Biomedicines. 2025 Mar 11;13(3):690. doi: 10.3390/biomedicines13030690.

ABSTRACT

Background: Cold exposure has an impact on various respiratory diseases. However, its relationship with idiopathic pulmonary fibrosis (IPF) remains to be elucidated. In this study, bioinformatics methods were utilized to explore the potential link between cold exposure and IPF. Methods: Cold exposure-related genes (CERGs) were identified using RNA-Seq data from mice exposed to cold versus room temperature conditions, along with cross-species orthologous gene conversion. Consensus clustering analysis was performed based on the CERGs. A prognostic model was established using univariate and multivariate risk analyses, as well as Lasso-Cox analysis. Differential analysis, WGCNA, and Lasso-Cox methods were employed to screen for signature genes. Results: This study identified 151 CERGs. Clustering analysis based on these CERGs revealed that IPF patients could be divided into two subgroups with differing severity levels. Significant differences were observed between these two subgroups in terms of hypoxia score, EMT score, GAP score, immune infiltration patterns, and mortality rates. A nine-gene prognostic model for IPF was established based on the CERG (AUC: 1 year: 0.81, 3 years: 0.79, 5 years: 0.91), which outperformed the GAP score (AUC: 1 year: 0.66, 3 years: 0.75, 5 years: 0.72) in prognostic accuracy. IPF patients were classified into high-risk and low-risk groups based on the RiskScore from the prognostic model, with significant differences observed between these groups in hypoxia score, EMT score, GAP score, immune infiltration patterns, and mortality rates. Ultimately, six high-risk signature genes associated with cold exposure in IPF were identified: GASK1B, HRK1, HTRA1, KCNN4, MMP9, and SPP1. Conclusions: This study suggests that cold exposure may be a potential environmental factor contributing to the progression of IPF. The prognostic model built upon cold exposure-related genes provides an effective tool for assessing the severity of IPF patients. Meanwhile, GASK1B, HRK1, HTRA1, KCNN4, MMP9, and SPP1 hold promise as potential biomarkers and therapeutic targets for IPF.

PMID:40149666 | DOI:10.3390/biomedicines13030690

Am J Hosp Palliat Care. 2025 Mar 27:10499091251329920. doi: 10.1177/10499091251329920. Online ahead of print.

ABSTRACT

BackgroundBreathlessness is a distressing and prevalent symptom in fibrotic interstitial lung disease. Dyspnea management requires systematic assessment including patients' lived experiences; however, most dyspnea tools are point-in-time numerical severity scales. The Edmonton Dyspnea Inventory was developed to assess severity at rest, during activities of daily living and self-reported activities. It enables documentation of crisis dyspnea episodes and triggers clinicians to guide action plans and dyspnea management. This study is part of a larger project to validate the tool. The purpose was to describe patient perceptions of assessment of breathlessness of patient use of the tool.MethodsPatients with fibrotic interstitial lung disease were invited to share their perceptions and experiences of breathlessness and the tool. Focus groups were led on Zoom©, with patient-participants in their homes. Data were analysed with inductive content analysis for development of themes.ResultsThirteen patients participated in 2 focus groups. There were 4 major themes, each with minor themes: physicians need to explicitly ask about breathlessness; the tool conveys breathlessness and disease progression; the tool increases self-awareness of breathlessness and complexity; and the tool helps prevent crises and manage breathlessness. Patient-participants perceived the tool provided the needed language and means to focus and relay their breathlessness to others.ConclusionPatient-participants reported the tool was easy to understand and integrate in daily living. They recommended its use for general and specialized practitioners. Developed to assess breathlessness, the tool may provide a framework to promote patient self-awareness, describe individual progression, and tailor breathlessness self-management.

PMID:40147029 | DOI:10.1177/10499091251329920

Am J Physiol Lung Cell Mol Physiol. 2025 Mar 27. doi: 10.1152/ajplung.00286.2024. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis(IPF) is a chronic progressive lung disease that leads to destruction of alveoli and replacement by fibrotic tissue. Metabolic profiling of lung tissue and serum from IPF patients has revealed that levels of tricarboxylic acid (TCA) cycle metabolites such as succinate are altered in patients with IPF. In our study, we aim to evaluate the role of succinate and its receptor- succinate receptor 1 (SUCNR1) in the pathogenesis of lung fibrosis, with a focus on fibroblasts, a central cell in IPF.

