing assay showed that Exo-Ber + Vit significantly inhibited the excessive proliferation of TGF-β1 induced Mlg and NIH-3 T3 cells compared with bergenin and vitexin alone. Cell uptake experiments showed that exosomes enhanced the uptake of coumarin 6 in Mlg and 3 T3 cells. In vivo studies, compared to bergenin-loaded exosomes, vitexin-loaded exosomes, and the combination of bergenin and vitexin, Exo-Ber + Vit demonstrated superior effects in reducing pulmonary fibrosis area, collagen deposition, and improving lung function. In conclusion, the co-delivery strategy of bergenin and vitexin via Mlg-derived exosomes offers a promising new approach to the treatment of IPF.

PMID:40456424 | DOI:10.1016/j.ijpharm.2025.125750

Rheumatology (Oxford). 2025 Jun 2:keaf299. doi: 10.1093/rheumatology/keaf299. Online ahead of print.

ABSTRACT

OBJECTIVE: Interstitial pneumonia with autoimmune features (IPAF) describes patients with interstitial lung disease (ILD) and autoimmune features without meeting criteria for a specific rheumatic disease. No longitudinal data exist on post-transplant outcomes in IPAF patients. We compared baseline demographics, pre-transplant characteristics, and post-transplant outcomes between IPAF and idiopathic pulmonary fibrosis (IPF) patients undergoing double lung transplantation.

METHODS: We retrospectively analyzed lung transplant recipients with ILD in British Columbia between Jan 1, 2014, and Apr 30, 2024. Diagnoses of IPAF and IPF were made by multidisciplinary review. Continuous variables were analyzed using the Mann-Whitney U test, categorical variables with Fisher's Exact test, and survival using Kaplan-Meier analysis.

RESULTS: We identified 20 IPAF and 64 IPF patients. IPAF patients were more likely female (50% vs 17%, p = 0.006), on pre-transplant immunosuppression (60% vs 6.3%, p < 0.001), and were less likely to receive antifibrotics (20% vs 64%, p < 0.001). No difference was seen in 1-year or cumulative survival, though survival curves diverged over time favouring IPAF. Post-transplant lung function, acute rejection, infection-related hospitalization, malignancy, and chronic lung allograft dysfunction (CLAD) were similar, with non-usual interstitial pneumonia (UIP) IPAF exhibiting a survival advantage over IPF (100% vs 66%, p = 0.044). Explant pathology revealed more UIP patterns in IPF, while IPAF showed nonspecific interstitial pneumonia (NSIP) or unclassifiable patterns.

CONCLUSIONS: Post-transplant survival, lung function, and complication rates were comparable between IPAF and IPF patients at one year and the last follow-up. This is the first study to report both short- and long-term lung transplant outcomes in IPAF patients.

PMID:40455051 | DOI:10.1093/rheumatology/keaf299

J Clin Invest. 2025 Jun 2;135(11):e184158. doi: 10.1172/JCI184158. eCollection 2025 Jun 2.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease characterized by the excessive accumulation of activated myofibroblasts that deposit extracellular matrix (ECM) protein, leading to progressive scar formation and mechanical stress. However, the cellular origin and fate of myofibroblasts remain controversial, and the mechanisms by which myofibroblasts sense mechanical cues in the lung are unclear. Here, we report that periostin (Postn) is a reliable and distinctive marker for pulmonary myofibroblasts, while ablation of Postn+ myofibroblasts after injury ameliorated lung fibrosis. PIEZO1 was highly expressed in Postn+ myofibroblast and played a vital role in mechanoactivation of Postn+ myofibroblast and development of lung fibrosis. Conditional deletion of Piezo1 in Postn+ myofibroblasts significantly inhibited lung fibrosis by suppressing myofibroblast activation and proliferation. Loss of Piezo1 led to disruption of actin organization and prevention of Yap/Taz nuclear localization, thus shifting the myofibroblasts from a proliferative state into a stressed and apoptotic state. Furthermore, myofibroblast-specific Yap/Taz deletion fully recapitulated the protective phenotypes of myofibroblast-Piezo1-KO mice. These findings show that periostin marks pulmonary myofibroblasts, and that PIEZO1-mediated mechanosensation is essential for myofibroblast activation in the lung. Targeting PIEZO1 in the periostin-expressing cells is a novel therapeutic option to interfere with fibrotic diseases such as IPF .

