Eur Respir Rev. 2025 Mar 19;34(175):240147. doi: 10.1183/16000617.0147-2024. Print 2025 Jan.

ABSTRACT

Heat shock protein 90 (HSP 90) and its isoforms are a group of homodimeric proteins that regulate several cellular processes, such as the elimination of misfolded proteins, cell development and post-translational modifications of kinase proteins and receptors. Due to its involvement in extracellular matrix (ECM) remodelling, myofibroblast differentiation and apoptosis, HSP 90 has been investigated as a key player in the pathogenesis of lung fibrosis. Idiopathic pulmonary fibrosis (IPF) is the most common and deadly interstitial lung disease, due to the progressive distortion of lung parenchyma related to the overproduction and deposition of altered ECM, driven by transforming growth factor-β (TGF-β) dependent and independent pathways. The inhibition or induction of HSP 90 is associated with a reduced or increased expression of TGF-β receptors, respectively, suggesting a role for HSP 90 as a biomarker and therapeutic target in IPF. Experimental drugs such as geldanamycin and its derivatives 17-AAG (17-N-allylamino-17-demethoxygeldanamicin) and 17-DMAG (17-dimethylaminoethylamino-17-demethoxigeldanamycin), along with AUY-922, 1G6-D7, AT-13387, TAS-116 and myricetin, have been found to reduce lung fibrosis in both in vivo and in vitro models, supporting the role of this emerging target. This review aims to illustrate the structure and biological function of HSP 90 in the context of IPF pathobiology, as well as perspective application of this molecule as a biomarker and therapeutic target for IPF.

PMID:40107664 | DOI:10.1183/16000617.0147-2024

Eur Respir Rev. 2025 Mar 19;34(175):240238. doi: 10.1183/16000617.0238-2024. Print 2025 Jan.

ABSTRACT

BACKGROUND: Comorbidities can affect drug tolerability and health outcomes in patients with fibrotic interstitial lung disease. This systematic review and meta-analysis evaluated the types and prevalence of comorbidities amongst participants in pharmaceutical randomised controlled trials (RCTs) of idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF).

METHODS: Ovid Medline, Embase and CENTRAL databases were searched to identify phase II and III pharmaceutical RCTs of IPF or PPF. Reporting of comorbidities was evaluated, with meta-analyses being performed for the prevalence of different conditions.

RESULTS: 34 articles were included, with 23 unique trials for IPF and one for PPF. A mean of 14 (range 1-44) comorbidities per study was reported in the IPF RCTs, with 11 being reported in the PPF RCT. Common comorbidities in the IPF RCT cohorts were systemic hypertension (pooled prevalence 45%, 95% CI 39-50%), hyperlipidaemia (38%, 95% CI 27-49%), gastro-oesophageal reflux disease (45%, 95% CI 36-54%), ischaemic heart disease (18%, 95% CI 13-42%) and diabetes mellitus (16%, 95% CI 13-20%). The PPF trial cohort had similar types and prevalence of comorbidities to those reported in the IPF trial cohorts.

CONCLUSIONS: Reporting of comorbidities varied across previous IPF RCTs, with limited data available for PPF. Prevalence of comorbidities reported in the IPF and PPF trial cohorts appear to be lower than those reported in prospective patient registries. There is a need for careful consideration of trial eligibility criteria with detailed reporting of comorbidities in future pharmaceutical RCTs to better understand the applicability of trial findings to real-world patients.

PMID:40107663 | DOI:10.1183/16000617.0238-2024

Respir Investig. 2025 Mar 18;63(3):394-398. doi: 10.1016/j.resinv.2025.03.006. Online ahead of print.

ABSTRACT

Both serum and bronchoalveolar lavage fluid levels of galectin-3 (Gal-3) are elevated in patients with idiopathic pulmonary fibrosis (IPF). Phase II study on inhaler with Gal-3 inhibitor for IPF has been ongoing. In this study, 30 treatment-naive patients of IPF were prospectively enrolled and their sera were stored before and after nintedanib treatment. Though Gal-3 levels tended to increase after nintedanib treatment, in some patients, Gal-3 levels decreased immediately after the treatment. Patients whose serum Gal-3 levels decreased 1 month after nintedanib treatment tended to experience a smaller annual decline in forced vital capacity (FVC) than patients with increased Gal-3 levels. Furthermore, the rate of change in Gal-3 levels 1 month after nintedanib treatment positively correlated with the rate of annual FVC decline, whereas that of other fibrotic markers did not correlate with the rate of annual FVC decline. This study suggested that a decline in serum Gal-3 levels immediately after nintedanib treatment may predict less progression of IPF treated with nintedanib.