METHODS: SUCNR1 expression was investigated using Western blots, qPCR, and FISH. In vitro assays with IPF and normal human lung fibroblasts(NHLF) were used to evaluate the effect of succinate treatment on the expression of fibrotic markers, fibroblast-myofibroblast transition, apoptosis and signaling mechanisms. Studies with the bleomycin mouse model of PF were used to evaluate the effect of succinate in vivo.

RESULTS: Several cell types in the lung express SUCNR1 including ATII cells, fibroblasts, and macrophages. In IPF patient fibroblasts, succinate treatment increased expression of fibrosis associated markers such as alpha smooth muscle actin and collagen. Moreover, succinate exaggerated TGF-β-mediated fibroblast-to-myofibroblast transition in NHLF. In vivo, succinate treatment significantly increased collagen accumulation in the lung and enhanced weight loss in bleomycin-treated mice. Importantly, succinate-mediated elevation of fibrosis-associated markers was lost upon knockdown of SUCNR1 or inhibition of ERK activation in IPF patient-derived fibroblasts.

CONCLUSION: Succinate exerted pro-fibrotic effects in vitro and in vivo. Thus, SUCNR1 antagonism may be a potential therapeutic target for the treatment of IPF.

PMID:40146935 | DOI:10.1152/ajplung.00286.2024

Curr Opin Pulm Med. 2025 Mar 27. doi: 10.1097/MCP.0000000000001169. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: This review examines the current understanding of telomere biology disorders (TBDs) in advanced lung disease, with particular focus on their implications for lung transplantation outcomes and management.

RECENT FINDINGS: Recent studies have revealed that TBDs are enriched in lung transplant populations, with many idiopathic pulmonary fibrosis transplant recipients having short telomeres and/or carrying variants in telomere-related genes. While survival outcomes remain debated, recipients with short telomeres consistently show increased susceptibility to cytopenias, cytomegalovirus (CMV) infection, and may require modified immunosuppression regimens. New evidence suggests potential protection against acute cellular rejection in some cases, and novel approaches using letermovir for CMV prophylaxis show promise in managing these complex patients.

SUMMARY: Management of lung transplant recipients with TBDs requires careful consideration of multiorgan manifestations and individualized management strategies. A multidisciplinary approach incorporating genetics, haematology, and hepatology expertise is increasingly essential for optimal outcomes in this unique population.

PMID:40145203 | DOI:10.1097/MCP.0000000000001169

JHLT Open. 2023 Oct 20;2:100011. doi: 10.1016/j.jhlto.2023.100011. eCollection 2023 Dec.

ABSTRACT

BACKGROUND: Acute exacerbations of interstitial lung disease (AE-ILD) cause severe respiratory failure, and mortality is high despite treatment. Lung transplantation is an effective therapy for late-stage interstitial lung disease (ILD), but prior studies on post-transplant outcomes for patients trandsplanted in AE-ILD are conflicting.

METHODS: We performed a retrospective evaluation of all first-time lung transplant recipients for ILD performed at our institution between May 1, 2005, and April 1, 2019. Patients were stratified according to a published consensus definition into AE-ILD recipients, other inpatients, or outpatients. One-year survival was compared with a Cox proportional hazards model. Subset analysis was performed on those with idiopathic pulmonary fibrosis (IPF). Patients were also assessed for survival free of long-term chronic lung allograft dysfunction (CLAD).

RESULTS: We identified 717 first-time lung transplant ILD recipients: 41 inpatients in AE-ILD, 31 other inpatients, and 645 outpatients. One-year survival was 93% for AE-ILD recipients, 61% for other inpatient recipients, and 82% for outpatient recipients. Those transplanted in AE-ILD had a lower hazard of death or retransplantation compared to other inpatients (hazard ratio [HR] 0.16, 95% confidence interval [CI] 0.04-0.56) and outpatients (HR 0.29, CI 0.09-1.00). Results were similar among the subset of patients with IPF, but differences were not significant. For those transplanted during AE-ILD, rates of CLAD were not significantly different compared to other inpatients (HR 1.34, CI 0.51-3.54) or to outpatients (HR 1.05, CI 0.52-2.13).

