Ther Adv Respir Dis. 2025 Jan-Dec;19:17534666251346108. doi: 10.1177/17534666251346108. Epub 2025 Jun 24.

ABSTRACT

Pulmonary fibrosis (PF) is a progressive and fatal interstitial lung disease characterized by excessive extracellular matrix deposition and fibroblast activation. Current antifibrotic therapies, such as nintedanib and pirfenidone, slow disease progression but fail to halt fibrosis or significantly improve survival. Macrolides, a class of antibiotics with immunomodulatory and anti-inflammatory properties, have emerged as potential adjunctive therapies for PF. Preclinical studies demonstrate that macrolides attenuate fibrogenesis through multifaceted mechanisms: suppression of TGF-β/Smad and JNK/c-Jun signaling, inhibition of pro-fibrotic cytokine release, modulation of macrophage polarization toward antifibrotic M2 phenotypes, and induction of apoptosis in senescent cells. Clinically, macrolides have shown promise in reducing acute exacerbations in idiopathic pulmonary fibrosis (IPF), mitigating radiation pneumonitis, and attenuating post-infectious fibrotic changes. However, conflicting results from clinical trials and the absence of large-scale randomized studies highlight the need for further validation. This review evaluates the antifibrotic mechanisms and therapeutic potential of macrolides in PF, integrating preclinical and clinical evidence. We aim to inform future research directions by elucidating their role in modulating key pathways and addressing unresolved efficacy questions.

PMID:40554453 | DOI:10.1177/17534666251346108

Pharmacol Rev. 2025 May 28;77(4):100069. doi: 10.1016/j.pharmr.2025.100069. Online ahead of print.

ABSTRACT

Chronic respiratory diseases are an enormous burden on healthcare and the third ranked cause of death globally. There is now compelling evidence that acceleration of lung aging and associated cellular senescence is a key driving mechanism of several chronic lung diseases, particularly chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Senescent cells, arising from oxidative stress and unrepaired damage, can accumulate in the lung and develop a senescence-associated secretory phenotype, spreading senescence and resulting in disease progression. In addition, there is a reduction in normally protective antiaging molecules, such as sirtuins, in the lungs. The role of cellular senescence in chronic lung disease has driven interest in senotherapy that targets senescent cells as a novel approach to treating respiratory diseases, and includes repurposing of existing drugs or developing new therapies. Senomorphics, which prevent the development of senescence and inhibit senescence-associated secretory phenotype mediators, include inhibitors of phosphoinositide-3-kinase-mechanistic target of rapamycin signaling, novel antioxidants, and sirtuin activators. Senolytics remove senescent cells by inducing apoptosis and include inhibitors of antiapoptotic proteins, such as B-cell lymphoma-extra large, inhibitors of forkhead box O-4-p53 interaction, heat shock protein 90 inhibitors, and cardiac glycosides. Senotherapies have been effective in animal models of chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, and several clinical trials are currently underway. The safety of these treatments after long-term administration requires further study, but this could potentially to be a promising approach to treating chronic lung diseases. SIGNIFICANCE STATEMENT: Cellular senescence induced by oxidative stress is a key driving mechanism in chronic lung diseases, such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis and may account for disease progression. Senotherapies, including senomorphics that inhibit senescent cells and senolytics that eliminate them, are promising therapeutic approaches to these common diseases, either with repurposed drugs or several new drugs that are in development.

PMID:40554265 | DOI:10.1016/j.pharmr.2025.100069

ERJ Open Res. 2025 Jun 23;11(3):00738-2024. doi: 10.1183/23120541.00738-2024. eCollection 2025 May.

ABSTRACT

BACKGROUND: Prostasin is expressed in the lung epithelium where it regulates fluid and electrolyte balance via sodium channel proteolysis. We investigated whether circulating prostasin levels are associated with the presence and severity of idiopathic pulmonary fibrosis (IPF) and whether prostasin levels, or changes in them, are associated with mortality.

METHODS: Patients with IPF came from the IPF-PRO Registry. Controls without lung disease had a similar age/sex distribution. Prostasin was quantified in plasma taken at enrolment and, in the IPF cohort, ∼6 months post-enrolment, by immunoassay. Linear regression was used to compare prostasin levels at enrolment in patients with IPF versus controls and, in the IPF cohort, determine associations between prostasin level and lung function. Multivariable Cox proportional hazards models determined associations between prostasin level at enrolment and change in prostasin level over 6 months and respiratory death.

