Sci Rep. 2025 Mar 23;15(1):10009. doi: 10.1038/s41598-025-94801-9.

ABSTRACT

The swift transmission rate and unfavorable prognosis associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have prompted the pursuit of more effective therapeutic interventions. Azithromycin (AZM) has garnered significant attention for its distinctive pharmacological mechanisms in the treatment of SARS-CoV-2. This study aims to elucidate the biological rationale for employing AZM in patients with chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) who are infected with SARS-CoV-2. Genetic data about COVID-19, COPD, and IPF were independently obtained from the GeneCards database. And 40 drug targets about AZM were retrieved from the STITCH database. The analysis revealed that 311 DEGs were common among COPD, IPF, and COVID-19, and we further found eight genes that interacted with AZM targets. We conducted an analysis of hub genes and their corresponding signaling pathways in these patient cohorts. Additionally, we explored the inhibitory effects of AZM on these hub genes. AZM demonstrated a significant inhibitory effect on eight key genes, except for AR and IL-17 A. These findings suggest that AZM may serve as a promising therapeutic agent for patients with COPD and IPF and SARS-CoV-2 infection.

PMID:40122903 | DOI:10.1038/s41598-025-94801-9

Respirology. 2025 Mar 23. doi: 10.1111/resp.70030. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Real-world data on lung function course of patients with progressive pulmonary fibrosis (PPF) treated with anti-fibrotic medication are limited. We evaluated forced vital capacity (FVC) decline in patients with PPF and idiopathic pulmonary fibrosis (IPF) who started anti-fibrotic treatment.

METHODS: This was a nationwide multi-centre registry study in 16 hospitals throughout the Netherlands. Patients treated with anti-fibrotic medication, with at least two in-hospital pulmonary function tests before and after the initiation of anti-fibrotic treatment, were included. Linear mixed-effects modelling was used to analyse lung function trajectories 1 year before and after the start of anti-fibrotic treatment.

RESULTS: Data from 538 patients (n = 142 with PPF, n = 396 with IPF) were analysed. In PPF, the mean annualised FVC decline was 412 mL (95% confidence interval [CI]: 308-517 mL) before the initiation of anti-fibrotic treatment, and 18 mL (95% CI: 9-124 mL) in the first year after. The corresponding declines for IPF were 158 mL (95% CI: 78-239 mL) and 38 mL (95% CI: 24-101 mL). In both groups, treatment significantly slowed down FVC decline, although the change was larger in the PPF group (p = 0.0006). In the first year after treatment initiation, 28.0% of patients with PPF and 27.4% with IPF had disease progression.

CONCLUSION: The FVC decline significantly slowed after the initiation of treatment for both IPF and PPF. Nevertheless, a significant proportion of patients exhibited disease progression, despite the start of anti-fibrotic treatment. Early identification of these patients is crucial for treatment adaptations and inclusion in clinical trials.

PMID:40122143 | DOI:10.1111/resp.70030

Respir Res. 2025 Mar 22;26(1):111. doi: 10.1186/s12931-025-03187-9.

ABSTRACT

The coronavirus disease 2019 (COVID-19) global pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, our understanding of SARS-CoV-2-induced inflammation in alveolar epithelial cells remains very limited. The contributions of intracellular insulin-like growth factor binding protein-2 (IGFBP2) to SARS-CoV-2 pathogenesis are also unclear. In this study, we have uncovered a critical role for IGFBP2, specifically in alveolar epithelial type 2 cells (AEC2), in the immunopathogenesis of COVID-19. Using bulk RNA sequencing, we show that IGFBP2 mRNA expression is significantly downregulated in primary AEC2 cells isolated from fibrotic lung regions from patients with COVID-19-acute respiratory distress syndrome (ARDS) compared to those with idiopathic pulmonary fibrosis (IPF) alone or IPF with a history of COVID-19. Using multicolor immunohistochemistry, we demonstrated that IGFBP2 and its selective ligands IGF1 and IGF2 were significantly reduced in AEC2 cells from patients with COVID-ARDS, IPF alone, or IPF with COVID history than in those from age-matched donor controls. Further, we demonstrated that lentiviral expression of Igfbp2 significantly reduced mRNA expression of proinflammatory cytokines-Tnf-α, Il1β, Il6, Stat3, Stat6 and chemokine receptors-Ccr2 and Ccr5-in mouse lung epithelial cells challenged with SARS-CoV-2 spike protein injury (S2; 500 ng/mL). Finally, we demonstrated higher levels of cytokines-TNF-α; IL-6 and chemokine receptor-CCR5 in AEC2 cells from COVID-ARDS patients compared to the IPF alone and the IPF with COVID history patients. Altogether, these data suggest that anti-inflammatory properties of IGFBP2 in AEC2 cells and its localized delivery may serve as potential therapeutic strategy for patients with COVID-19.