CONCLUSIONS: With careful selection, patients in AE-ILD can be transplanted and have acceptable 1-year outcomes without increased risk of long-term graft dysfunction.

PMID:40144010 | PMC:PMC11935389 | DOI:10.1016/j.jhlto.2023.100011

JHLT Open. 2024 Apr 25;5:100101. doi: 10.1016/j.jhlto.2024.100101. eCollection 2024 Aug.

ABSTRACT

Chimeric antigen receptor T-cell therapy (CAR-T) has been used to treat refractory post-transplant lymphoproliferative disorder (PTLD) in solid organ transplant patients, including heart, kidney, liver, intestine, and pancreas. We report the use of CAR-T for treating refractory PTLD in a 73-year-old female who was 7 years post bilateral lung transplantation for idiopathic pulmonary fibrosis. We discuss the immunosuppression management in this patient, as well as her clinical course and outcome.

PMID:40143897 | PMC:PMC11935479 | DOI:10.1016/j.jhlto.2024.100101

JHLT Open. 2024 Jul 1;5:100122. doi: 10.1016/j.jhlto.2024.100122. eCollection 2024 Aug.

ABSTRACT

BACKGROUND: Predicting post-transplant (PT) survival in lung allocation remains an elusive goal. We analyzed the impact of donor factors on PT survival and how these relationships vary among transplant recipients.

METHODS: We studied primary bilateral lung transplant recipients (n = 7,609) from the US Scientific Registry of Transplant Recipients (19 February 2015-1 February 2020). Main and interaction effects were evaluated and adjusted across candidate age, sex, and diagnosis. Models predicting PT survival were compared to the PT Composite Allocation Score model (PT-CAS): (1) Cox regression donor multivariable model (COX), (2) COX + PT-CAS, (3) random forest model (RF), and (4) RF + PT-CAS. Model discrimination and calibration measures were compared.

RESULTS: Interactions between donor and recipient factors emerged by age: lower survival for donation after circulatory death organs for recipients aged 55 to 69 years, donor smoking for recipients aged 30 to 54 and 70+, Hispanic donor for recipients <30, non-Hispanic Black donor for recipients aged 30+; sex: cytomegalovirus mismatch for males; diagnosis: higher donor recipient weight ratio for diagnosis group C (e.g., cystic fibrosis), donor diabetes for diagnosis group D (e.g., idiopathic pulmonary fibrosis). COX and RF models performed similarly to PT-CAS; however, the combined COX + PT-CAS model had improved discrimination (1-year area under the receiver operator characteristic curve [AUC] PT-CAS 0.609 vs 1-year AUC COX + PT-CAS 0.626) and improved calibration across a broader range of predicted risk.

CONCLUSIONS: The influence of donor factors on recipient PT survival differed by age, sex, and diagnosis. The addition of donor factors to existing models predicting PT survival led to only modest improvement in prediction accuracy. Future efforts may focus on optimizing matching strategies to improve donor utilization.

PMID:40143895 | PMC:PMC11935449 | DOI:10.1016/j.jhlto.2024.100122

Pharmaceuticals (Basel). 2025 Mar 14;18(3):411. doi: 10.3390/ph18030411.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown aetiology. Evidence on the progression of idiopathic pulmonary fibrosis (IPF) following the introduction of antifibrotic therapies still indicates a generally poor prognosis. IPF is associated with both respiratory and non-respiratory comorbidities, which can worsen symptoms and impact overall survival. Background/Objectives: The study aimed to investigate the effect of these comorbidities on the early and permanent discontinuation of pirfenidone or nintedanib in IPF patients. Methods: In this single-centre retrospective study, 101 patients diagnosed with IPF according to ATS/ERS/JRS/ALAT guidelines were treated with AFT. Clinical data were collected at 12 months prior to and up to 24 months following treatment initiation, including age, gender, smoking history, and the presence of respiratory and non-respiratory comorbidities. Results: The data showed that 21 patients (20.8%) discontinued treatment within the first 12 months. Additionally, pre-treatment comorbidities were not statistically correlated with the suspension of antifibrotic treatment. Among the overall cohort, 77 patients (76.2%) had at least one comorbidity and 27 (26.7%) had three or more comorbidities. Notably, 24 (23.8%) had respiratory comorbidities, while 75 (74.3%) had non-respiratory comorbidities. Conclusions: This real-life study emphasises the complexities involved in managing IPF, particularly regarding adherence to treatment when significant comorbidities are present. The evidence suggests that in patients with IPF, pre-treatment respiratory or non-respiratory conditions do not affect AFT discontinuation.