PMID:40454481 | DOI:10.1172/JCI184158

Int J Pharm. 2025 May 30:125789. doi: 10.1016/j.ijpharm.2025.125789. Online ahead of print.

ABSTRACT

Integrating artificial intelligence (AI) into drug discovery has revolutionized pharmaceutical innovation, addressing the challenges of traditional methods that are costly, time-consuming, and suffer from high failure rates. By utilizing machine learning (ML), deep learning (DL), and natural language processing (NLP), AI enhances various stages of drug development, including target identification, lead optimization, de novo drug design, and drug repurposing. AI tools, such as AlphaFold for protein structure prediction and AtomNet for structure-based drug design, have significantly accelerated the discovery process, improved efficiency and reduced costs. Success stories like Insilico Medicine's AI-designed molecule for idiopathic pulmonary fibrosis and BenevolentAI's identification of baricitinib for COVID-19 highlight AI's transformative potential. Additionally, AI enables the exploration of vast chemical spaces, optimization of clinical trials, and the identification of novel therapeutic targets, paving the way for precision medicine. However, challenges such as limited data accessibility, integration of diverse datasets, interpretability of AI models, and ethical concerns remain critical hurdles. Overcoming these limitations through enhanced algorithms, standardized databases, and interdisciplinary collaboration is essential. Overall, AI continues to reshape drug discovery, reducing timelines, increasing success rates, and driving the development of innovative and accessible therapies for unmet medical needs.

PMID:40451590 | DOI:10.1016/j.ijpharm.2025.125789

J Evid Based Med. 2025 Jun;18(2):e70035. doi: 10.1111/jebm.70035.

ABSTRACT

OBJECTIVES: To evaluate the relationship between socioeconomic status (SES), lifestyle factors, and their combined impact on chronic respiratory diseases (CRDs).

METHODS: Participants were from the UK Biobank and were categorized into SES groups using latent class analysis based on family income, education, and employment status. Lifestyle factors were assessed via 24-hour dietary recalls and structured questionnaires. Each criterion scored 1 (healthy) or 0 (unhealthy), creating a total score from 0 to 4. Multivariable Cox proportional hazards models, interaction analyses, and mediation analyses were conducted.

RESULTS: Among 296,731 participants, 12,128 (4.1%) participants were diagnosed with CRDs. Among low SES groups, healthy lifestyle groups with scores 2, 1, and 0 showed significantly increased hazard ratios of 1.32 (95% CI: 1.21-1.44), 1.77 (95% CI: 1.63-1.93) and 2.36 (95% CI: 2.15-2.60) compared with the healthy lifestyle scores ≥3. The combined effect of SES and healthy lifestyle increased the risk of CRDs by 15% over the risk expected from simply adding their respective effects. The proportion of SES on CRDs incidence mediated by healthy lifestyle factors was statistically significant (p < 0.001), accounting for about 2%.

CONCLUSIONS: The risk of incident CRDs in the low SES population with an unhealthy lifestyle increased by 32%-136%. Unhealthy lifestyles significantly affect the incidence of CRDs in different SES subgroups. About 2% of the risk between SES and incident CRDs was mediated by lifestyle factors. These findings highlight the importance of addressing socioeconomic disparities and unhealthy lifestyle behaviors in public health strategies aimed at preventing CRDs.

PMID:40450702 | DOI:10.1111/jebm.70035

J Ethnopharmacol. 2025 May 30:120071. doi: 10.1016/j.jep.2025.120071. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Qingfeiyin decoction (QFY), a well-documented traditional Chinese medicine formula, is used to treat a variety of lung diseases. However, the effect of QFY on idiopathic pulmonary fibrosis (IPF) is still unclear.

AIM OF THE STUDY: This study aimed to investigate the effect of QFY on IPF, identify its bioactive components, and reveal the possible mechanism.

MATERIALS AND METHODS: A bleomycin-induced pulmonary fibrosis mouse model was established to evaluate the anti-IPF effects of QFY. The bioactive ingredients in QFY were identified by HPLC-MS, following which their in vitro effects were examined by the cell models of epithelial-to-mesenchymal transition, fibroblast-to-myofibroblast transition and macrophage polarization. Network pharmacology and clinical dataset (GSE110147) were integrated to predict the possible mechanism of the bioactive ingredients, which were verified by in vitro experiments, molecular docking and molecular dynamics simulation.