PMID:40121473 | DOI:10.1186/s12931-025-03187-9

BMJ Open Respir Res. 2025 Mar 22;12(1):e002327. doi: 10.1136/bmjresp-2024-002327.

ABSTRACT

INTRODUCTION: Breathlessness is common and impairs the quality of life of people with idiopathic pulmonary fibrosis (IPF) and non-IPF fibrotic interstitial lung diseases (ILD). We report the findings of a multicentre, fast-track (wait-list), mixed-methods, randomised controlled, feasibility study of a complex breathlessness intervention in breathless IPF and non-IPF fibrotic ILD patients.

METHODS: Breathless IPF and non-IPF fibrotic ILD patients were randomised to receive the intervention within 1 week (fast-track) or after 8 weeks (wait-list). The intervention comprised two face-to-face and one telephone appointment during a 3-week period covering breathing control, handheld fan-use, pacing and breathlessness management techniques, and techniques to manage anxiety. Feasibility and clinical outcomes were assessed to inform progression to, and optimal design for, a definitive trial. A qualitative substudy explored barriers and facilitators to trial and intervention delivery.

RESULTS: 47 patients (M:F 38:9, mean (SD) age 73.9 (7.2)) were randomised with a recruitment rate of 2.5 participants per month across three sites. The adjusted mean differences (95% CI) for key clinical outcomes at 4 weeks post randomisation were as follows: Chronic Respiratory Questionnaire breathlessness mastery domain (0.45 (-0.07, 0.97)); and numerical rating scales for 'worst' (-0.93 (-1.95, 0.10)), 'best' (-0.19 (-1.38, 1.00)), 'distress caused by' (-1.84 (-3.29, -0.39)) and 'ability to cope with' (0.71 (-0.57, 1.99)) breathlessness within the past 24 hours. The qualitative substudy confirmed intervention acceptability and informed feasibility and acceptability of study outcome measures.

CONCLUSION: A definitive trial of a complex breathlessness intervention in patients with IPF and non-IPF fibrotic ILD is feasible with preliminary data supporting intervention effectiveness.

TRIAL REGISTRATION NUMBER: ISRCTN13784514.

PMID:40121019 | DOI:10.1136/bmjresp-2024-002327

Aging Clin Exp Res. 2025 Mar 22;37(1):101. doi: 10.1007/s40520-025-03009-4.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is more likely to occur in the elderly population, and these patients often become depressed. It has been recognized that psychological disorders are not conducive to the control of many diseases. Thus, this study aims to determine whether alleviating depression can delay the progression of IPF and frailty in elderly patients with IPF.

METHODS: IPF patients over 60 years old were included in the study. None had a prior history of psychological disorders. All developed depression after being diagnosed with IPF. During the 12-month follow-up, some patients received anti-depression interventions and the rest didn't. Depression, IPF, frailty and peripheral inflammation at baseline and after follow-up were evaluated by indicators and scales such as BDI-II, FVC %pred, 6MWT, mMRC, CFS, TFI, SGRQ, K-BILD, IL-6, and TNF-α. Multivariate logistic regression was employed for data analysis.

RESULTS: There were 213 elderly patients with IPF. Among the 89 patients who received anti-depression interventions, the above-mentioned indicators and scales did not deteriorate during the follow-up period (P > 0.05). Among the remaining 124 patients, the FVC %pred, and 6MWT levels decreased, and the mMRC grade, CFS, TFI, SGRQ and K-BILD scores, and peripheral IL-6 and TNF-α levels increased during the follow-up period (P < 0.05).

DISCUSSION: Compared with non-intervened IPF patients, those receiving anti-depression interventions seemed to maintain a certain stability in IPF, frailty, and peripheral inflammation over a period.