RESULTS: Prostasin level at enrolment was higher in patients with IPF (n=624) versus controls (n=100) (fold-difference 1.75; p<0.001). In the IPF cohort, the difference in disease severity per 1 standard deviation (sd) difference in prostasin was -3.85 for forced vital capacity % predicted and -4.24 for diffusing capacity of the lung for carbon monoxide % predicted (both p<0.001). The adjusted hazard ratio (HR) for respiratory death per 1 sd difference in prostasin at enrolment was 1.20 (95% CI 1.04-1.40, p=0.014, n=624). The adjusted HR for subsequent respiratory death per 1 sd difference in change in prostasin over 6 months was 1.33 (95% CI 1.01-1.74, p=0.041, n=290).

CONCLUSIONS: Circulating prostasin is an independent marker of mortality risk in patients with IPF.

PMID:40551789 | PMC:PMC12183712 | DOI:10.1183/23120541.00738-2024

ERJ Open Res. 2025 Jun 23;11(3):00981-2024. doi: 10.1183/23120541.00981-2024. eCollection 2025 May.

ABSTRACT

BACKGROUND: In this study, we combine proteomics with functional parameters and imaging to examine potential biomarkers that may identify patients at risk of developing persistent lung sequelae following coronavirus disease 2019 (COVID-19).

METHODS: We performed multiplex profiling of serum and collected clinical data from intensive care unit (ICU)-treated patients with COVID-19 (n=43) at 4 and 10 months post hospitalisation.

RESULTS: Four months post discharge, patients with COVID-19 demonstrated lower % predicted forced vital capacity (72.2% versus 113% (p<0.0001)) and % predicted forced expiratory volume in 1 s (74.5% versus 103% (p<0.0001)) compared with healthy controls. A persistent upregulation (versus healthy controls) of inflammatory and remodelling factors, including among others, Galectin-1 (Gal-1), C-X-C motif chemokine 13 (CXCL13), monocyte chemoattractant protein 3 (MCP-3) and matrix metalloproteinase 7 (MMP7), were observed. Patients with moderate to severe parenchymal involvement (>5% of lung tissue) on high-resolution computed tomography (HRCT) had higher levels of the proteins lysosomal associated membrane protein-3 (LAMP3) and MMP7 compared with patients with minor (<5%) or no findings on HRCT. Both proteins demonstrated consecutive associations to lung function and parenchymal involvement. Histological evaluation of LAMP3 in lung tissue confirmed LAMP3 localisation to alveolar type 2 cells in more preserved areas of the parenchyma. However, areas of remodelling were devoid of LAMP3 concurrent with the appearance of KRT5+ and KRT17+ basal cells.

CONCLUSION: Despite functional and radiological improvements following COVID-19, persistent upregulation of inflammation and remodelling factors were observed. Similarities in the expression of LAMP3 in COVID-19 and idiopathic pulmonary fibrosis may suggest it as a potential biomarker for chronic lung damage.

PMID:40551787 | PMC:PMC12183704 | DOI:10.1183/23120541.00981-2024

Transplantation. 2025 Jun 24. doi: 10.1097/TP.0000000000005419. Online ahead of print.

ABSTRACT

The human genome contains sequences of DNA enriched in cytosine-guanine dinucleotides known as CpG islands (CGIs). CGIs play a crucial role in gene regulation and expression, making them an important target for genetic therapies. In this article, hidden Markov models (HMMs) and adaptive window techniques (AWTs) were used to identify CGIs in MUC5B and DSP genes. Both genes are associated with idiopathic pulmonary fibrosis, a progressive pulmonary disease that leads to a lung transplant. The University of California, Santa Cruz Genome Browser was used to obtain the MUC5B and DSP gene sequences and predefined CGI locations. The HMM and AWT algorithms were developed using Python version 3.11.5, and the outcomes analyzed were sensitivity, specificity, computational memory, and runtime. Both HMM and AWT exhibited high specificity; however, HMM was more accurate than AWT for both genes, 99% versus 96%, respectively. The HMM sensitivity was higher for both MUC5B and DSP genes (87% and 88%) compared with only 58% for MUC5B and 57% for DSP with AWT. Regarding computational efficiency, AWT was faster and required less memory than HMM for both genes. By accurately detecting CpG-rich regions, HMM offers a powerful approach to understanding gene regulation mechanisms. This could pave the way for more precise therapeutic interventions, enabling targeted treatment strategies for a range of genetic disorders, including idiopathic pulmonary fibrosis, improving patient outcomes, and advancing personalized medicine.