PMID:40143187 | DOI:10.3390/ph18030411

Molecules. 2025 Mar 14;30(6):1311. doi: 10.3390/molecules30061311.

ABSTRACT

Silicosis is an interstitial lung disease (ILD) caused by prolonged inhalation of silica particles. Acute lung injury (ALI) is a critical clinical syndrome involving bilateral lung infiltration and acute hypoxic respiratory failure. However, there is currently no effective treatment for these two diseases. Previous research has established that cyclic adenosine monophosphate (cAMP) is pivotal in the pathogenesis of silicosis and acute lung injury. Phosphodiesterase 4 (PDE4) is a hydrolase enzyme of cAMP, and BI 1015550, as an inhibitor of PDE4B, is expected to be a candidate drug for treating both. BI 1015550 has shown certain anti-inflammatory and anti-fibrotic properties in systemic sclerosis-associated interstitial lung disease (SSc-ILD) and idiopathic pulmonary fibrosis (IPF), but there is a lack of research on silicosis and acute lung injury. In this research, we successfully synthesized BI 1015550 autonomously and demonstrated that it could significantly improve lung fibrosis and inflammation in a silica-induced silicosis mouse model. Furthermore, we found that BI 1015550 could also alleviate lung inflammation in a Lipopolysaccharide (LPS)-induced acute lung injury mouse model. The mechanism of action may involve the regulation of cAMP-related signaling pathways.

PMID:40142089 | DOI:10.3390/molecules30061311

Int J Mol Sci. 2025 Mar 19;26(6):2760. doi: 10.3390/ijms26062760.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by the disruption of the alveolar and interstitial architecture due to extracellular matrix deposition. Emerging evidence suggests that genetic susceptibility plays a crucial role in IPF development. This study explores the role of human leukocyte antigen (HLA) alleles and haplotypes in IPF susceptibility and progression within the genetically distinct Sardinian population. Genotypic data were analyzed for associations with disease onset and progression, focusing on allele and haplotype frequencies in patients exhibiting slow (S) or rapid (R) progression. While no significant differences in HLA allele frequencies were observed between IPF patients and controls, the HLA-DRB1*04:05 allele and the extended haplotype (HLA-A*30:02, B*18:01, C*05:01, DQA1*05:01, DQB1*02:01, DRB1*03:01) were associated with a slower disease progression and improved survival (log-rank = 0.032 and 0.01, respectively). At 36 months, carriers of these variants demonstrated significantly better pulmonary function, measured with single-breath carbon monoxide diffusing capacity (DLCO%p) (p = 0.005 and 0.02, respectively). Multivariate analysis confirmed these findings as being independent of confounding factors. These results highlight the impact of HLA alleles and haplotypes on IPF outcomes and underscore the potential of the Sardinian genetic landscape to illuminate immunological mechanisms, paving the way for predictive biomarkers and personalized therapies.

PMID:40141400 | DOI:10.3390/ijms26062760

Int J Mol Sci. 2025 Mar 17;26(6):2705. doi: 10.3390/ijms26062705.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable chronic interstitial lung disease characterized by excessive fibrosis and impaired lung function. Current treatments, such as pirfenidone and nintedanib, slow disease progression but fail to halt or reverse fibrosis, highlighting the need for novel approaches. Activin A, which belongs to the TGF-β superfamily, is implicated in various fibrosis-related mechanisms, including epithelial-mesenchymal transition (EMT), a process where epithelial cells acquire mesenchymal characteristics, and fibroblast-myofibroblast transformation (FMT), in which fibroblasts differentiate into contractile myofibroblasts. It also promotes inflammatory cytokine release and extracellular matrix buildup. This study aimed to inhibit Activin A activity using synthetic peptides identified through phage display screening. Of the ten peptides isolated, A7, B9, and E10 demonstrated high binding affinity and inhibitory activity. Computational modeling confirmed that these peptides target the receptor-binding domain of Activin A, with peptide E10 exhibiting superior efficacy. Functional assays showed that E10 reduced cell migration, inhibited EMT in A549 cells, and suppressed FMT in fibroblast cultures, even under pro-fibrotic stimulation with TGF-β. These findings underscore the therapeutic potential of targeting Activin A with synthetic peptides, offering a promising avenue for IPF treatment and expanding the arsenal of anti-fibrotic strategies.