CONCLUSION: Improving depression may help delay the deterioration of patients' IPF and frailty at certain stages.

TRIAL REGISTRATION: Registration on UMIN-CTR.

REGISTRATION NUMBER: UMIN000057161. Date of registration: February 27th, 2025.

PMID:40120048 | DOI:10.1007/s40520-025-03009-4

Fam Cancer. 2025 Mar 22;24(2):31. doi: 10.1007/s10689-025-00455-x.

ABSTRACT

Telomere biology disorders (TBDs) are a group of genetic conditions characterized by defects in telomere maintenance leading to multisystemic organ involvement and a predisposition to hematologic malignancies. The management of patients with TBDs who develop acute myeloid leukemia (AML) presents a significant challenge due to their limited bone marrow reserve and non-hematopoietic organ dysfunction. We present the case of a 45-year-old patient with a previously unrecognized TBD who presented with AML. The patient's history of longstanding cytopenias, idiopathic avascular necrosis, and pulmonary fibrosis were suggestive of a TBD, which was confirmed through telomere length testing and the presence of a TERT variant. Due to his underlying TBD, he was treated with dose-reduced azacitidine and venetoclax, adapting the approach commonly employed in elderly, co-morbid AML patients ineligible for intensive chemotherapy. This resulted in a complete remission with incomplete count recovery that has persisted for greater than 12 months to date. Aside from prolonged myelosuppression, the patient tolerated the regimen well with minimal toxicity. To our knowledge, this is the first report of the successful utilization of azacitidine and venetoclax as an AML treatment modality in TBD patients and underscores the potential of this regimen as an effective non-intensive treatment strategy for high grade myeloid neoplasms arising in the context of inherited bone marrow failure syndromes.

PMID:40119960 | DOI:10.1007/s10689-025-00455-x

Environ Sci Technol. 2025 Mar 22. doi: 10.1021/acs.est.4c11275. Online ahead of print.

ABSTRACT

Gaseous pollutants such as CO, NO2, O3, and SO2 are linked to adverse clinical outcomes in patients with fibrotic interstitial lung diseases (fILDs), particularly idiopathic pulmonary fibrosis. However, the effect of various exposure estimation methods on these findings remains unclear. This study aims to evaluate three spatial approaches─nearest neighbor (NN), inverse distance weighting (IDW), and Kriging─for estimating gaseous pollutant exposures and to assess how these methods affect health outcome estimates in fILD patients. A 10-fold cross-validation showed that Kriging had the lowest prediction error compared to NN and IDW, with RMSE for CO = 0.43 ppm (11%), O3 = 5.9 ppb (14%), SO2 = 2.7 ppb (12%), and NO2 = 7.6 ppb (9%), respectively. Kriging also excelled over other methods across wide spatial and temporal ranges, showing the highest spatial R2 for CO and O3 and the highest temporal R2 for SO2 and NO2. In a large cohort of patients with fILD, higher levels of CO, SO2, and NO2 exposure were associated with lower pulmonary function. The magnitude of association and its precision were higher in SO2 and CO estimated by the Kriging method. This study underscores Kriging as a robust method for estimating gaseous pollutant levels and offers valuable insights for future epidemiological studies.

PMID:40119855 | DOI:10.1021/acs.est.4c11275

Adv Sci (Weinh). 2025 Mar 22:e2405434. doi: 10.1002/advs.202405434. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) remains an incurable form of interstitial lung disease with sub-optimal treatments that merely address adverse symptoms or slow fibrotic progression. Here, inhalable hsa-miR-30a-3p-loaded liposomes (miR-30a) for the treatment of bleomycin-induced pulmonary fibrosis in mice are presented. It was previously found that exosomes (Exo) derived from lung spheroid cells are therapeutic in multiple animal models of pulmonary fibrosis and are highly enriched for hsa-miR-30a-3p. The present study investigates this miRNA as a singular factor to treat IPF. Liposomes containing miR-30a mimic can be delivered to rodents through dry powder inhalation. Inhaled miR-30a and Exo consistently lead to improved pulmonary function across six consecutive pulmonary function tests and promote de-differentiation of profibrotic myofibroblasts. The heterogenous composure of Exo also promotes reparative alveolar type I and II cell remodeling and vascular wound healing through broad transforming growth factor-beta signaling downregulation, while miR-30a targets myofibroblast de-differentiation through CNPY2/PERK/DDIT3 signaling. Overall, inhaled miR-30a represses the epithelial-mesenchymal transition of myofibroblasts, providing fibrotic attenuation and subsequent improvements in pulmonary function.