PMID:40551300 | DOI:10.1097/TP.0000000000005419

Acta Pharmacol Sin. 2025 Jun 23. doi: 10.1038/s41401-025-01596-6. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease; however, effective clinical treatments for IPF are lacking. High serum amyloid A (SAA) expression in serum is closely related to the severity of pulmonary fibrosis, but the underlying mechanisms remain incompletely understood. This study found that the expression of endogenous SAA3 was significantly induced in mice with bleomycin-induced fibrosis. Saa3 deletion alleviated pulmonary fibrosis in mice. Additionally, recombinant IL-36α treatment aggravated fibrosis in bleomycin-induced Saa3-/- mice. Furthermore, SAA3 could induce the expression of IL-36α in macrophages through the NF-κB pathway and transcription factor Krűppel-like factor 6 (KLF6). Also, the Klf6 knockdown alleviated severe lung fibrosis after recombinant SAA3 treatment. In conclusion, our study suggested that SAA3 aggravated bleomycin-induced pulmonary fibrosis by inducing IL-36α expression in macrophages through the NF-κB-KLF6 pathway. It provides new theoretical bases and potential therapeutic targets for treating fibrosis-related diseases.

PMID:40550960 | DOI:10.1038/s41401-025-01596-6

JHLT Open. 2025 May 28;9:100291. doi: 10.1016/j.jhlto.2025.100291. eCollection 2025 Aug.

ABSTRACT

OBJECTIVE: Extracorporeal Membrane Oxygenation (ECMO) plays an important role in bridge-to-transplant, but the ideal bridging strategy is not well-defined for idiopathic pulmonary fibrosis (IPF), particularly in the setting of pulmonary hypertension (PH).

METHODS: We queried data from the Scientific Registry of Transplant Recipients database for adult lung transplant candidates with IPF who were bridged to lung transplant, either with venovenous (VV)-ECMO, venoarterial (VA)-ECMO, or mechanical ventilator (MV) alone. A subgroup analysis was performed on patients with moderate-severe PH (mean pulmonary artery pressure ≥ 40 mmHg).

RESULTS: During the period, 1485 patients were identified who met inclusion criteria: 653 on VV-ECMO, 234 on VA-ECMO, and 598 on MV. The competing risk analysis found that relative to VV-ECMO, both VA-ECMO and MV bridge were associated with lower rates of survival to transplant (HR 0.69 [0.57-0.84], p < 0.001; HR 0.39 [0.383-0.46], p < 0.001, respectively). Within the PH subgroup, there was no difference in survival to transplant between VV- and VA-ECMO (HR 1.01 [0.64-1.58]; p > 0.9), but patients bridged with ventilator had a lower waitlist survival rate HR 0.46 [0.27, 0.79]; p = 0.005) relative to VV-ECMO. There was no difference in long-term survival among the three bridging strategies, either in the complete cohort (p = 0.52) or the PH cohort (p = 0.84).

CONCLUSIONS: Even in the presence of severe PH, VA- and VV-ECMO were both effective in bridging IPF patients to lung transplant, and VV-ECMO can be an initial setup for bridging. Conversion to VA ECMO may be considered early when there is a sign of right ventricular dysfunction.

PMID:40546420 | PMC:PMC12182311 | DOI:10.1016/j.jhlto.2025.100291

Aging Cell. 2025 Jun 22:e70141. doi: 10.1111/acel.70141. Online ahead of print.

ABSTRACT

The accumulation of senescent cells (SEN) with aging produces a chronic inflammatory state that accelerates age-related diseases. Eliminating SEN has been shown to delay, prevent, and in some cases reverse aging in animal disease models and extend lifespan. There is thus an unmet clinical need to identify and target SEN while sparing healthy cells. Here, we show that Lysosomal-Associated Membrane Protein 1 (LAMP1) is a membrane-specific biomarker of cellular senescence. We have validated selective LAMP1 upregulation in SEN in human and mouse cells. Lamp1+ cells express high levels of the prototypical senescence markers p16, p21, Glb1, and have low Lmnb1 expression as compared to Lamp1- cells. The percentage of Lamp1+ cells is increased with age and in mice with fibrotic lungs due to bleomycin (BLM) instillation. The RNA-Sequencing analysis of the Lamp1-enriched populations in sham and BLM mice lung tissue revealed enrichment of several senescence-related genes in both groups when compared to the SenMayo gene set derived from transcriptomic profiling of senescence markers in Mayo Clinic research datasets. Finally, we use a dual antibody-drug conjugate (ADC) strategy to eliminate SEN in cell culture assay.