RESULTS: QFY demonstrated dose-dependent amelioration of IPF pathological phenotypes. Oroxylin A (OA), Geniposide (GDS), Baicalin (BCL), and Genipin-1-gentiobioside (GG) were identified with significant lung tissue enrichment, where OA and BCL exhibited obvious improvement in EMT, FMT, and macrophage polarization experiments. Network pharmacology and bioinformatics analyses revealed the association of OA/GDS/BCL/GG with the PI3K-AKT signaling pathway, which were confirmed by their effects on the migration and apoptosis of A549 and HFL1 cells. Concurrently, molecular docking and molecular dynamics simulations demonstrated strong binding affinities of BCL and OA for p110α and p110γ subunits of PI3K.

CONCLUSIONS: Our work demonstrates the potential of QFY in the treatment of IPF, which might due to the bioactive ingredients in the lung affecting the PI3K signaling pathway.

PMID:40451494 | DOI:10.1016/j.jep.2025.120071

Respir Med. 2025 May 29:108185. doi: 10.1016/j.rmed.2025.108185. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Comorbid depression in idiopathic pulmonary fibrosis (IPF) has been linked to reduced quality of life and worsened symptoms. However, the incidence of depression and its association with mortality in IPF, based on large-scale epidemiological data, remains unclear. This study investigated the clinical significance of depression in patients with IPF using the National Database of Health Insurance Claims and Specific Health Checkups of Japan.

METHODS: We analysed data from 31,386 patients with IPF. The prevalence of depression at IPF diagnosis, its post-diagnosis incidence rates and its associations with mortality and anti-fibrotic therapy were evaluated using propensity score matching, landmark analysis and a Cox model with time-dependent covariates.

RESULTS: The prevalence of depression at IPF diagnosis was 6.7% and the annual incidence rate post-diagnosis was 32.4 cases per 1,000 person-years. Pre-existing depression was not associated with mortality (hazard ratio [HR] 0.978; 95% confidence interval [CI] 0.887-1.080). Conversely, depression developing post-IPF diagnosis significantly increased the mortality risk (HR 2.71; 95% CI 2.55-2.87). While pre-existing depression was not associated with the cumulative initiation rate of anti-fibrotic therapy, depression developing post-IPF diagnosis was associated with a lower cumulative initiation rate.

CONCLUSIONS: Depression arising after an IPF diagnosis was associated with both a lower cumulative initiation rate of anti-fibrotic therapy and increased mortality, emphasising the need for the early detection and management of mental health issues in patients with IPF. Given the high incidence of depression post-IPF diagnosis, integrating mental health care into comprehensive management strategies is crucial for improving patient outcomes.

PMID:40449566 | DOI:10.1016/j.rmed.2025.108185

Int Immunopharmacol. 2025 May 30;160:114971. doi: 10.1016/j.intimp.2025.114971. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Pulmonary fibrosis, a pathological process where the extracellular matrix overly deposits in lung tissue because of various pathogenic factors, leads to lung structure damage and function decline. Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and high mortality, lacking effective drug treatments. Mefunidone (MFD), a new small-molecule compound, showed therapeutic effects on it in previous studies, but its specific molecular target is unknown. This study aims to clarify MFD's target and its potential mechanism. By exploring this, we hope to offer new insights and potential solutions for treating IPF and improving patients' outcomes.

METHODS: Mice with pulmonary fibrosis induced by bleomycin (BLM) were used as experimental models. MFD was administered by gavage. The changes in inflammation and fibrosis were evaluated through histopathological examinations. Subsequently, single-cell sequencing technology was used to explore how MFD affects the phenotype of pro-fibrotic macrophages, and verification was carried out in vitro to prove that MFD treats pulmonary fibrosis by influencing the phenotype of pro-fibrotic macrophages.

RESULT: MFD can inhibit the generation of succinate by binding and inhibiting the activity of succinate dehydrogenase (SDH). MFD can also inhibit the transformation of MMP12+CCL2+ profibrotic macrophages in the BLM pulmonary fibrosis model. Treatment with succinate can induce the transformation of macrophages into MMP12+CCL2+ profibrotic macrophages, and this induction depends on the succinate-specific receptor GPR91.

CONCLUSION: Our research results have revealed for the first time that MFD can treat pulmonary fibrosis by targeting SDH and regulating the transformation of MMP12+CCL2+ profibrotic macrophages.