PMID:40119620 | DOI:10.1002/advs.202405434

Cell Death Dis. 2025 Mar 21;16(1):196. doi: 10.1038/s41419-025-07522-2.

ABSTRACT

The intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyzes the interconversion of active glucocorticoid (cortisol) and its intrinsically inert form (cortisone) in metabolic tissues. Although 11βHSD1 is considered a promising therapeutic target in metabolic disorders such as type 2 diabetes, obesity, and nonalcoholic steatohepatitis because of its hepatic functions, its roles in other tissues have received less attention. In this study, we show that the 11βHSD1-specific inhibitor J2H-1702 facilitates the reversion of endothelial-to-mesenchymal transition in multicellular lung spheroid models encapsulating the complex crosstalk among lung cancer cells, vascular endothelial cells, and macrophages. In vascular endothelial cells, J2H-1702 not only suppressed interleukin-1α (IL-1α) expression but also attenuated reactive oxygen species-induced DNA damage by upregulating heme oxygenase-1. Additionally, in macrophages, which are key regulators of fibrogenesis, inhibition of 11βHSD1 markedly reduced IL-1β expression, thereby modulating the pro-inflammatory phenotype of activated macrophages. In mouse models of pulmonary fibrosis, including a bleomycin-induced idiopathic model and a radiation-induced model, J2H-1702 alleviated pulmonary fibrosis and markedly improved the efficacy of nintedanib. Collectively, our data suggest that J2H-1702 holds promise as a clinical candidate for the treatment of pulmonary fibrosis associated with reactive oxygen species-induced DNA damage, endothelial-to-mesenchymal transition, and inflammatory responses.

PMID:40118823 | DOI:10.1038/s41419-025-07522-2

Clin Exp Immunol. 2025 Mar 21:uxaf019. doi: 10.1093/cei/uxaf019. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic inflammatory myopathy (IIM) is a progressive autoimmune disease characterized by interstitial lung disease (ILD) with limited therapeutics available. Pirfenidone (PFD), a medication utilized for the treatment of idiopathic pulmonary fibrosis, exhibits notable antioxidant, anti-inflammatory and inhibition of collagen synthesis. This study aims to clarify its efficacy and mechanism in treating IIM-ILD.

METHODS: A murine myositis-associated interstitial lung disease (MAILD) model was used to assess the therapeutic effect of PFD. The serum levels of IL-1β, IL-6 and TNF-α were detected by ELISA. PFD was utilized to disrupt neutrophil extracellular traps (NETs) formation in vitro, and its inhibitory effect on NETs was assessed through immunohistochemistry of CitH3 and MPO in the lung tissue and the serum cfDNA level in mice. Immunohistochemical and western blot was utilized to examine alterations in epithelial-mesenchymal transition (EMT) and NLRP3 inflammasome markers.

RESULTS: PFD treatment inhibited pulmonary inflammation and fibrosis in the MAILD model. PFD intervention reduced NETs formation in vitro. PFD treatment significantly reduce NETs infiltration in the lung tissue and the level of cfDNA in the serum of mice. Additionally, PFD down-regulated EMT and NLRP3-related proteins in vivo. PFD treatment also notably reduced serum levels of IL-1β, IL-6 and TNF-α. After NETs stimulation, A549 cells exhibited EMT and activation of NLRP3 inflammasome. PFD attenuated EMT in A549 cells and suppressed the activation of NLRP3 inflammasome.

CONCLUSION: PFD alleviates ILD in a murine MAILD model by inhibiting NETs formation and NLRP3 inflammasome activation, suggesting that PFD might be a potential therapeutic agent for IIM-ILD.

PMID:40117382 | DOI:10.1093/cei/uxaf019

J Family Med Prim Care. 2025 Feb;14(2):807-810. doi: 10.4103/jfmpc.jfmpc_642_24. Epub 2025 Feb 21.