PMID:40107223 | DOI:10.1016/j.resinv.2025.03.006

Respir Med Case Rep. 2025 Feb 27;54:102184. doi: 10.1016/j.rmcr.2025.102184. eCollection 2025.

ABSTRACT

An 81-year-old man with a history of interstitial lung disease attributed to idiopathic pulmonary fibrosis, severe aortic stenosis, and stable coronary artery disease was started on inhaled treprostinil for pulmonary hypertension associated with interstitial lung disease to optimize hemodynamics prior to the valve replacement procedure. However, two days after starting this treatment, the patient presented with an inferior-posterior ST elevation myocardial infarction. Urgent coronary angiography revealed a 95 % proximal right coronary artery stenosis, successfully treated with percutaneous coronary intervention and drug-eluting stent placement. This case raises a question of whether there could be a potential association between inhaled treprostinil initiation and acute myocardial infarction in patients with underlying coronary artery disease. With the documented stability of the patient's coronary artery disease prior to medication initiation, it is plausible to question whether treprostinil may have played a role in plaque destabilization.

PMID:40104432 | PMC:PMC11915154 | DOI:10.1016/j.rmcr.2025.102184

Nat Rev Drug Discov. 2025 Mar 18. doi: 10.1038/s41573-025-01158-9. Online ahead of print.

ABSTRACT

Fibrosis is a pathophysiological mechanism involved in chronic and progressive diseases that results in excessive tissue scarring. Diseases associated with fibrosis include metabolic dysfunction-associated steatohepatitis (MASH), inflammatory bowel diseases (IBDs), chronic kidney disease (CKD), idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc), which are collectively responsible for substantial morbidity and mortality. Although a few drugs with direct antifibrotic activity are approved for pulmonary fibrosis and considerable progress has been made in the understanding of mechanisms of fibrosis, translation of this knowledge into effective therapies continues to be limited and challenging. With the aim of assisting developers of novel antifibrotic drugs, this Review integrates viewpoints of biologists and physician-scientists on core pathways involved in fibrosis across organs, as well as on specific characteristics and approaches to assess therapeutic interventions for fibrotic diseases of the lung, gut, kidney, skin and liver. This discussion is used as a basis to propose strategies to improve the translation of potential antifibrotic therapies.

PMID:40102636 | DOI:10.1038/s41573-025-01158-9

Respir Investig. 2025 Mar 17;63(3):365-372. doi: 10.1016/j.resinv.2025.02.009. Online ahead of print.

ABSTRACT

BACKGROUND: Prognostic factors in patients with newly diagnosed idiopathic interstitial pneumonia (IIP) have rarely been analyzed using prospective data. This study investigated prognostic factors in patients with IIP.

METHODS: Central interstitial lung disease (ILD) experts established the diagnoses for fibrotic ILD. Prognostic factors using baseline data, including the pathological confidence level of usual interstitial pneumonia (UIP) assessed on a 0%-100% linear analog scale by high-resolution CT (HRCT), pulmonary function tests, and patient-reported outcomes were investigated.

RESULTS: Overall, 866 eligible patients were registered. Patients with unclassifiable idiopathic interstitial pneumonia (n = 272) survived longer than those with idiopathic pulmonary fibrosis (IPF) (n = 469) (hazard ratio [HR] = 0.67; [95% confidence interval [CI]: 0.47-0.95]; P = 0.022); however, IPF as IIPs classification was not a significant prognostic factor at diagnosis (P = 0.577). UIP pattern on HRCT, age, body mass index, forced vital capacity, diffusing capacity of the lungs for carbon monoxide, and St. George's Respiratory Questionnaire were risk factors for survival (P < 0.05). Patients with proposed progressive pulmonary fibrosis (PPF) had poorer prognoses than those without proposed PPF (HR = 5.63; [95% CI: 3.17-10.00]; P < 0.001). Patients with progressive fibrosing ILD (PF-ILD) had poorer prognoses than those without PF-ILD (HR = 7.85; [95% CI: 3.38-18.3]; P < 0.001).