PMID:40141346 | DOI:10.3390/ijms26062705

AAPS PharmSciTech. 2025 Mar 26;26(4):94. doi: 10.1208/s12249-025-03086-8.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is a rare and serious chronic interstitial lung disease that may endanger the lives of patients. The median survival time of patients with idiopathic pulmonary fibrosis is short, and the mortality rate is higher than that of many types of cancer. At present, pirfenidone (PFD) and nintedanib (NDNB) have been approved by FDA for IPF, but they can only delay the process of pulmonary fibrosis and cannot cure the disease. Therefore, it is urgent to develop other drugs with the effect of improving pulmonary fibrosis. Ellagic acid (EA) can inhibit the Wnt-signaling pathway and has an effect in treating pulmonary fibrosis induced by bleomycin (BLM) in mice. However, its solubility is poor, resulting in its low bioavailability and limited therapeutic benefits, so its clinical application has been limited. Herein, based on the characteristics of nano-drug lung delivery system, chitosan (CS) was selected as the carrier, and ellagic acid-loaded chitosan nanoparticles (EA-CS-NPs) were prepared by ionic gelation method. The EE% and DL% of prepared EA-CS-NPs was 73.73 ± 4.52% and 6.23 ± 1.09%, the particle size was 119.6 ± 5.51 nm (PDI = 0.234 ± 0.017), the zeta potential was 29.833 ± 0.503 mV. The morphology of the nanoparticles was observed by TEM microscope, which was round, uniform dispersion, indicating that the preparation process is stable and feasible. The toxicity experiment showed that EA-CS-NPs maintained 80% cell viability, significantly higher than that of the NDNB group, indicating lower toxicity and better inhibitory effects on TGF-β1-stimulated MLg and NIH-3T3 cells. Wound healing assay results showed that the inhibitory effect of EA-CS-NPs on cell migration was more pronounced than that of EA in the same amount of EA-containing drugs. Drug uptake experiments revealed that EA-CS-NPs significantly enhanced drug uptake in MLg and NIH-3T3 cells. In vivo, Cy7-CS-NPs exhibited higher fluorescence intensity in rat lungs compared to Cy7 solution, indicating better lung retention. The in vivo efficacy test showed that compared with the EA group, EA-CS-NPs could better reduce the area of pulmonary fibrosis and collagen deposition, improve lung function, and have a longer retention time in the lung. In summary, our results revealed that EA-CS-NPs may be a good choice for the treatment of pulmonary fibrosis.

PMID:40140157 | DOI:10.1208/s12249-025-03086-8

Cells. 2025 Mar 7;14(6):394. doi: 10.3390/cells14060394.

ABSTRACT

Pulmonary fibrosis due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is the leading cause of death in patients with COVID-19. β-catenin, a key molecule in the Wnt/β-catenin signaling pathway, has been shown to be involved in the development of pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis, silicosis). In this study, we developed a SARS-CoV-2-infected A549-hACE2 cell model to evaluate the efficacy of the A549-hACE2 monoclonal cell line against SARS-CoV-2 infection. The A549-hACE2 cells were then subjected to either knockdown or overexpression of the effector β-catenin, and the modified cells were subsequently infected with SARS-CoV-2. Additionally, we employed transcriptomics and raw letter analysis approaches to investigate other potential effects of β-catenin on SARS-CoV-2 infection. We successfully established a model of cellular fibrosis induced by SARS-CoV-2 infection in lung-derived cells. This model can be utilized to investigate the molecular biological mechanisms and cellular signaling pathways associated with virus-induced lung fibrosis. The results of our mechanistic studies indicate that β-catenin plays a significant role in lung fibrosis resulting from SARS-CoV-2 infection. Furthermore, the inhibition of β-catenin mitigated the accumulation of mesenchymal stroma in A549-hACE2 cells. Additionally, β-catenin knockdown was found to facilitate multi-pathway crosstalk following SARS-CoV-2 infection. The fact that β-catenin overexpression did not exacerbate cellular fibrosis may be attributed to the activation of PPP2R2B.