ABSTRACT

IPF is a chronic lung disease that is characterized by progressive deterioration of pulmonary function associated with scarring of the lung interstitium, resulting in decreased vital capacity and lung compliance. The disease usually manifests in the sixth and seventh decades of life and incidence increases with advance in age and is more common in males.[1] Risk factors include hereditary factors, chronic viral infection, history of smoking, exposure to hazardous substances in the environment, acid reflux disease, etc. An inexplicable cough, low-grade fever, difficulty in breathing, loss of weight, and appetite are common presentations in patients with IPF. Respiratory examination shows bibasilar inspiratory crepitations. Here, we describe a unique case of ILD presented at an upper middle age of 45 years and so misdiagnosed as pulmonary tuberculosis which presented as a diagnostic and clinical challenge.

PMID:40115548 | PMC:PMC11922384 | DOI:10.4103/jfmpc.jfmpc_642_24

Thorax. 2025 Mar 20:thorax-2023-221063. doi: 10.1136/thorax-2023-221063. Online ahead of print.

ABSTRACT

BACKGROUND: Long-term oxygen therapy (LTOT) improves survival in patients with chronic severe resting hypoxaemia, but effects on hospitalisation are unknown. This study evaluated the potential impact of starting LTOT on acute exacerbation and hospital burden in patients with chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD) and pulmonary hypertension (PH).

METHODS: Longitudinal analysis of consecutive patients in the population-based Swedish DISCOVERY cohort who started LTOT between 2000 and 2018 with a follow-up duration≥3 months. Total and hospitalised acute exacerbations of the underlying disease, all-cause hospitalisations, and all-cause outpatient visits were annualised and compared between the year before and after LTOT initiation for each disease cohort, and by hypercapnic status in patients with COPD.

RESULTS: Patients with COPD (n=10 134) had significant reduction in annualised rates of total and hospitalised acute exacerbations, as well as all-cause hospitalisations, following LTOT initiation, with increment in those with ILD (n=2507) and PH (n=850). All-cause outpatient visits increased across all cohorts following LTOT initiation. Similar findings were observed in patients with hypercapnic and non-hypercapnic COPD. Sensitivity analyses of patients with 12 months of follow-up showed reduced acute exacerbations and all-cause hospitalisations in the ILD and PH cohorts.

CONCLUSION: LTOT is associated with reduced rates of both total and hospitalised acute exacerbations and all-cause hospitalisations in patients with COPD, as well as patients with ILD and PH with 12 months of follow-up. There is increased all-cause outpatient visits in all disease groups following LTOT initiation.

PMID:40113248 | DOI:10.1136/thorax-2023-221063

Bioorg Chem. 2025 Mar 11;159:108360. doi: 10.1016/j.bioorg.2025.108360. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and fatal pulmonary disease. Owing to its complex pathogenesis and lack of effective treatment, patients have a short survival time after diagnosis. Although pirfenidone and nintedanib can mitigate declines in lung function, neither has stopped the progression of IPF nor significantly improved long-term survival in patients. HDAC6 inhibitors have been reported to inhibit TGF-β1-induced collagen expression to protect mice from pulmonary fibrosis, and this pharmacological mechanism has been supported by immunohistochemical studies of HDAC6 overexpression in IPF lung tissue. In this study, a series of novel derivatives were obtained based on the reported active compounds through the ring closure strategy in scaffold hopping theory. Compound W28 was selected from in vitro screening for better HDAC6 selectivity, and it was used for in-depth pharmacokinetic and pharmacodynamic studies. Detailed molecular docking studies, molecular dynamics (MD) simulations and the structure-activity relationship (SAR) discussion will contribute to guiding the design of new molecules. In further studies, the ability of W28 to inhibit the IPF phenotype was confirmed, and the corresponding pharmacological mechanism was also demonstrated. Moreover, the pharmacokinetic characteristics of W28 were also tested to guide pharmacodynamic studies in vivo, and the therapeutic effect of W28 on bleomycin-induced pulmonary fibrosis in mice was found to be satisfactory. The results reported in this paper may provide a reference for promoting the discovery of new selective HDAC6 inhibitors as drug molecules for the treatment of IPF.