CONCLUSIONS: A prospective registry of patients with newly diagnosed IIP provided evidence that the UIP pattern on HRCT by analog scale was a prognostic predictor. Proposed PPF and PF-ILD were valuable for discriminating prognosis. (JIPS Registry, ClinTrials.gov, NCT03041623).

PMID:40101437 | DOI:10.1016/j.resinv.2025.02.009

J Clin Invest. 2025 Mar 18:e181775. doi: 10.1172/JCI181775. Online ahead of print.

ABSTRACT

Tissue regenerative responses involve complex interactions between resident structural and immune cells. Recent reports indicate that accumulation of senescent cells during injury repair contributes to pathological tissue fibrosis. Using tissue-based spatial transcriptomics and proteomics, we identified upregulation of the immune checkpoint protein, cytotoxic T-lymphocyte associated protein 4 (CTLA4) on CD8+ T cells adjacent to regions of active fibrogenesis in human idiopathic pulmonary fibrosis (IPF) and in a murine model of repetitive bleomycin lung injury model of persistent fibrosis. In humanized CTLA4 knock-in mice, treatment with ipilimumab, an FDA-approved drug that targets CTLA4, resulted in accelerated lung epithelial regeneration and diminished fibrosis from repetitive bleomycin injury. Ipilimumab treatment resulted in the expansion of Cd3e+ T cells, diminished accumulation of senescent cells, and robust expansion of type 2 alveolar epithelial cells, facultative progenitor cells of the alveolar epithelium. Ex-vivo activation of isolated CTLA4-expressing CD8+ cells from mice with established fibrosis resulted in enhanced cytolysis of senescent cells, suggesting that impaired immune-mediated clearance of these cells contribute to persistence of lung fibrosis in this murine model. Our studies support the concept that endogenous immune surveillance of senescent cells may be essential in promoting tissue regenerative responses that facilitate the resolution of fibrosis.

PMID:40100323 | DOI:10.1172/JCI181775

Sarcoidosis Vasc Diffuse Lung Dis. 2025 Mar 18;42(1):15604. doi: 10.36141/svdld.v42i1.15604.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease. Lung cancer (LC) is among the most crucial comorbidity factors in patients with IPF. IPF patients that are diagnosed with LC have a reduced mean survival time. Therapeutic strategies for LC in patients with IPF need to be adapted according to the individual treatment risk. Life-threatening acute exacerbation (AE) of IPF may occur in association with cancer treatment, thereby severely restricting the therapeutic options for IPF-associated LC. Because LC and anticancer treatments can worsen the prognosis of IPF, the prevention of LC is as critical as managing patients with IPF.

PMID:40100103 | DOI:10.36141/svdld.v42i1.15604

Cureus. 2025 Feb 15;17(2):e79036. doi: 10.7759/cureus.79036. eCollection 2025 Feb.

ABSTRACT

Erasmus syndrome (ES) is a rare condition characterized by the link between crystalline silica exposure, with or without silicosis, and systemic sclerosis (SSc). Although first noted over a century ago, its underlying mechanisms remain unclear. However, it is indistinguishable from idiopathic SSc in the general population. Its clinical presentation is heterogeneous, depending on the affected systems, with notable features, including skin fibrosis, microstomia, telangiectasia, Raynaud's phenomenon, arthralgia, and interstitial lung disease. Currently, there is no unified consensus on its treatment; however, organ-specific therapy is a reasonable approach. We report the case of a 43-year-old miner diagnosed with diffuse cutaneous SSc, where ES was diagnosed after an exhaustive history was taken, occupational exposure was characterized, differential diagnoses were excluded, and radiological and histopathological evidence of pulmonary silicosis was presented.

PMID:40099047 | PMC:PMC11912300 | DOI:10.7759/cureus.79036

BMC Med Genomics. 2025 Mar 17;18(1):54. doi: 10.1186/s12920-025-02110-x.

ABSTRACT

BACKGROUND: Post-Covid Pulmonary Fibrosis (PCPF) has emerged as a significant global issue associated with a poor quality of life and significant morbidity. Currently, our understanding of the molecular pathways of PCPF is limited. Hence, in this study, we performed whole transcriptome sequencing of the RNA isolated from the bronchoalveolar lavage (BAL) samples of PCPF and compared it with idiopathic pulmonary fibrosis (IPF) and non-ILD (Interstitial Lung Disease) control to understand the gene expression profile and associated pathways.

