J Evid Based Med. 2024 Dec 21:e12659. doi: 10.1111/jebm.12659. Online ahead of print.

ABSTRACT

PURPOSE: To develop and validate the patient-reported outcome scale for idiopathic pulmonary fibrosis (IPF-PRO) to provide a reliable and scientific measure for clinical trials on idiopathic pulmonary fibrosis (IPF).

METHODS: We analyzed the relevant literature and medical records and conducted interviews and panel discussions to develop the conceptual framework and generate the item pool. We subjected the collected items to removal, mergence, or modification to form the initial scale through a qualitative review by experts and patients. Subsequently, we conducted two field surveys to select items for the final scale based on the classical test theory and item response theory (IRT). Finally, we conducted a formal survey to assess the measurement properties of the IPF-PRO.

RESULTS: The IPF-PRO included 18 items across four domains, namely physiology, psychology, environment, and satisfaction. The Cronbach's α coefficient and generalized coefficient of the IPF-PRO were 0.917 and 0.931, respectively. The content validity, structural validity, criterion validity, and discriminant validity all met relevant standards. The results of the item analysis based on IRT were considered acceptable. The ordinal logistic regression analysis findings showed that all items' p values were greater than 0.01 when the domain scores matched variables. The IPF-PRO response and completion rates were both 100%. The median completion time was 7 min [IRQ = 3.7 min (Q3 = 9.0 min, Q1 = 5.3 min)].

CONCLUSION: The 18-item IPF-PRO developed in this study has demonstrated good reliability and validity, indicating that it is a reliable and scientific measure for IPF clinical trials.

PMID:39708363 | DOI:10.1111/jebm.12659

J Transl Med. 2024 Dec 20;22(1):1114. doi: 10.1186/s12967-024-05869-2.

ABSTRACT

BACKGROUND: Glycolysis plays a major role in progression of idiopathic pulmonary fibrosis (IPF). Here, we aim to explore the predictive signature based on glycolysis-related genes for predicting the prognosis and identified a potential therapeutic target for IPF.

METHODS: Gene expression data of bronchoalveolar lavage (BAL) cells and clinical information were downloaded from the Gene Expression Omnibus database. Bioinformatic analysis was then performed to identify differentially expressed genes (DEGs). Lasso multivariate cox analysis and multivariate Cox regression were used to establish a gene signature. The prediction model was evaluated using the time-dependent receiver operating characteristic (ROC) curve and validated using an external independent dataset. The expression of these key genes in cellular level analyzed from Single Cell Expression Atlas. Cell Counting Kit-8 assay, immunofluorescence, wound healing and plasmid transfection were performed.

RESULTS: A total of 4 gene (ANGPTL4, ME2, TPBG and IER3), which were associated with the prognosis of IPF patients, were selected to establish our signature. The prediction model was an independent prognostic indicator for IPF patients. ANGPTL4 was significantly upregulated in pleural mesothelial cells (PMCs). In vitro assay showed that ANGPTL4 promoted PMCs proliferation and migration. Knockdown of ANGPTL4 can inhibit mesothelial-mesenchymal transition by suppressed glycolysis-associated gene, such as PGM1, GPI, PGK1, LDHA, ALDOA, ENO1 and TPI1.

CONCLUSIONS: Our research established a glycolysis-associated gene signature that holds potential to assist clinicians in the personalized management of IPF. Furthermore, we identified that ANGPTL4 mediates mesothelial-mesenchymal transition, suggesting its viability as a therapeutic target for IPF treatment.

PMID:39707362 | DOI:10.1186/s12967-024-05869-2

Tuberculosis (Edinb). 2024 Dec 13;150:102591. doi: 10.1016/j.tube.2024.102591. Online ahead of print.

ABSTRACT

We surveyed 15 persons with a medical qualification, 133 graduate students doing biomedical research and 56 students or working people with a college education in any discipline. Questions were designed to gauge awareness about inhaled therapies for tuberculosis (TB), non-tubercular mycobacterial lung disease (NTM-LD) and idiopathic pulmonary fibrosis (IPF). Respondents from six cities in North India, aged between 21 and 57 years answered 20 questions. All physicians, 99.25 % of graduate students and 85.71 % of the rest were aware and positive about inhalations for asthma, but these proportions fell to 69.92 and 66.07 in respect of other diseases. All respondents in the first two categories agreed that it was easy to train patients in the use of inhalation devices, while the third group was unanimous that there would be no aversion to using inhalation devices. A question asking whether the respondent would prescribe or opt for inhaled therapies for own use elicited an affirmative answer only from 40.00 % of physicians, 43.61 % of researchers and 23.21 % of college-educated persons (overall: 37.56 %). We concluded that inhaled therapies for diseases other than asthma are not well known and find limited acceptance among the populations sampled.

PMID:39705857 | DOI:10.1016/j.tube.2024.102591

Clin Pharmacol Ther. 2024 Dec 20. doi: 10.1002/cpt.3503. Online ahead of print.