PMID:40136643 | DOI:10.3390/cells14060394

Radiology. 2025 Mar;314(3):e242292. doi: 10.1148/radiol.242292.

ABSTRACT

Background The clinical, radiologic, and prognostic implications of interstitial pneumonia with autoimmune features (IPAF) in patients with idiopathic interstitial pneumonia and pathologic usual interstitial pneumonia (UIP) have not been fully evaluated. Purpose To compare autoimmune features according to CT patterns for the diagnosis of idiopathic pulmonary fibrosis (IPF) and to assess the diagnostic and prognostic implications of IPAF in patients with IPF-UIP. Materials and Methods This retrospective study included patients with UIP confirmed by surgical lung biopsy between January 2013 and February 2020. Data regarding clinical, radiologic, and pathologic autoimmune features were collected, and patients were diagnosed with IPAF according to current guidelines. CT signs for connective tissue disease (CTD; anterior upper lobe, straightedge, and exuberant honeycombing signs) were also evaluated. Overall survival (OS) was evaluated using Cox proportional hazards models. Results Among 210 patients included (median age, 64 years; IQR, 60-68 years; 158 male patients), 23 (11.0%) had IPAF. Patients with an alternative diagnosis or CT pattern indeterminate for UIP showed a higher prevalence of autoimmune features that were pathologic (38% [33 of 87] vs 20.3% [25 of 123]; P = .005) and serologic (20% [17 of 87] vs 9.8% [12 of 123]; P = .04) and IPAF (4.1% [five of 123] vs 21% [18 of 87]; P < .001) compared with patients with UIP or probable UIP pattern. However, IPAF was not predictive of OS (hazard ratio [HR], 0.81; 95% CI: 0.38, 1.72; P = .58). Lymphoid follicles (HR, 0.59; 95% CI: 0.37, 0.93; P = .02), CT signs for CTD (HR, 0.31; 95% CI: 0.09, 0.99; P = .047), and use of an antifibrotic agent (HR, 0.31; 95% CI: 0.19, 0.51; P < .001) were independently associated with higher OS, and greater extent of fibrosis on CT scans was associated with worse OS (HR, 1.08; 95% CI: 1.05, 1.11; P < .001). Conclusion In patients with IPF-pathologic UIP, serologic and pathologic autoimmune features were associated with indeterminate or alternative CT patterns. Certain histopathologic and radiologic autoimmune features, but not current IPAF criteria, were associated with survival. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Ackman in this issue.

PMID:40131107 | DOI:10.1148/radiol.242292

J Mol Model. 2025 Mar 24;31(4):124. doi: 10.1007/s00894-025-06338-3.

ABSTRACT

CONTEXT: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease characterized by very limited treatment options and significant side effects from existing therapies, highlighting the urgent need for more effective drug-like molecules. Transforming growth factor-beta receptor 1 (TGF-βR1) is a key player in the pathogenesis of IPF and represents a critical target for therapeutic intervention. In this study, the potential of plant-derived flavonoid and coumarin compounds as novel TGF-βR1 inhibitors was explored. A total of 1206 flavonoid and coumarin derivatives were investigated through a series of computational approaches, including drug-like filtering, virtual screening, molecular docking, 200-ns molecular dynamics (MD) simulations in triplicate, maximum common substructure (MCS) analysis, and absorption-distribution-metabolism-excretion-toxicity (ADMET) profiling. 2',3',4'-trihydroxyflavone and dicoumarol emerged as promising plant-based hit candidates, exhibiting comparable docking scores, MD-based structural stability, and more negative MM/PBSA binding free energy relative to the co-crystallized inhibitor, while surpassing pirfenidone in these parameters and demonstrating superior pharmacological properties. In light of the findings from this study, 2',3',4'-trihydroxyflavone and dicoumarol could be considered novel TGF-βR1 inhibitors for IPF treatment, and it is recommended that their structural optimization be pursued through in vitro binding assays and in vivo animal studies.