METHODS: BAL samples from PCPF (n = 3), IPF (n = 3), and non-ILD Control (n = 3) (individuals with apparent healthy lung without interstitial lung disease) groups were obtained and RNA were isolated for whole transcriptomic sequencing. Differentially Expressed Genes (DEGs) were determined followed by functional enrichment analysis and qPCR validation.

RESULTS: A panel of differentially expressed genes were identified in bronchoalveolar lavage fluid cells (BALF) of PCPF as compare to control and IPF. Our analysis revealed dysregulated pathways associated with cell cycle regulation, immune responses, and neuroinflammatory processes. Real-time validation further supported these findings. The PPI network and module analysis shed light on potential biomarkers and underscore the complex interplay of molecular mechanisms in PCPF. The comparison of PCPF and IPF identified a significant downregulation of pathways that were more prominent in IPF.

CONCLUSION: This investigation provides crucial insights into the molecular mechanism of PCPF and also outlines avenues for prospective research and the development of therapeutic approaches.

PMID:40098116 | DOI:10.1186/s12920-025-02110-x

J Clin Med. 2025 Mar 3;14(5):1693. doi: 10.3390/jcm14051693.

ABSTRACT

Background: Patients suffering from idiopathic pulmonary fibrosis (IPF) may experience acute exacerbation (AE-IPF), which frequently results in acute respiratory failure (ARF) requiring hospitalization. Objective: This study aims to determine if survival has improved over the last decade in patients hospitalized for ARF consequent to AE-IPF, in view of the progress recently made in pharmacological and supportive treatment strategies. Methods: This was an observational retrospective single-center study. The data of 14 patients admitted to an Intermediate Respiratory Care Unit (IRCU) between 1 January 2004 and 31 December 2013 (group A) were compared with those of 26 patients admitted between 1 January 2014 and 31 December 2023 (group B). This study's primary endpoint was survival following IRCU admission. Results: Survival time was significantly longer in the second group of patients compared to the first one [median survival time: 134 (31-257) vs. 25.5 (20-50) days; p < 0.001]. Group B patients also had a lower IRCU mortality rate (6/26 vs. 10/14; p = 0.003) and a significantly shorter stay in the IRCU [6 (1-60) vs. 14 (1-43) days; p = 0.039]. Conclusions: Innovative pharmacologic treatments and supportive therapeutic strategies are able to prolong survival and reduce the risk of in-hospital mortality in patients with AE-IPF hospitalized for ARF.

PMID:40095670 | DOI:10.3390/jcm14051693

J Epidemiol Glob Health. 2025 Mar 17;15(1):44. doi: 10.1007/s44197-025-00377-y.

ABSTRACT

BACKGROUND: Advances in the understanding of idiopathic pulmonary fibrosis (IPF) and international cooperation have led to the publication and subsequent updates of international practice guidelines. The impact of these guidelines, especially significant updates occurring after 2011, on IPF epidemiology and clinical practices remains relatively unexplored.

METHODS: This retrospective nationwide population-based study utilized the Whole-Population Datafiles (WPD) of Taiwan's National Health Insurance Research Database that contained basic demographics, complete claim data, and causes of death for all insured persons. We refined the code-based definition to identify IPF cases from the WPD between 2011 and 2019. Independent validation confirmed the high accuracy of this definition. We analyzed the annual standardized rates of IPF incidence, prevalence, overall and IPF-specific all-cause mortality. Additionally, we examined trends in the prescription of selected medications and the proportions of patients with respiratory failure receiving invasive (IMV) and non-invasive (NIV) mechanical ventilation.

RESULTS: We included 4359 incident cases of IPF. From 2011 to 2019, the annual standardized incidence rates increased from 1.66 (95% confidence interval [CI], 1.36-1.97) to 11.35 (95% CI, 10.65-12.04) per 100,000 standard population, and the annual standardized prevalence rates increased from 1.98 (95% CI, 1.65-2.31) to 27.25 (95% CI, 26.17-28.33) per 100,000 standard population. The standardized IPF-specific all-cause mortality and respiratory failure rates remained stable. Male and older patients received IPF diagnoses more frequently, and experienced higher mortality rates, compared to their female and younger counterparts. Most deaths were attributed to respiratory causes, without significant seasonal variation. Changing trends in the management of IPF mirrored with the evolving guideline recommendations, and showed diminishing roles of immunosuppressants, growing usage of antifibrotics, and NIV usage surpassing IMV.