PMID:40545776 | DOI:10.1111/acel.70141

Autoimmun Rev. 2025 Jun 20:103856. doi: 10.1016/j.autrev.2025.103856. Online ahead of print.

ABSTRACT

BACKGROUND: Currently, no tools can monitor ongoing fibrotic activity properly, making early identification of and timely therapeutic intervention with antifibrotics in patients with progressive fibrosing interstitial lung disease (ILD) difficult. Fibroblast activation protein-α inhibitor (FAPI) radiotracers could address these challenges.

OBJECTIVE: This review examines the association between pulmonary FAPI tracer uptake, fibrotic activity, and clinical parameters used for disease monitoring and prognostication in ILD to provide insights into its clinical potential.

METHODS: In January 2025, a systematic literature search on PubMed, Ovid Medline, and Cochrane Library, utilizing the block-search strategy and snowballing, was conducted, and 13 studies were included.

RESULTS: Both murine and human studies support that FAPI tracer uptake reflects fibrotic activity in ILDs, as uptake was consistently elevated in subject groups compared to controls. In murine ILD models, increased uptake was associated with fibrosis and fibroblast activation protein-α (FAP-α) expression upon histological examination. Uptake preceded the development of fibrosis on computed tomography (CT) and attenuated once fibrosis was established. In human ILD patients (Idiopathic pulmonary fibrosis (IPF) = 55, Connective tissue disease (CTD) ILD = 68, other ILDs = 55), FAPI uptake was localized to fibrotic lesions on high-resolution computed tomography (HRCT) and associated with increased FAP-α expression ex vivo. Uptake correlated with baseline pulmonary function tests (PFTs) and fibrosis extent on HRCT. Increased FAPI tracer uptake at baseline predicted disease progression upon follow-up.

CONCLUSION: An increasing body of evidence supports that FAPI tracers hold great clinical potential for the management of ILD by accurately monitoring fibrotic disease activity and identifying patients at risk of progression. Further research is required to confirm these findings.

PMID:40544983 | DOI:10.1016/j.autrev.2025.103856

Respir Investig. 2025 Jun 20;63(5):744-748. doi: 10.1016/j.resinv.2025.06.007. Online ahead of print.

ABSTRACT

BACKGROUND: Pneumothorax is a serious complication in patients with idiopathic pulmonary fibrosis (IPF). This study aimed to clarify the clinical course of and risk factors for pneumothorax in patients with IPF.

METHODS: This was a retrospective, cohort study of 164 patients with IPF diagnosed based on relevant guideline criteria. The clinical course of patients with pneumothorax was summarized, and risk factors for pneumothorax were assessed using Fine-Gray proportional hazards model analysis with time-dependent covariates.

RESULTS: Of the 164 patients, 30 (18.3 %) developed pneumothorax. Of the 30 patients with pneumothorax, 4 (13.3 %) died in hospital, and the median duration of chest tube insertion was 11 (6-17.5) days. Low body mass index (BMI) and upper lobe pleuroparenchymal thickening on high-resolution computed tomography (HRCT) were significantly associated with pneumothorax onset (hazard ratio [HR] = 0.85 and 2.55; 95 % confidence interval [CI]: 0.73-0.98 and 1.14-5.73; P = 0.031 and 0.023, respectively). In patients who had repeat pulmonary function tests 6-18 months after diagnosis, annual reduction rates of forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) were significantly associated with pneumothorax onset (HR = 0.97 and 0.97; 95 % CI: 0.93-1.00 and 0.94-0.99; P = 0.034 and 0.013, respectively).

CONCLUSION: Pneumothorax is a serious event having a poor prognosis and requiring long-term treatment in patients with IPF. Low BMI, upper lobe pleuroparenchymal thickening on HRCT, annual FVC reduction rates, and annual DLCO reduction rates are associated with the onset of pneumothorax in patients with IPF.