METHODS: The initial dataset of 1206 flavonoid and coumarin derivatives was filtered for drug-likeness using Lipinski's Rule of Five in the ChemMaster-Pro 1.2 program, resulting in 161 potential candidates. These compounds were then subjected to virtual screening against the TGF-βR1 kinase domain (PDB ID: 6B8Y) using AutoDock Vina 1.2.5, identifying the top three hit compounds-dicoumarol, 2',3',4'-trihydroxyflavone, and 2',3'-dihydroxyflavone. These hits underwent further exhaustive molecular docking for refinement of docking poses, followed by 200-ns MD simulations in triplicate using the AMBER03 force field in GROMACS. Subsequently, the binding free energies were calculated using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. MCS analysis was conducted to determine shared structural features among the top three hits, while ADMET properties were predicted using Deep-PK, a deep learning-based platform. Finally, the ligand-protein interactions were further visualized, analyzed, and rendered using ChimeraX, Discovery Studio Visualizer, and Visual Molecular Dynamics (VMD) program.

PMID:40126695 | DOI:10.1007/s00894-025-06338-3

Am J Respir Cell Mol Biol. 2025 Mar 24. doi: 10.1165/rcmb.2024-0342OC. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disorder without curative therapies, underscoring the critical unmet need for identification of novel therapeutics. Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a damage-associated molecular pattern protein (DAMP) and Toll-Like Receptor 4 (TLR4) ligand that contributes to the severity of radiation-induced lung fibrosis and NASH-associated hepatic fibrosis. This study investigates eNAMPT as a druggable target in human and preclinical IPF utilizing the eNAMPT-neutralizing ALT-100 monoclonal antibody (mAb). Blood, PBMCs, and lung tissues from IPF patients and from an experimental bleomycin-induced lung fibrosis model in C57Bl6 mice were analyzed. Biochemical and histologic measurements, as well as gene expression through bulk and single-cell RNA sequencing of human PBMCs and murine lung tissues were performed. Human studies revealed NAMPT expression to be significantly elevated in plasma, lung tissues, and in PBMCs from IPF subjects, correlating with disease severity and inversely associated with IPF survival. Bleomycin-exposed mice exhibited increased inflammatory indices associated with lung fibrosis development (including NAMPT levels), as well as physiologic lung stiffening, and TGFβ pathway-related protein and gene expression with each indice significantly mitigated in mice receiving ALT-100 mAb. scRNAseq studies demonstrated the ALT-100 mAb to reverse bleomycin-induced dramatic expansion of alveolar type 2 epithelium (AT2) and indiction of endothelial- and epithelial cell-to-mesenchymal/myofibroblast transitions (EndMT, EMT). These finding support the fundamental involvement of eNAMPT/TLR4 signaling pathway in lung fibrosis pathobiology with eNAMPT neutralization a viable therapeutic strategy to directly address the unmet need for novel IPF treatments.

PMID:40126452 | DOI:10.1165/rcmb.2024-0342OC

Ther Deliv. 2025 Mar 24:1-14. doi: 10.1080/20415990.2025.2478803. Online ahead of print.

ABSTRACT

AIMS: Diltiazem (DIL), a calcium channel blocker, has demonstrated potential ininhibiting fibrosis-related processes, including TGF-β activation, collagen production, and epithelial-mesenchymal transition, making it a promising candidate for idiopathic pulmonary fibrosis (IPF). This study evaluates the anti-fibrotic efficacy of DIL-loaded chitosan (DIL-CHT) and trimethyl chitosan (DIL-TMC) nanoparticles through molecular and experimental approaches.

METHODS: DIL-CHT and DIL-TMC nanoformulations were developed and analyzed particle size, ζ-potential, entrapment efficiency, and in vitro release. Antifibrotic efficacy in bleomycin (BLM)-induced IPF rat model, was tested at subtherapeutic doses (3 mg/kg/day, i.t.) and DIL alone (10 mg/kg/day, p.o.). DFT (B3LYP/6-31 G**) optimization and molecular docking were conducted to assess electronic properties and interactions among CHT, TMC, and DIL.

RESULTS: DIL-TMC and DIL-CHT nanoparticles were 175.6 nm and 267.8 nm, with entrapment efficiencies of 81.72% and 66.0%, respectively; TMC showed a superior 24-hour sustained release. TMC's larger HOMO-LUMO gap (ΔE = -0.260 eV vs. -0.253 eV for CHT) suggests greater stability, supporting its enhanced interaction with DIL. TMC nanoparticles significantly reduced BLM-induced IPF symptoms, i.e. BLM induced increased lung index, hydroxyproline accumulation, oxidative stress in lung tissue, and blood pressure.