PMID:40112668 | DOI:10.1016/j.bioorg.2025.108360

Adv Sci (Weinh). 2025 Mar 20:e2415007. doi: 10.1002/advs.202415007. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is characterized by excessive fibroblast recruitment and persistent extracellular matrix deposition at sites of tissue injury, leading to severe morbidity and mortality. However, the precise mechanisms by which fibroblasts contribute to IPF pathogenesis remain poorly understood. The study reveals that Sema3E and its receptor Plexin D1 are significantly overexpressed in the lungs of IPF patients and bleomycin (BLM)-induced lung fibrotic mice. Elevated plasma levels of Sema3E in IPF patients are negatively correlated with lung function. Importantly, Sema3E in IPF lungs predominantly exists as the P61-Sema3E. The knockdown of Sema3E or Plexin D1 effectively inhibits fibroblast activation, proliferation, and migration. Mechanistically, Furin-mediated cleavage of P87-Sema3E into P61-Sema3E drives these pro-fibrotic activities, with P61-Sema3E-PlexinD1 axis promoting fibroblast activation, proliferation, and migration by affecting the phosphorylation of ErbB2, which subsequently activates the ErbB2 pathways. Additionally, Furin inhibition reduces fibroblast activity by decreasing P61-Sema3E production. In vivo, both whole-lung Sema3E knockdown and fibroblast-specific Sema3E knockout confer protection against BLM-induced lung fibrosis. These findings underscore the crucial role of the P61-Sema3E-Plexin D1 axis in IPF pathogenesis and suggest that targeting this pathway may hold promise for the development of novel therapeutic strategies for IPF treatment.

PMID:40112179 | DOI:10.1002/advs.202415007

Am J Physiol Cell Physiol. 2025 Mar 20. doi: 10.1152/ajpcell.00374.2024. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and degenerative interstitial lung disease characterized by complex etiology, unclear pathogenesis, and high mortality. Long non-coding RNAs (lncRNAs) have been identified as key regulators in modulating the initiation, maintenance, and progression of pulmonary fibrosis. However, the precise pathological mechanisms through which lncRNAs are involved in IPF remain limited and require further elucidation. A novel lncABCE1-5 was identified as significantly decreased by an ncRNA microarray analysis in our eight IPF lung samples compared with three donor tissues and validated by qRT-PCR analysis in clinical lung samples. To investigate the biological function of ABCE1-5, we performed loss-and gain-of-function experiments in vitro and in vivo. LncABCE1-5 silencing promoted A549 cell migration and A549 and BEAS-2B cell apoptosis, while enhancing the expression of proteins associated with extracellular matrix deposition, whereas overexpression of ABCE1-5 partially attenuated TGF-β-induced fibrogenesis. Forced ABCE1-5 expression by intratracheal injection of adeno-associated virus 6 (AAV6) revealing the anti-fibrotic effect of ABCE1-5 in BLM-treated mice. Mechanistically, RNA pull-down-mass spectrometry and RIP assay demonstrated that ABCE1-5 directly binds to keratin14 (krt14) sequences, potentially impeding its expression by perturbing mRNA stability. Furthermore, decreased ABCE1-5 levels can promote krt14 expression and enhance the phosphorylation of both mTOR and Akt; overexpression of ABCE1-5 in BLM mouse lung tissue significantly attenuated the elevated levels of p-mTOR and p-AKT. Knockdown of krt14 reversed the activation of mTOR signaling mediated by ABCE1-5 silencing. Collectively, the downregulation of ABCE1-5 mediated krt14 activation, thereby activating mTOR/AKT signaling, to facilitate pulmonary fibrosis progression in IPF.

PMID:40111939 | DOI:10.1152/ajpcell.00374.2024

Med Phys. 2025 Mar 20. doi: 10.1002/mp.17752. Online ahead of print.

ABSTRACT

BACKGROUND: Deep learning (DL)-based systems have not yet been broadly implemented in clinical practice, in part due to unknown robustness across multiple imaging protocols.

PURPOSE: To this end, we aim to evaluate the performance of several previously developed DL-based models, which were trained to distinguish idiopathic pulmonary fibrosis (IPF) from non-IPF among interstitial lung disease (ILD) patients, under standardized reference CT imaging protocols. In this study, we utilized CT scans from non-IPF ILD subjects, acquired using various imaging protocols, to assess the model performance.