PMID:40543434 | DOI:10.1016/j.resinv.2025.06.007

Appl Biochem Biotechnol. 2025 Jun 21. doi: 10.1007/s12010-025-05289-y. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and severe lung disease characterized by the buildup of interstitial fibrosis, where excessive collagen accumulates, leading to airway obstruction. This condition is initiated by the abnormal proliferation of alveolar type II (AT2) cells. Metformin, an established antidiabetic drug, has gained attention for its repurposed use as an anti-fibrotic agent. Meanwhile, adipose-derived mesenchymal stem cells (ADMSCs) exhibit potent anti-inflammatory and regenerative properties, and they have been shown to reduce collagen deposition. In this study, we hypothesize that the combination of metformin and ADMSCs can synergistically alleviate IPF and promote healthy lung tissue regeneration in a rat model. The goal is to evaluate the safety and efficacy of this approach at multiple levels; biochemical, molecular, histopathological, and histochemical. To induce IPF, Wistar albino rats received a single intratracheal dose of bleomycin (5 mg/kg body weight). The therapeutic phase involved treatment with either metformin or ADMSCs or a combination of both. Metformin was administered intraperitoneally (65 mg/kg body weight) every other day, while ADMSCs were delivered intravenously (1 × 10⁶ cells/0.5 ml DMEM/rat) through the tail vein. Our results demonstrated the effectiveness of combinational therapy, especially in mitigating oxidative stress. This was evidenced by the restoration of oxidative stress biomarkers, malondialdehyde (MDA), and catalase (CAT), as well as the regulation of collagenase type IV (MMP9), bovine serum albumin (BSA), and total protein levels in lung tissues. Moreover, the therapy modulated the expression of key inflammatory and fibrotic genes, including the pro-fibrotic marker TGF-β1, proinflammatory cytokine IL-6, and anti-inflammatory cytokine IL-10. Histopathological and histochemical analyses further supported the therapeutic benefits, showing significant recovery from bleomycin-induced fibrosis in rats treated with either the single or combined therapy. The findings suggest that this combinational approach could be a promising strategy for IPF treatment by simultaneously reducing inflammation, oxidative stress, and fibrosis while promoting tissue regeneration.

PMID:40542974 | DOI:10.1007/s12010-025-05289-y

Nat Biomed Eng. 2025 Jun 20. doi: 10.1038/s41551-025-01423-7. Online ahead of print.

ABSTRACT

Human diseases are characterized by intricate cellular dynamics. Single-cell transcriptomics provides critical insights, yet a persistent gap remains in computational tools for detailed disease progression analysis and targeted in silico drug interventions. Here we introduce UNAGI, a deep generative neural network tailored to analyse time-series single-cell transcriptomic data. This tool captures the complex cellular dynamics underlying disease progression, enhancing drug perturbation modelling and screening. When applied to a dataset from patients with idiopathic pulmonary fibrosis, UNAGI learns disease-informed cell embeddings that sharpen our understanding of disease progression, leading to the identification of potential therapeutic drug candidates. Validation using proteomics reveals the accuracy of UNAGI's cellular dynamics analysis, and the use of the fibrotic cocktail-treated human precision-cut lung slices confirms UNAGI's predictions that nifedipine, an antihypertensive drug, may have anti-fibrotic effects on human tissues. UNAGI's versatility extends to other diseases, including COVID, demonstrating adaptability and confirming its broader applicability in decoding complex cellular dynamics beyond idiopathic pulmonary fibrosis, amplifying its use in the quest for therapeutic solutions across diverse pathological landscapes.

PMID:40542107 | DOI:10.1038/s41551-025-01423-7

Cell Signal. 2025 Jun 18:111951. doi: 10.1016/j.cellsig.2025.111951. Online ahead of print.