CONCLUSIONS: Our findings reflected the longitudinal impact of the recently evolving guideline recommendations on IPF epidemiology and real-world management.

PMID:40095261 | DOI:10.1007/s44197-025-00377-y

J Clin Med. 2025 Feb 24;14(5):1496. doi: 10.3390/jcm14051496.

ABSTRACT

Telomeropathies, or telomere biology disorders (TBDs), are syndromes that can cause a number of medical conditions, including interstitial lung disease (ILD), bone marrow failure, liver fibrosis, and other diseases. They occur due to genetic mutations to the telomerase complex enzymes that result in premature shortening of telomeres, the caps on the ends of cellular DNA that protect chromosome length during cell division, leading to early cell senescence and death. Idiopathic pulmonary fibrosis (IPF) is the most common manifestation of the telomere biology disorders, although it has been described in other interstitial lung diseases as well, such as rheumatoid arthritis-associated ILD and chronic hypersensitivity pneumonitis. Telomere-related mutations can be inherited or can occur sporadically. Identifying these patients and offering genetic counseling is important because telomerapathies have been associated with poorer outcomes including death, lung transplantation, hospitalization, and FVC decline. Additionally, treatment with immunosuppressants has been shown to be associated with worse outcomes. Currently, there is no specific treatment for TBD except to transplant the organ that is failing, although there are a number of promising treatment strategies currently under investigation. Shortened telomere length is routinely discovered in patients undergoing lung transplantation for IPF. Testing to detect early TBD in patients with suggestive signs or symptoms can allow for more comprehensive treatment and multidisciplinary care pre- and post-transplant. Patients with TBD undergoing lung transplantation have been reported to have both pulmonary and extrapulmonary complications at a higher frequency than other lung transplant recipients, such as graft-specific complications, increased infections, and complications related to immunosuppressive therapy.

PMID:40095034 | DOI:10.3390/jcm14051496

J Inflamm Res. 2025 Mar 11;18:3449-3468. doi: 10.2147/JIR.S497734. eCollection 2025.

ABSTRACT

BACKGROUND: Rheumatoid arthritis (RA) and idiopathic pulmonary fibrosis (IPF) share a common pathogenic mechanism, but the underlying mechanisms remain ambiguous. Our study aims at exploring the genetic-level pathogenic mechanism of these two diseases.

METHODS: We carried out bioinformatics analysis on the GSE55235 and GSE213001 datasets. Machine learning was employed to identify candidate genes, which were further verified using the GSE92592 and GSE89408 datasets, as well as quantitative real-time PCR (qRT-PCR). The expression levels of TOP2A in RA and IPF in vitro models were confirmed using Western blotting and qRT-PCR. Furthermore, we explored the influence of TOP2A on the occurrence and development of RA and IPF by using the selective inhibitor PluriSIn #2 in an in vitro model. Finally, an in vivo model of RA and IPF was constructed to assess TOP2A expression levels via immunohistochemistry.

RESULTS: Our bioinformatics analysis suggests a potential intersection in the pathogenic mechanisms of RA and IPF. We have identified 7 candidate genes: CXCL13, TOP2A, MMP13, MMP1, LY9, TENM4, and SEMA3E. Our findings reveal that the expression level of TOP2A is significantly elevated in both in vivo and in vitro models of RA and IPF. Additionally, our research indicates that PluriSIn #2 can effectively restrain inflammatory factors, extracellular matrix deposition, migration, invasion, the expression and nuclear uptake of p-smad2/3 protein in RA and IPF in vitro models.

CONCLUSION: There is a certain correlation between RA and IPF at the genetic level, and the molecular mechanisms of their pathogenesis overlap, which might be the reason for the progression of RA. Among the candidate genes we identified, TOP2A may influence the occurrence and development of RA and IPF through the TGF-β/Smad signal pathway. This could be beneficial to the study of the pathogenesis and treatment of RA and IPF.