PMID:40449267 | DOI:10.1016/j.intimp.2025.114971

Arch Bronconeumol. 2025 May 15:S0300-2896(25)00175-9. doi: 10.1016/j.arbres.2025.05.001. Online ahead of print.

NO ABSTRACT

PMID:40447522 | DOI:10.1016/j.arbres.2025.05.001

PLoS One. 2025 May 30;20(5):e0323784. doi: 10.1371/journal.pone.0323784. eCollection 2025.

ABSTRACT

BACKGROUND: This study evaluated the role of blood Krebs von den Lungen-6 (KL-6) in predicting acute exacerbation (AE) in patients with idiopathic pulmonary fibrosis (IPF).

METHODS: From April 2018 to March 2023, clinical data of 233 IPF patients with baseline and follow-up KL-6 values at Haeundae Paik Hospital were retrospectively analyzed. AE was defined following the criteria proposed by Collard et al. in 2016.

RESULTS: The mean age was 71.8 years; 79% were male. During follow-up (median: 18.7 months), 33 (14.2%) patients experienced AE. Throughout the entire period from baseline, KL-6 values were higher in the AE group compared to the non-AE group (P < 0.001), and the patterns of change over time also showed significant differences between both groups (P < 0.001). The KL-6 values in the post-exacerbation phase were higher than those in the pre-exacerbation phase among the AE group (P = 0.004). The AE group showed lower 1-year (86.4% vs. 95.9%) and 3-year (50.2% vs. 91.4%) survival rates compared to the non-AE group (P < 0.001). The occurrence of AE (hazard ratio (HR) 74.09, 95% confidence interval (CI) 31.97-171.7, P < 0.001) and higher lactate dehydrogenase (HR 1.02, 95% CI: 1.01-1.02, P < 0.001) were independently associated with mortality in patients with IPF.

CONCLUSIONS: Our data suggest that the trend in changes in KL-6 values may be utilized as a tool for predicting AE-IPF. Further research is needed to establish the clinical significance of changes in KL-6 for predicting AE-IPF and to validate the cut-off values for prediction.

PMID:40446067 | DOI:10.1371/journal.pone.0323784

Adv Sci (Weinh). 2025 May 30:e01956. doi: 10.1002/advs.202501956. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a prototype of chronic, progressive, and fibrotic lung disease. While advancing age is recognized as the most significant risk factor for both the development and mortality associated with pulmonary fibrosis, precise mechanisms underlying this association remain elusive. Here, Nephronectin (NPNT) is identified as an antiaging molecule, a potential major regulator of the progression of pulmonary fibrosis. In IPF patients, a marked reduction in NPNT expression is detected in lung tissues, which correlated with a decline in lung function. The study reveals that NPNT deficiency exacerbates bleomycin-induced senescence in alveolar epithelial cells, potentially intensifying fibrosis severity due to diminishes extracellular matrix turnover. Conversely, NPNT overexpression in the alveolar epithelium improves lung respiratory function and enhances resistance to aging and fibrosis. Mechanistically, NPNT inhibits the hyperactivation of LATS1 and MOB1, facilitates YAP1 nuclear translocation, and suppresses YAP1 ubiquitination and degradation, contingent upon the interaction between NPNT and ITGA3. Notably, pharmacological elevation of NPNT protein levels using Escin has been shown to alleviate pulmonary fibrosis and improve lung function in mice. The findings shed light on the key mechanism underlying stress-induced senescence and fibrosis, and offer a promising framework for interventions targeting aging-related diseases.

PMID:40444575 | DOI:10.1002/advs.202501956

Ther Adv Respir Dis. 2025 Jan-Dec;19:17534666251342661. doi: 10.1177/17534666251342661. Epub 2025 May 30.

ABSTRACT

BACKGROUND: Non-idiopathic pulmonary fibrosis interstitial lung diseases (non-IPF ILDs) comprise a broad spectrum of pathologies with varying degrees of inflammation and fibrosis. Progressive fibrosing ILD is associated with significant mortality and limited treatment options. Standard regimens employ multimodal immunosuppression, most commonly prolonged courses of oral corticosteroids (OCS), that are associated with a high risk of adverse effects and limited proven efficacy.

OBJECTIVES: This study investigates the safety, tolerability, and effectiveness of monthly intravenous pulse methylprednisolone (PMP) for the treatment of patients with progressive non-IPF ILD.