METHODS: Three DL-based models, including one 2D and two 3D models, have been previously developed to classify ILD patients into IPF or non-IPF based on chest CT scans. These models were trained on CT image data from 389 IPF and 700 non-IPF ILD patients, retrospectively, obtained from five multicenter studies. For some patients, multiple CT scans were acquired (e.g., one at inhalation and one at exhalation) and/or reconstructed (e.g., thin slice and/or thick slice). Thus, for each patient, one CT image dataset was selected to be used in the construction of the classification model, so the parameters of that data set serve as the reference conditions. In one non-IPF ILD study, due to its specific study protocol, many patients had multiple CT image data sets that were acquired under both prone and supine positions and/or reconstructed under different imaging parameters. Therefore, to assess the robustness of the previously developed models under different (e.g., non-reference) imaging protocols, we identified 343 subjects from this study who had CT data from both the reference condition (used in model construction) and non-reference conditions (e.g., evaluation conditions), which we used in this model evaluation analysis. We reported the specificities from three model under the non-reference conditions. Generalized linear mixed effects model (GLMM) was utilized to identify the significant CT technical and clinical parameters that were associated with getting inconsistent diagnostic results between reference and evaluation conditions. Selected parameters include effective tube current-time product (known as "effective mAs"), reconstruction kernels, slice thickness, patient orientation (prone or supine), CT scanner model, and clinical diagnosis. Limitations include the retrospective nature of this study.

RESULTS: For all three DL models, the overall specificity of the previously trained IPF diagnosis model decreased (p < 0.05 for two out of three models). GLMM further suggests that for at least one out of three models, mean effective mAs across the scan is the key factor that leads to the decrease in model predictive performance (p < 0.001); the difference of mean effective mAs between the reference and evaluation conditions (p = 0.03) and slice thickness (3 mm; p = 0.03) are flagged as significant factors for one out of three models; other factors are not statistically significant (p > 0.05).

CONCLUSION: Preliminary findings demonstrated the lack of robustness of IPF diagnosis model when the DL-based model is applied to CT series collected under different imaging protocols, which indicated that care should be taken as to the acquisition and reconstruction conditions used when developing and deploying DL models into clinical practice.

PMID:40111345 | DOI:10.1002/mp.17752

Aging Biol. 2024;2:e20240023. doi: 10.59368/agingbio.20240023. Epub 2024 Feb 13.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an age-associated lung disease of unknown etiology that is characterized by exaggerated deposition of extracellular matrix (ECM), leading to distorted lung architecture, respiratory failure, and death. There are no truly effective treatment options for IPF, thus highlighting the importance of exploring new pathogenic mechanisms that underlie the development of fibrosis and of identifying new therapeutic targets. Insulin-like growth factors (IGFs) are known to be pro-fibrotic. However, the ubiquity and essentiality of IGF receptor signaling in normal physiology limit its potential as a direct therapeutic target. In a recent study, we found a highly significant correlation between expression of pregnancy-associated plasma protein (PAPP)-A in human IPF lung tissue and disease severity. PAPP-A is a unique metalloprotease that enhances local IGF action. In vitro studies support a role for proteolytically active PAPP-A in promoting a fibrotic phenotype in adult human lung fibroblasts. Here, we show that PAPP-A is preferentially expressed in mouse lung fibroblasts and that inhibition of PAPP-A in vivo through PAPP-A gene deletion or a specific neutralizing monoclonal antibody against PAPP-A markedly reduced the progression of bleomycin-induced lung fibrosis, as measured by significantly decreased ECM expression and improved lung histology. Surrogate markers of local IGF receptor activity in the lung were also significantly reduced, indicating indirect modulation of IGF signaling through PAPP-A. These results establish a role for PAPP-A in pulmonary fibrosis and point to PAPP-A as a selective and pharmacologically tractable target for IPF and possibly other fibrotic disorders.

PMID:40110162 | PMC:PMC11922547 | DOI:10.59368/agingbio.20240023

Front Pharmacol. 2025 Mar 5;16:1524505. doi: 10.3389/fphar.2025.1524505. eCollection 2025.

ABSTRACT

OBJECTIVE: This systematic review and meta-analysis aims to assess the efficacy of GBE in the treatment of IPF by evaluating its impact on total effective rate, blood gas analysis, pulmonary function tests, and markers of inflammation and fibrosis.

METHODS: We conducted a comprehensive search across seven databases, including PubMed, EMBASE, Web of Science, CNKI, Wanfang DATA, VIP, and CBM, without restrictions on publication date. Randomized controlled trials (RCTs) that investigated the effects of GBE on IPF patients were eligible for inclusion. Relevant literature was screened, and the data in the included studies were extracted for quality assessment according to the Risk of bias tool.