PMID:40093950 | PMC:PMC11910056 | DOI:10.2147/JIR.S497734

Front Pharmacol. 2025 Feb 28;16:1486357. doi: 10.3389/fphar.2025.1486357. eCollection 2025.

ABSTRACT

BACKGROUND: Glycolysis plays a crucial role in fibrosis, but the specific genes involved in glycolysis in idiopathic pulmonary fibrosis (IPF) are not well understood.

METHODS: Three IPF gene expression datasets were obtained from the Gene Expression Omnibus (GEO), while glycolysis-related genes were retrieved from the Molecular Signatures Database (MsigDB). Differentially expressed glycolysis-related genes (DEGRGs) were identified using the "limma" R package. Diagnostic glycolysis-related genes (GRGs) were selected through least absolute shrinkage and selection operator (LASSO) regression regression and support vector machine-recursive feature elimination (SVM-RFE). A prognostic signature was developed using LASSO regression, and time-dependent receiver operating characteristic (ROC) curves were generated to evaluate predictive performance. Single-cell RNA sequencing (scRNA-seq) data were analyzed to examine GRG expression across various cell types. Immune infiltration analysis, Gene Set Enrichment Analysis (GSEA), and Gene Set Variation Analysis (GSVA) were performed to elucidate potential molecular mechanisms. A bleomycin (BLM)-induced pulmonary fibrosis mouse model was used for experimental validation via reverse transcription-quantitative polymerase chain reaction (RT-qPCR).

RESULTS: 14 GRGs (VCAN, MERTK, FBP2, TPBG, SDC1, AURKA, ARTN, PGP, PLOD2, PKLR, PFKM, DEPDC1, AGRN, CXCR4) were identified as diagnostic markers for IPF, with seven (ARTN, AURKA, DEPDC1, FBP2, MERTK, PFKM, SDC1) forming a prognostic model demonstrating predictive power (AUC: 0.831-0.793). scRNA-seq revealed cell-type-specific GRG expression, particularly in macrophages and fibroblasts. Immune infiltration analysis linked GRGs to imbalanced immune responses. Experimental validation in a bleomycin-induced fibrosis model confirmed the upregulation of GRGs (such as AURKA, CXCR4). Drug prediction identified inhibitors (such as Tozasertib for AURKA, Plerixafor for CXCR4) as potential therapeutic agents.

CONCLUSION: This study identifies GRGs as potential prognostic biomarkers for IPF and highlights their role in modulating immune responses within the fibrotic lung microenvironment. Notably, AURKA, MERTK, and CXCR4 were associated with pathways linked to fibrosis progression and represent potential therapeutic targets. Our findings provide insights into metabolic reprogramming in IPF and suggest that targeting glycolysis-related pathways may offer novel pharmacological strategies for antifibrotic therapy.

PMID:40093327 | PMC:PMC11906445 | DOI:10.3389/fphar.2025.1486357

Open Vet J. 2025 Jan;15(1):118-125. doi: 10.5455/OVJ.2024.v15.i1.11. Epub 2025 Jan 31.

ABSTRACT

BACKGROUND: Pulmonary fibrosis represents the most prevalent form of idiopathic interstitial pneumonia. The pathogenesis of pulmonary fibrosis using a bleomycin-induced mice model has indicated an imbalanced immune response such as an early massive inflammatory response, followed by fibrosis development. Therapy focused on restraining inflammation is one of the ways to inhibit fibrosis development. Elephantopus scaber ethanolic extract (ESEE) is known to have many beneficial compounds that were proven to possess anti-inflammatory activities, but its prospect in inhibiting pulmonary fibrosis development needs to be investigated.

AIM: This study aimed to evaluate the potency of ESEE treatment in inhibiting fibrosis development in the bleomycin-induced pulmonary fibrosis mice model.

METHODS: Healthy male BALB/c mice were divided into seven experimental groups (n = 8): healthy mice (N), vehicle mice (VC), pulmonary fibrosis mice (C-), pulmonary fibrosis received dexamethasone (C+), and pulmonary fibrosis mice received ESEE at a 0.0504 mg/kg body weight (BW) (D1), 0.1008 mg/kg BW (D2), and 0.2016 mg/kg BW (D3). Mice were given ESEE orally and intraperitoneal bleomycin injection daily for 14 days. Mice were then sacrificed on days 7 and 14 and spleens were isolated to determine the production of IL-10, TNF-α, and IFN-γ using flow cytometry.