DESIGN: Retrospective single-center cohort study of patients at an academic tertiary referral center for ILD between October 2019 and September 2022.

METHODS: All non-IPF ILD patients who received intravenous PMP (1000 mg daily for three consecutive days/month) between October 2019 and September 2022 were included. The decision to treat was based on a multidisciplinary consensus diagnosis following ATS/ERS/JRS/ALAT guidelines and confirmed or at high risk for ILD progression. Treatment continuation was contingent upon pulmonary function test (PFT) improvement (assessed approximately every 3 months), tolerable adverse events, and shared decision making with patients. Effectiveness was measured by a change in forced vital capacity (FVC) and diffusion limit of carbon monoxide (DLCO), with improvement being defined as an absolute increase in either FVC >5% or DLCO >10% from baseline.

RESULTS: Thirty-three patients received PMP at our center. One patient died of an acute exacerbation of ILD. Of the 32 patients included for analysis, 17 (53%) exhibited improved lung function with PMP between PFTs, which was maintained for a median follow-up of 209 days. The regimen was generally well-tolerated, with the most common adverse effects being insomnia and restlessness on infusion days. Advanced disease, indicated by lower FVC, traction bronchiectasis, and oxygen dependence, predicted poor response.

CONCLUSIONS: PMP may offer a safer, better-tolerated, and more effective treatment for progressive non-IPF ILD than prolonged OCS. Notably, a third of fibrotic hypersensitivity pneumonitis patients showed improved FVC after 3 months of PMP, defying expectations of steroid non-responsiveness. However, further well-designed controlled prospective clinical trials are needed to confirm our findings and establish long-term safety.

PMID:40444328 | DOI:10.1177/17534666251342661

Tuberc Respir Dis (Seoul). 2025 May 30. doi: 10.4046/trd.2025.0044. Online ahead of print.

ABSTRACT

Interstitial lung disease (ILD) comprises a heterogeneous group of disorders characterized by interstitial compartment proliferation, inflammatory infiltration, and potential fibrosis with abnormal collagen deposition. Diagnosis requires a multidisciplinary consensus integrating clinical, radiological, and pathological findings. Idiopathic interstitial pneumonia (IIP) includes idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP), acute interstitial pneumonia (AIP), and respiratory bronchiolitis-ILD (RB-ILD), each exhibiting distinct prognostic and therapeutic implications. Some non-IPF ILDs progress despite standard treatment, classified as progressive fibrosing interstitial lung disease (PF-ILD) or progressive pulmonary fibrosis (PPF), diagnosed by worsening symptoms, physiological decline, and radiological progression. Nintedanib is conditionally recommended for refractory PPF cases. Combined pulmonary fibrosis and emphysema (CPFE) is characterized by upper-lobe predominant emphysema and lower-lobe fibrosis, frequently complicated by pulmonary hypertension and lung cancer. Interstitial lung abnormality (ILA), observed in both smokers and the general population, is associated with increased mortality and disease risk, warranting further research. Despite advancements, refinement in classification, diagnostic criteria, and therapeutic strategies remains crucial for improving patient outcomes.

PMID:40443216 | DOI:10.4046/trd.2025.0044

BMC Pulm Med. 2025 May 29;25(1):271. doi: 10.1186/s12890-025-03736-4.

ABSTRACT

BACKGROUND: Patients with anti-neutrophil cytoplasmic antibody (ANCA)-positive interstitial lung disease (ILD) but without evidence of systemic vasculitis have been reported in studies and are classified as isolated ANCA-positive idiopathic interstitial pneumonia (IIP). However, the clinical significance of ANCA, particularly myeloperoxidase (MPO) -ANCA in IIP remains poorly understood. This study aims to investigate the differences between ANCA-positive and ANCA-negative IIP patients and further explore the impact of MPO-ANCA on clinical manifestations and prognostic outcomes.

METHODS: We reviewed 408 ILD patients with available ANCA results from January 2012 to September 2021. 61 patients diagnosed with microscopic polyangiitis-associated ILD were not included in the analysis. A comparative analysis was performed between 61 isolated ANCA-positive IIP patients (ANCA-IIP group) and 286 ANCA-negative IIP patients (IIP group). We further conducted subgroup analyses based on the status of MPO-ANCA.