ABSTRACT

Chemokine (C-C motif) ligand 8 (CCL8), also known as monocyte chemotactic protein-2 (MCP-2) is involved in immune cell recruitment, inflammation, and disease progression. While essential for host defense, dysregulated CCL8 expression and signaling contribute to the progression of infectious diseases, inflammatory disorders, and various cancers. CCL8 is also transcriptionally regulated under hypoxic conditions, linking it to the remodeling of the tumor microenvironment, placental dysfunction, and ischemic injury. In infections such as HIV, tuberculosis, and viral pneumonias, CCL8 regulates immune cell trafficking, enhancing both pathogen clearance and excessive immune activation. Inflammatory conditions such as graft-versus-host disease (GVHD), idiopathic pulmonary fibrosis (IPF), and preeclampsia are also associated with elevated CCL8 expression, promoting immune dysregulation and tissue damage. In allergic diseases such as asthma and atopic dermatitis, CCL8 contributes to Th2-driven inflammation by recruiting eosinophils and CCR8+ T cells to affected tissues. In cancer, CCL8 promotes tumor progression, metastasis, immune evasion, and therapeutic resistance through the recruitment of immunosuppressive cells such as M2 macrophages and regulatory T cells. Given its widespread role in immune modulation, CCL8 represents both a potential diagnostic biomarker and a therapeutic target. Recent advances in antibody-based therapies and ligand-directed strategies, including cytotoxic CCL8 analogs, highlight new opportunities for translational application. Further research is needed to clarify its specific mechanisms and explore targeted interventions that modulate CCL8 signaling for clinical applications.

PMID:40541814 | DOI:10.1016/j.cellsig.2025.111951

JAAD Case Rep. 2025 Mar 25;61:110-112. doi: 10.1016/j.jdcr.2025.03.006. eCollection 2025 Jul.

NO ABSTRACT

PMID:40538793 | PMC:PMC12176664 | DOI:10.1016/j.jdcr.2025.03.006

Front Pharmacol. 2025 Jun 5;16:1586197. doi: 10.3389/fphar.2025.1586197. eCollection 2025.

ABSTRACT

BACKGROUND: Persistence with antifibrotic medications in patients with idiopathic pulmonary fibrosis (IPF) is crucial for long-term outcomes. However, real-world data regarding treatment persistence patterns in IPF are scarce.

METHODS: We conducted a post hoc analysis of two retrospective, real-world, multicenter observational studies (PolExPIR and PolExNIB) that collected clinical data on Polish patients with IPF managed at specialized centers between January 2017 and October 2021. We compared clinical variables between groups of patients who continued and discontinued antifibrotics and evaluated predictive factors for treatment discontinuation.

RESULTS: Overall, 808 patients were included in the analysis. Of these, 278 subjects (34.4%) discontinued therapy over a median follow-up of 16 (8-24) months. The proportion of patients discontinuing therapy was comparable between pirfenidone and nintedanib (37.5% vs. 32.5% respectively; p = 0.15). Additionally, no statistical difference was observed between antifibrotic agents in the distribution of time until treatment discontinuation (log-rank test, p = 0.3). Predictive factors associated with the probability of treatment discontinuation included age (hazard ratio [HR] 1.04; 95% confidence interval [CI] 1.02-1.05), body mass index (BMI, HR 0.97; 95% CI 0.94-0.99), transfer factor of the lung for carbon monoxide (TLco)% predicted (HR 0.98, 95% CI 0.97-0.99), Gender-Age-Physiology (GAP) index score (HR 1.3, 95% CI 1.18-1.42), use of long-term oxygen therapy (LTOT) (HR = 1.7, 95% CI 1.28-2.27) and intermittent dosing adjustment (HR 1.66, 95% CI 1.29-2.15).

CONCLUSION: In this large population-based cohort of patients with IPF, around one-third discontinued antifibrotics during a study follow-up with no difference in the rates and time to discontinuation between pirfenidone and nintedanib. Clinical predictive factors including age, BMI, TLco% predicted, GAP index score, use of LTOT and intermittent dosing adjustment were associated with the risk of treatment discontinuation.

PMID:40538535 | PMC:PMC12177363 | DOI:10.3389/fphar.2025.1586197

J Multidiscip Healthc. 2025 Jun 15;18:3465-3475. doi: 10.2147/JMDH.S515745. eCollection 2025.

ABSTRACT

INTRODUCTION: To elucidate the currently unknown relationship between chronic lung diseases (CLDs) and depressive symptoms among older adults.

METHODS: A total of 8079 older adults from China Longitudinal Aging Social Survey (CLASS) and 1119 individuals from a Sichuan Province cohort were included in this study. We used regression analysis and propensity score matching (PSM) to assess the association between CLDs and depressive symptoms among older adults, while the causal relationship was assessed using Mendelian randomization (MR). Our sensitivity analyses included heterogeneity tests, tests of multiple validity, and leave-one-out tests. A two-way mediation analysis was also used to assess the mediating role of basic activities of daily living (BADL) between CLDs and depressive symptoms.