RESULTS: The results revealed that a remarkable increase of TNF-α was found in the macrophage of pulmonary fibrosis mice model from day 7 to 14. An increase in IFN-γ production was also observed on day 7 and then decreased on day 14. The production of IL-10 was reduced in the fibrosis group at day 7 and continued to increase at day 14. Interestingly, ESEE treatment for 14 days could effectively reduce TNF-α and increase IFN-γ production. ESEE treatment could also maintain a stable production of IL-10 at each time point. ESEE at 0.1004 mg/kg BW (D2) showed the most effective activity in reducing pro-fibrotic cytokine than the dexamethasone group.

CONCLUSION: Ethanolic extract of ESEE has demonstrated its beneficial prospect in regulating pro-inflammatory and pro-fibrotic cytokine to inhibit fibrosis development.

PMID:40092211 | PMC:PMC11910286 | DOI:10.5455/OVJ.2024.v15.i1.11

J Transl Med. 2025 Mar 16;23(1):337. doi: 10.1186/s12967-025-06368-8.

ABSTRACT

OBJECTIVE: To identify potential therapeutic targets and evaluate the safety profiles for Idiopathic Pulmonary Fibrosis (IPF) using a comprehensive multi-omics approach.

METHOD: We integrated genomic and transcriptomic data to identify therapeutic targets for IPF. First, we conducted a transcriptome-wide association study (TWAS) using the Omnibus Transcriptome Test using Expression Reference Summary data (OTTERS) framework, combining plasma expression quantitative trait loci (eQTL) data with IPF Genome-Wide Association Studies (GWAS) summary statistics from the Global Biobank (discovery) and Finngen (duplication). We then applied Mendelian randomization (MR) to explore causal relationships. RNA-seq co-expression analysis (bulk, single-cell and spatial transcriptomics) was used to identify critical genes, followed by molecular docking to evaluate their druggability. Finally, phenome-wide MR (PheW-MR) using GWAS data from 679 diseases in the UK Biobank assessed the potential adverse effects of the identified genes.

RESULT: We identified 696 genes associated with IPF in the discovery dataset and 986 genes in the duplication dataset, with 126 overlapping genes through TWAS. MR analysis revealed 29 causal genes in the discovery dataset, with 13 linked to increased and 16 to decreased IPF risk. Summary data-based MR (SMR) confirmed six essential genes: ANO9, BRCA1, CCDC200, EZH1, FAM13A, and SFR1. Bulk RNA-seq showed FAM13A upregulation and SFR1 and EZH1 downregulation in IPF. Single-cell RNA-seq revealed gene expression changes across cell types. Molecular docking identified binding solid affinities for essential genes with respiratory drugs, and PheW-MR highlighted potential side effects.

CONCLUSION: We identified six key genes-ANO9, BRCA1, CCDC200, EZH1, FAM13A, and SFR1-as potential drug targets for IPF. Molecular docking revealed strong drug affinities, while PheW-MR analysis highlighted therapeutic potential and associated risks. These findings offer new insights for IPF treatment and further investigation of potential side effects.

PMID:40091050 | DOI:10.1186/s12967-025-06368-8

Contemp Clin Trials. 2025 Mar 14:107883. doi: 10.1016/j.cct.2025.107883. Online ahead of print.

ABSTRACT

BACKGROUND: Pulmonary fibrosis is a major complication of the Acute Respiratory Distress Syndrome (ARDS). Pirfenidone is an approved treatment for idiopathic pulmonary fibrosis. It may attenuate ARDS-related fibrosis and decrease the need for prolonged ventilation. Accordingly, we aimed to evaluate the effect of pirfenidone on ventilator-free days in patients with ARDS.

METHODS: In a multi-center, randomized, double-blind, placebo-controlled trial, we plan to randomly assign 130 adults invasively ventilated for ARDS to receive pirfenidone or placebo for up to 28 days. The primary outcome is days alive and ventilator free at 28 days. Secondary outcomes include ICU-free days, hospital free days all at 28 day, ICU mortality and hospital mortality. We will also assess fibroproliferative changes on high-resolution CT scans at ICU discharge and quality of life. Data analysis will be on an intention-to-treat basis.