RESULTS: A total of 14 RCTs involving 1043 patients were included in the analysis. GBE significantly improved the total effective rate, arterial oxygen partial pressure, arterial oxygen saturation, forced vital capacity, forced expiratory volume in one second, maximum voluntary ventilation, and 6-min walk test compared to the control group. Additionally, there was a significant reduction in arterial carbon dioxide partial pressure, interleukin-4, hyaluronan, and laminin levels.

CONCLUSION: GBE may offer therapeutic benefits in IPF by improving respiratory function, modulating inflammation, and affecting fibrosis markers. These findings support the potential use of GBE as an adjunct therapy in IPF and suggest that further large-scale, multicenter trials are warranted to confirm its efficacy and safety.

PMID:40110130 | PMC:PMC11919911 | DOI:10.3389/fphar.2025.1524505

Clin Transplant. 2025 Mar;39(3):e70136. doi: 10.1111/ctr.70136.

ABSTRACT

BACKGROUND: Lung transplantation (LT) is a critical option for patients with advanced respiratory diseases, especially interstitial lung diseases (ILD). The GAP score (Gender, Age, Physiology) has shown prognostic value in idiopathic pulmonary fibrosis (IPF), but its utility in other progressive fibrotic diseases and LT candidates is less well-studied.

METHODS: This retrospective study included ILD patients evaluated as LT candidates between January 2017 and December 2023 at a single center. The GAP score was calculated for each patient, and patients were classified into GAP stages I, II, or III. Outcomes evaluated included LT waiting list inclusion, LT performed, death, and active follow-up without waiting list inclusion. The prognostic utility was analyzed using survival analysis, including Cox regression and Kaplan-Meier methods.

RESULTS: Of 413 ILD patients, 119 were included on the LT waiting list. GAP stage III was an independent predictor of transplant-free survival (HR = 2.720; p = 0.011). Patients in stage II showed a transplant-free survival of 51.3% at 2 years, while stage III had 49.2% survival at 1 year. GAP stages significantly predicted transplant outcomes and survival rates (p < 0.001).

CONCLUSION: The GAP score is a reliable prognostic tool for ILD patients being evaluated for LT, aiding in decision-making regarding referral and waiting list inclusion. It may serve as a useful marker for early referral and prioritization.

PMID:40109152 | DOI:10.1111/ctr.70136

Nature. 2025 Mar 19. doi: 10.1038/s41586-025-08727-3. Online ahead of print.

ABSTRACT

Fibrosis, the replacement of healthy tissue with collagen-rich matrix, can occur following injury in almost every organ1,2. Mouse lungs follow a stereotyped sequence of fibrogenesis-to-resolution after bleomycin injury3, and we reasoned that profiling post-injury histological stages could uncover pro-fibrotic versus anti-fibrotic features with functional value for human fibrosis. Here we quantified spatiotemporally resolved matrix transformations for integration with multi-omic data. First, we charted stepwise trajectories of matrix aberration versus resolution, derived from a high-dimensional set of histological fibre features, that denoted a reversible transition in uniform-to-disordered histological architecture. Single-cell sequencing along these trajectories identified temporally enriched 'ECM-secreting' (Csmd1-expressing) and 'pro-resolving' (Cd248-expressing) fibroblasts at the respective post-injury stages. Visium-based spatial analysis further suggested divergent matrix architectures and spatial-transcriptional neighbourhoods by fibroblast subtype, identifying distinct fibrotic versus non-fibrotic biomolecular milieu. Critically, pro-resolving fibroblast instillation helped to ameliorate fibrosis in vivo. Furthermore, the fibroblast neighbourhood-associated factors SERPINE2 and PI16 functionally modulated human lung fibrosis ex vivo. Spatial phenotyping of idiopathic pulmonary fibrosis at protein level additionally uncovered analogous fibroblast subtypes and neighbourhoods in human disease. Collectively, these findings establish an atlas of pro- and anti-fibrotic factors that underlie lung matrix architecture and implicate fibroblast-associated biological features in modulating fibrotic progression versus resolution.

PMID:40108456 | DOI:10.1038/s41586-025-08727-3