RESULTS: Baseline clinical characteristics, pulmonary function tests, radiological features and all-cause mortality were similar between ANCA-IIP and IIP groups. When comparing the MPO-ANCA-IIP group with the IIP group and the non-MPO-ANCA-IIP group separately, a higher proportion of fibrotic features was observed on imaging (P = 0.004 vs IIP group; P = 0.031 vs non-MPO-ANCA-IIP group). After one year of treatment, the MPO-ANCA-IIP group showed a significantly greater decline in pulmonary function parameters compared to both the IIP group and the non-MPO-ANCA-IIP group. The frequency of pulmonary function decline was significantly higher in the MPO-ANCA-IIP group compared to the non-MPO-ANCA-IIP group (P = 0.026). Additionally, MPO-ANCA was not found to be statistically associated with mortality among patients with IIP.

CONCLUSION: ANCA-IIP patients had similar clinical characteristics and prognoses with IIP patients. MPO-ANCA-IIP patients had more prominent fibrosis on imaging and a greater decline in pulmonary function following treatment. Special attention should be paid to MPO-ANCA positivity during the diagnosis and treatment of IIP patients.

TRIAL REGISTRATION: ClinicalTrials.gov: NCT04413149, May 2020.

PMID:40442650 | DOI:10.1186/s12890-025-03736-4

Medicine (Baltimore). 2025 May 30;104(22):e42671. doi: 10.1097/MD.0000000000042671.

ABSTRACT

It has been demonstrated that bactericidal/permeability-increasing-fold-containing family B member 1 (BPIFB1) is highly expressed in idiopathic pulmonary fibrosis (IPF) and is linked to a dismal prognosis; nevertheless, its molecular role and connection to lung function in IPF are still unknown. The Gene Expression Omnibus database provided the data. Functional enrichment analyses, Kaplan-Meier, Cox regression, and the Pearson correlation coefficient were applied. Studies and single-cell ribonucleic acid sequencing research verified the impact of BPIFB1 on IPF. BPIFB1 was highly expressed in differentiating ciliated cells and MUC5B + cells, and single-cell sequencing and transcriptome analysis revealed that it was up-regulated in the lungs of IPF; however, blood BPIFB1 expression was similar in the control group and IPF. In addition, we identified 24 genes that interact with BPIFB1 and the top 5 transcription factors that target these genes as reported by the hTFtarget database. Clinical samples show that in the IPF, BPIFB1 is inversely correlated with lung function. According to bioinformatics analysis, elevated levels of BPIFB1 expression might be correlated with lung fibroblast differentiation and collagen synthesis. BPIFB1 may be a useful indicator of the prognosis and severity of the IPF. BPIFB1 may be associated with lung fibroblast differentiation and collagen production.

PMID:40441200 | DOI:10.1097/MD.0000000000042671

Expert Rev Respir Med. 2025 May 29. doi: 10.1080/17476348.2025.2513512. Online ahead of print.

ABSTRACT

BACKGROUND: Fibrosing Interstitial Lung Diseases (F-ILDs) lead to reduced exercise capacity and quality of life. Pulmonary Rehabilitation (PR) exercise programs have shown potential in improving symptoms and functional capacity in these patients. This study aimed to compare the effectiveness of different PR exercise approaches in patients with F-ILDs.

RESEARCH DESIGN AND METHODS: This randomized, three-arm controlled trial included F-ILD patients divided into three groups: hospital-based supervised(HGr), synchronized-online(SOGr) with live video calls, and video-based (VGr) with recorded exercise videos. All groups underwent an 8-week program combining aerobic and resistance training. Clinical parameters assessed included 6-minute walking distance(6MWD), modified medical research council dyspnea score(mMRC), respiratory function tests, Saint George Respiratory Questionnaire (SGRQ), International Physical Activity Questionnaire Short Form(IPAQ-SF), fatigue severity scale (FSS), and muscle strength.

RESULTS: Of the 75 patients, 65 completed the study, with comparable demographic and baseline characteristics. Significant improvements in 6MWD, mMRC, maximal inspiratory pressure, IPAQ-SF, SGRQ, and peripheral muscle strength were seen in all groups. Post-hoc analysis showed HGr had greater improvements in forced vital capacity and FSS compared to SOGr.

CONCLUSION: Hospital-based, synchronized-online, and video-based PR programs all improve clinical outcomes in patients with F-ILDs. However, supervised in-hospital PR yielded greater benefits in lung function and fatigue reduction compared to the online approaches.

CLINICALTRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT05166057.

PMID:40440705 | DOI:10.1080/17476348.2025.2513512

Stem Cells Int. 2025 May 21;2025:6324980. doi: 10.1155/sci/6324980. eCollection 2025.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a long-term, diffuse pulmonary parenchyma lesion that primarily affects middle-aged and older adults. It is characterized by pulmonary interstitial fibrosis of unknown cause. The death rate upon diagnosis is higher than that of many other cancer types. Mesenchymal stem cell (MSC) treatment of organ fibrosis is a hot topic in preclinical and clinical research because it effectively treats IPF. In recent years, decorin (DCN) has been regarded as a critical mediator for its anti-inflammatory and antifibrotic effects. The purpose of this study was to generate human umbilical cord MSCs (HUC-MSCs) that overexpress DCN and to investigate the safety, mechanism, and effectiveness of using these cells to cure pulmonary fibrosis caused by bleomycin (BLM). First, lentiviral (LV) particles carrying the therapeutic DCN gene (LV-DCN) and control LV particles were created and transfected using the plasmid vector GV208 to create a viral solution for infecting HUC-MSCs. These solutions were used to create a DCN overexpression cell line and an MSC-Con. cell line infected with the control lentivirus. Intratracheal injection of BLM was used to establish a rat model of pulmonary fibrosis. On the second day following modeling, different treatments were administered, and the body weight and survival status of the rats were noted. The relevant tests were performed on days 15 and 29 following modeling. The results demonstrated that the overexpression of DCN did not affect the properties of HUC-MSCs and that these cells were effective in treating IPF. MSC-Con. and MSC-DCN reduced systemic inflammation by reducing serum interleukin (IL) 1β. Both cell types successfully treated pulmonary fibrosis in rats, as demonstrated by hematoxylin and eosin (HE) and Masson staining. MSC-DCN showed better efficacy due to lower mortality, higher weight gain, less alveolar inflammation, and less fibrosis. The safety of venous transplantation with MSCs was established by HE staining of the heart, liver, spleen, and kidney, as well as serum lactate dehydrogenase (LDH), creatinine (CRE), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels. Immunohistochemical (IHC) staining of CD68 and CD206 in lung tissue and in vitro experiments on THP-1-induced M2 macrophage polarization and transforming growth factor-beta 1 (TGF-β1)-induced MRC-5 fibrosis indicated that MSC-DCN may mitigate lung inflammation by altering macrophage recruitment and polarization and inhibiting TGF-β1 expression to reduce fibrous hyperplasia and collagen deposition, thereby improving the treatment of BLM-induced IPF.

PMID:40438789 | PMC:PMC12119169 | DOI:10.1155/sci/6324980

Front Pharmacol. 2025 May 14;16:1524654. doi: 10.3389/fphar.2025.1524654. eCollection 2025.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is a chronic fibrotic interstitial lung disease (ILD) of unknown etiology, characterized by increasing incidence and intricate pathogenesis. Current FDA-approved drugs suffer from significant side effects and limited efficacy, highlighting the urgent need for innovative therapeutic agents for IPF. Natural products (NPs), with their multi-target and multifaceted properties, present promising candidates for new drug development. This review delineates the anti-fibrotic pathways and targets of various natural products based on the established pathological mechanisms of IPF. It encompasses over 20 compounds, including flavonoids, saponins, polyphenols, terpenoids, natural polysaccharides, cyclic peptides, deep-sea fungal alkaloids, and algal proteins, sourced from both terrestrial and marine environments. The review explores their potential roles in mitigating pulmonary fibrosis, such as inhibiting inflammatory responses, protecting against lipid peroxidation damage, suppressing mesenchymal cell activation and proliferation, inhibiting fibroblast migration, influencing the synthesis and secretion of pro-fibrotic factors, and regulating extracellular matrix (ECM) synthesis and degradation. Additionally, it covers various in vivo and in vitro disease models, methodologies for analyzing marker expression and signaling pathways, and identifies potential new therapeutic targets informed by the latest research on IPF pathogenesis, as well as challenges in bioavailability and clinical translation. This review aims to provide essential theoretical and technical insights for the advancement of novel anti-pulmonary fibrosis drugs.

PMID:40438605 | PMC:PMC12116445 | DOI:10.3389/fphar.2025.1524654