DISCUSSION: The trial is ongoing and currently recruiting. It will be the first randomized controlled study to investigate whether, compared to placebo, pirfenidone reduces the number of days alive and ventilator-free in patients with ARDS. Its double-blind multicenter design will provide internal validity, minimal bias, and a degree of external validity. If our hypothesis is confirmed, this treatment would justify larger trials of this intervention.

TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov with the trial identification NCT05075161.

PMID:40090666 | DOI:10.1016/j.cct.2025.107883

SLAS Discov. 2025 Mar 14:100226. doi: 10.1016/j.slasd.2025.100226. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive age-related lung disease with an average survival of 3-5 years post-diagnosis if left untreated. It is characterized by lung fibrosis, inflammation, and destruction of lung architecture, leading to worsening respiratory symptoms and physiological impairment, ultimately culminating in progressive respiratory failure. The development of novel therapeutics for the treatment of IPF represents a significant unmet medical need. Fibroblast to myofibroblast transition (FMT) in response to fibrogenic mediators such as transforming growth factor beta 1 (TGF-β1) has been identified as a key cellular phenotype driving the formation of myofibroblasts and lung fibrosis in IPF. Establishing a robust and high-throughput in vitro human FMT assay is crucial for uncovering new disease targets and for efficiently screening compounds for the advancement of novel therapeutics aimed at targeting myofibroblast activity. However, creating a robust FMT assay suitable for high-throughput drug screening has proven challenging due to the requisite level of automation. In this study, we focus on evaluating different automation approaches for liquid exchange and compound dosing in the human FMT assay. A semi-automated assay, capable of screening a large number of compounds that inhibit TGF-β1-induced FMT in both Normal Human Lung Fibroblasts (NHLF) and IPF-patient derived Disease Human Lung Fibroblasts (IPF-DHLF), has been successfully developed and optimized. We demonstrate that the optimized FMT assay using liquid handling automation exhibits great assay reproducibility, shows good assay translation using human lung fibroblasts from normal healthy versus IPF-patients, and demonstrates acceptable human primary donor variability. This allows for the standardization of comparisons of compound anti-fibrotic potency across IPF projects.

PMID:40090552 | DOI:10.1016/j.slasd.2025.100226

Semin Arthritis Rheum. 2025 Mar 15;72:152708. doi: 10.1016/j.semarthrit.2025.152708. Online ahead of print.

ABSTRACT

OBJECTIVE: Genome-wide association studies (GWAS) facilitate construction of polygenic risk scores (PRSs) for rheumatoid arthritis (RA) and idiopathic pulmonary fibrosis (IPF). We investigated associations of RA and IPF PRSs with RA and high-resolution chest computed tomography (HRCT) parenchymal lung abnormalities.

METHODS: Participants in COPDGene, a prospective multicenter cohort of current/former smokers, had chest HRCT at study enrollment. Using genome-wide genotyping, RA and IPF PRSs were constructed using GWAS summary statistics. HRCT imaging underwent visual inspection for interstitial lung abnormalities (ILA) and quantitative CT (QCT) analysis using a machine-learning algorithm that quantified percentage of normal lung, interstitial abnormalities, and emphysema. RA was identified through self-report and DMARD use. We investigated associations of RA and IPF PRSs with RA, ILA, and QCT features using multivariable logistic and linear regression.

RESULTS: We analyzed 9,230 COPDGene participants (mean age 59.6 years, 46.4 % female, 67.2 % non-Hispanic White, 32.8 % Black/African American). In non-Hispanic White participants, RA PRS was associated with RA diagnosis (OR 1.32 per unit, 95 %CI 1.18-1.49) but not ILA or QCT features. Among non-Hispanic White participants, IPF PRS was associated with ILA (OR 1.88 per unit, 95 %CI 1.52-2.32) and quantitative interstitial abnormalities (adjusted β=+0.50 % per unit, p = 7.3 × 10-8) but not RA. There were no statistically significant associations among Black/African American participants.

CONCLUSIONS: RA and IPF PRSs were associated with their intended phenotypes among non-Hispanic White participants but performed poorly among Black/African American participants. PRS may have future application to risk stratify for RA diagnosis among patients with ILD or for ILD among patients with RA.

PMID:40090204 | DOI:10.1016/j.semarthrit.2025.152708