RESULTS: In this cross-sectional study, we found that depressive symptoms significantly (P < 0.001) increased the risk of CLDs (β = 0.047). The robustness test showed that there were significant association between CLDs and depressive symptoms (β = 0.220, P < 0.001), Qi depression constitution (β = 8.564, P < 0.001). This finding was also confirmed through robustness tests using different PSM methods. The results of the inverse-variance weighting (IVW) analysis showed that depression increased the risk of idiopathic pulmonary fibrosis and asthma, with Beta coefficients of 2.822 [standard error (SE) = 1.087; P = 0.009] and -1.090 (SE = 0.491; P = 0.027), accordingly. The results of the IVW analysis showed that idiopathic pulmonary fibrosis and asthma increased the risk of depression, with Beta coefficients of 2.822 [standard error (SE) = 1.087; P = 0.009] and -1.559 (SE = 0.633; P = 0.013). The sensitivity analysis results confirmed the reliability of this conclusion. The mediating role of BADL was observed from depressive symptoms to CLDs.

CONCLUSION: Depressive symptoms are associated with an increased risk of CLDs, reduced BADL promote the risk of CLDs in older adults with depressive symptoms, but the underlying pathological mechanism still needs to be clarified in future research.

PMID:40538380 | PMC:PMC12178258 | DOI:10.2147/JMDH.S515745

Med Sci Monit. 2025 Jun 20;31:e948510. doi: 10.12659/MSM.948510.

ABSTRACT

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with limited effective treatments and significant challenges in early diagnosis. Identifying reliable biomarkers is crucial for improving diagnostic accuracy and patient outcomes. MATERIAL AND METHODS We analyzed TRIM family gene expression in IPF patients and healthy controls using GSE93606, GSE33566, and GSE38958 datasets. Consensus clustering and WGCNA identified IPF subtypes and hub genes. Machine learning models (RF, GLM, SVM, XGB) were built to identify key disease genes. A nomogram for clinical prediction was developed and validated. Peripheral blood samples from IPF patients and healthy controls were used to validate gene expression via qPCR. RESULTS TRIM family genes were significantly differentially expressed between IPF patients and healthy controls. Two distinct IPF subtypes (C1 and C2) were identified, each exhibiting unique biological functions and signaling pathways. The RF model outperformed other machine learning models, identifying TNIK, NCL, ROPN1L, MTR, and HNRNPH1 as key disease-characteristic genes. The nomogram demonstrated good predictive accuracy (AUC: 0.741, 95% CI: 0.556-0.897). qPCR validation confirmed increased expression of 4 genes in IPF patients, except for ROPN1L, which showed decreased expression. CONCLUSIONS This study identifies and validates TRIM family genes as potential biomarkers for IPF diagnosis using clinical samples. The findings support the integration of these biomarkers into diagnostic workflows, potentially enhancing early diagnosis and personalized treatment strategies for IPF patients. Further research is needed to explore the prognostic value and underlying mechanisms of these genes.

PMID:40538010 | DOI:10.12659/MSM.948510

Thorax. 2025 Jun 19:thorax-2024-221868. doi: 10.1136/thorax-2024-221868. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterised by damage to the epithelial layer, closely associated with the alveolar basement membrane (BM). We aimed to investigate how type IV collagen (COL4) in the BM changes with the progression of IPF.

METHODS: COL4 synthesis (PRO-C4) was detected in blood by the nordicPRO-C4 biomarker in patients with IPF from the two prospective, multicentre, observational, longitudinal cohorts, pulmonary fibrosis biomarker (PFBIO) and prospective observation of fibrosis in the lung clinical endpoints (PROFILE). PRO-C4 trajectories over 12 months were compared between progressors and non-progressors by linear mixed effects regression models. Rate of change in PRO-C4 and lung function were compared by Bayesian bivariate longitudinal models. Cox proportional hazards models analysed baseline PRO-C4 and 3 years mortality. COL4 staining in IPF and non-IPF lungs was evaluated by immunohistochemistry.

RESULTS: In PFBIO and PROFILE, 51/220 (23.2%) and 221/459 (48.1%) patients, respectively, had progressive disease at 12 months. Longitudinal PRO-C4 levels were higher in progressors versus non-progressors (average differences: PFBIO 21.5% (95% CI 3.4% to 42.9%, p=0.0184); PROFILE 10.9% (95% CI 0.8% to 22.1%; p=0.0340). Monthly rate of change in PRO-C4 was steeper in non-survivors versus survivors (mean difference up to 3.12% (95% CI 0.35% to 5.91%)) and was inversely correlated with the change in lung function. High baseline PRO-C4 was associated with increased mortality risk in PFBIO (HR 2.55 (95% CI 1.27 to 5.12), p=0.0083). COL4 staining was higher in IPF versus non-IPF lung but was less obvious in end-stage tissue.