CONCLUSIONS: These findings indicate the strong therapeutic potential of DIL-TMC for IPF with minimal cardiovascular side effects.

PMID:40125984 | DOI:10.1080/20415990.2025.2478803

Physiol Rev. 2025 Mar 24. doi: 10.1152/physrev.00032.2024. Online ahead of print.

ABSTRACT

Nanosized extracellular vesicles (EVs) are released by all cells to convey cell-to-cell communication. EVs, including exosomes and microvesicles, carry an array of bioactive molecules, such as proteins and RNAs, encapsulated by a membrane lipid bilayer. Epithelial cells, endothelial cells, and various immune cells in the lung contribute to the pool of EVs in the lung microenvironment and carry molecules reflecting their cellular origin. EVs can maintain lung health by regulating immune responses, inducing tissue repair, and maintaining lung homeostasis. They can be detected in lung tissues and biofluids such as bronchoalveolar lavage fluid and blood, offering information about disease processes and can function as disease biomarkers. Here, we discuss the role of EVs in lung homeostasis and pulmonary diseases such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, and lung injury. The mechanistic involvement of EVs in pathogenesis and their potential as disease biomarkers are discussed. Lastly, the pulmonary field benefits from EVs as clinical therapeutics in severe pulmonary inflammatory disease, as EVs from mesenchymal stem cells attenuate severe respiratory inflammation in multiple clinical trials. Further, EVs can be engineered to carry therapeutic molecules for enhanced and broadened therapeutic opportunities, such as the anti-inflammatory molecule CD24. Finally, we discuss the emerging opportunity of using different types of EVs for treating severe respiratory conditions.

PMID:40125970 | DOI:10.1152/physrev.00032.2024

Fibrosis (Hong Kong). 2025;3(1):10004. doi: 10.70322/fibrosis.2025.10004. Epub 2025 Feb 18.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is marked by progressive alveolar destruction, impaired tissue regeneration, and relentless fibrogenesis, culminating in respiratory failure and death. A diverse array of resident and non-resident cells within the lung contribute to disease pathogenesis. Notably, immune cells, both resident and recruited, respond to cues from sites of lung injury by undergoing phenotypic transitions and producing a wide range of mediators that influence, initiate, or dictate the function, or dysfunction, of key effector cells in IPF pathology, such as alveolar epithelial cells, lung fibroblasts, and capillary endothelial cells. The role of the immune system in IPF has undergone an interesting evolution, oscillating from initial enthusiasm to skepticism, and now to a renewed focus. This shift reflects both the past failures of immune-targeting therapies for IPF and the unprecedented insights into immune cell heterogeneity provided by emerging technologies. In this article, we review the historical evolution of perspectives on the immune system's role in IPF pathogenesis and examine the lessons learned from previous therapeutic failures targeting immune responses. We discuss the major immune cell types implicated in IPF progression, highlighting their phenotypic transitions and mechanisms of action. Finally, we identify key knowledge gaps and propose future directions for research on the immune system in IPF.

PMID:40124525 | PMC:PMC11928166 | DOI:10.70322/fibrosis.2025.10004

Anal Chem. 2025 Mar 23. doi: 10.1021/acs.analchem.4c06786. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible fatal disease, the prevalence of which has been increasing in recent years. Nonradiographic and noninvasive early diagnosis of pulmonary fibrosis could improve prognosis but is a formidable challenge. As one of the fundamental microenvironmental parameters, viscosity is relevant to various pathological states, such as acute inflammation. Nevertheless, the potential biological roles of viscosity during the IPF process have been relatively underexplored. To address this issue, herein, we developed a new viscosity-responsive probe (JZ-2), which displayed high sensitivity and selectivity for viscosity, as well as excellent characteristics for targeting mitochondria. JZ-2 was successfully applied to map the changes in mitochondrial viscosity in cells caused by various stimuli, such as nystatin and lipopolysaccharide. Besides, JZ-2 was capable of differentiating cancer cells from normal cells and even tissues. More importantly, JZ-2 has been demonstrated to be sufficiently sensitive for tumor detection and early identification of IPF in vivo, revealing a significant increase in the viscosity of lung fibrosis tissues. Thus, JZ-2 is expected to be a swift and reliable diagnostic modality for the prediction of IPF progression in clinical settings.

PMID:40123047 | DOI:10.1021/acs.analchem.4c06786