CONCLUSIONS: High and increasing serological PRO-C4 levels were prognostic for progression in two independent IPF cohorts. This study suggests that COL4 synthesis assessed by PRO-C4 is a pathologically relevant biomarker of alveolar BM repair in IPF.

PMID:40537217 | DOI:10.1136/thorax-2024-221868

Biomed Pharmacother. 2025 Jun 17;189:118267. doi: 10.1016/j.biopha.2025.118267. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease of unknown etiology, affecting about 3 million individuals worldwide. Significant risk factors for IPF include advanced age and infectious agents. Current FDA-approved antifibrotic drugs slow the progression of pulmonary fibrosis with limited outcomes in overall survival, highlighting the need for novel pharmacological agents. Ugonin L (UL), a cyclized geranylflavonoid derived from Helminthostachys zeylanica, has been reported to have anti-inflammatory and antioxidant activities. However, the therapeutic potential of UL for pulmonary fibrosis remains unexplored. In this study, we demonstrated that UL mitigated pulmonary fibrosis in bleomycin (BLM)-induced mice. Specifically, UL improved the alveolar-capillary barrier integrity, decreasing inflammatory cytokines (TGF-β1, TNF-α, IL-1β, IL-6) in bronchoalveolar lavage fluid (BALF). UL ameliorated lesions in BLM-induced fibrotic lungs, reducing radiological signs of lung injury, alveolar septal thickening, and collagen deposition. In RNA-seq analysis, UL downregulated genes related to cell migration and ECM remodeling in TGF-β1-induced LL29 human lung fibroblasts. In particular, UL decreased cell migration, fibrotic marker expression, MMP-2 activity, and myofibroblast activation. In molecular modeling, UL interacted with key pharmacophores and the putative ATP-binding sites of the TβRI and TβRII kinase domains. Correspondingly, UL reduced the phosphorylation of key mediators in both the canonical (SMAD2/3) and non-canonical (ERK1/2 and PI3K) TGF-β signaling pathways. Furthermore, UL downregulated the PI3K/Akt/mTOR axis and promoted autophagy in TGF-β1-induced LL29 cells. Taken together, our findings demonstrate that UL acts as a novel TβRs inhibitor and shows therapeutic potential for pulmonary fibrosis.

PMID:40532575 | DOI:10.1016/j.biopha.2025.118267

ACS Nano. 2025 Jun 18. doi: 10.1021/acsnano.5c04686. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) remains an age-related, fatal, incurable, epithelial-driven fibrotic lung disease despite the availability of approved antifibrotic drugs. The medical need for effective antipulmonary fibrotic therapies is thus very high. A promising therapeutic intervention for IPF is to target key cellular senescence processes in alveolar type 2 (AT2) cells. Herein, we introduce an inhalable gene-editable nanoplatform, comprising a CRISPR-Cas9 gene-editing system linked to a core FePt diatomic catalyst, encapsulated within a biocompatible hyaluronic acid (HA) surface layer (FePtR@HA). The FePt diatomic site facilitates H2O2 bridge adsorption, enabling efficient O-O bond cleavage and rapid catalytic conversion. The strong Fe-Pt interaction modulates the metal's d-band center, optimizing the adsorption of oxygen-containing intermediates. This precise regulation efficiently clears ROS, delivering robust antioxidant and antisenescence effects to AT2 cells. Simultaneously, the CRISPR-Cas9 gene editing system knocks down the pro-aging gene KAT7, reducing senescence-associated secretory phenotype (SASP) factors and further reversing AT2 cell senescence. Additionally, we demonstrated the antifibrotic efficacy of FePtR@HA in a lung-on-a-chip model, where it reprogrammed the fibrotic microenvironment, prevented myofibroblast recruitment to AT2 cells. Moreover, FePtR@HA showed satisfactory results in IPF mouse models, alleviating fibrosis and presenting a highly promising approach to combat the progression of IPF.

PMID:40532220 | DOI:10.1021/acsnano.5c04686