ABSTRACT

Axatilimab, a high-affinity humanized immunoglobulin G4 monoclonal antibody against colony-stimulating factor 1 receptor (CSF-1R), is approved for the treatment of chronic graft-versus-host disease (cGVHD), and under investigation for idiopathic pulmonary fibrosis and solid tumors. The population pharmacokinetics (PK) and pharmacodynamics (PD) of axatilimab were characterized in healthy participants and patients with solid tumors or cGVHD using data from four clinical studies with 325 participants, including 278 patients with cGVHD. The model structure reflected the mechanism of action of axatilimab: blocking CSF-1R signaling with axatilimab reduces the circulating levels of cells in the mononuclear phagocytic cell lineage (including nonclassical monocytic cells (NCMCs) and Kupffer cells), resulting in increases in circulating enzymes owing to reduced clearance by Kupffer cells. The structural model consisted of a two-compartment axatilimab PK model and turnover PD models for CSF-1, NCMCs, aspartate transaminase (AST), and creatine phosphokinase (CPK). Axatilimab PK and CSF-1 equations also included saturable clearance components to reflect the competitive binding of axatilimab and CSF-1 to CSF-1R. Covariate search was conducted with the conditional sampling use for the stepwise approach based on correlation tests (COSSAC) approach. Covariate effects on model parameters, steady-state axatilimab exposure, and NCMC concentrations were assessed. The final population PK/PD model was mathematically described with 6 ordinary differential equations and 39 model parameters. Among the 11 statistically significant covariates, one (body weight) and two (participant population type and baseline CPK) covariates affected axatilimab steady-state exposure and steady-state NCMC levels by > 20%, respectively. These results informed the axatilimab dosing strategy in patients with cGVHD.

PMID:39704205 | DOI:10.1002/cpt.3503

Mol Med Rep. 2025 Feb;31(2):53. doi: 10.3892/mmr.2024.13418. Epub 2024 Dec 20.

ABSTRACT

In patients with idiopathic pulmonary fibrosis (IPF), the role of 5‑methylcytosine (m5C)‑associated genes in the pathogenesis and development of the disease remains unclear. The present study aimed to identify reliable diagnostic markers based on the expression of m5C‑associated genes for the early detection of IPF. Count data were obtained by screening the IPF genome‑wide assay in the Gene Expression Omnibus database, followed by a comparison of m5C gene expression in patients with IPF and controls. The GSE150910 and GSE173355 datasets yielded a total of 23 differentially expressed m5C‑associated genes, which were then investigated for their functions. A diagnostic model was built using eight m5C genes and validated with training sets and the GSE124685 dataset. IPF subtypes were identified based on expression of m5C‑related genes as well as clinical and immunological characteristics. Furthermore, a pulmonary fibrosis model was established in mice by administering bleomycin into the trachea. Lungs were harvested and analyzed using quantitative PCR to determine the expression of m5C‑related genes. The Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that these genes were significantly enriched in 'base excision repair'. Immunoassay results revealed that 13 immune cell markers (naive, memory and B cell plasma, T cell CD4 naive, T cell CD4 memory resting, T cell follicular helper, T cell regulatory Tregs, NK cell resting, Monocyte, Macrophage M0, Mast cell activated, Eosinophil, and Neutrophil) were significantly associated with IPF. Patients with IPF had lower levels of resting memory CD4+ T cells, which were positively associated with Tet methylcytosine dioxygenase2 (TET2) and Thymine‑DNA glycosylase (TDG) but negatively correlated with NOP2/Sun RNA methyltransferase5 (NSUN5) expression. All samples were classified into based on the levels of the eight diagnostic m5C genes. Samples with high m5C scores are subtype 1, and those with low m5C scores are subtype 2. In subtype 2, male patients had lower levels of CD27 and CD70 but higher levels of CD274, CD86, Cytotoxic T‑lymphocyte‑associated protein4 and Hepatitis A virus cellular receptor2 (HAVCR2). When compared with normal mouse lung tissue samples, expression levels of NOP2/Sun RNA methyltransferase6 (NSUN6), Ubiquitin‑like with PHD and RING Finger Domains1, TDG and TET2 in lung fibrosis tissue samples were significantly higher, while expression levels of NSUN5, NTH‑like DNA glycosylase1, DNA (cytosine‑5‑)‑methyltransferase3 β and Methyl‑CpG binding domain protein 3) were lower. It is possible that m5C‑associated genes play an important role in the diagnosis and typing of IPF. These genes may facilitate investigation of the pathophysiology of IPF and identification of potential treatment targets.

PMID:39704195 | DOI:10.3892/mmr.2024.13418

ACS Pharmacol Transl Sci. 2024 Nov 5;7(12):4083-4095. doi: 10.1021/acsptsci.4c00524. eCollection 2024 Dec 13.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) represents a grave challenge as it is characterized by high fatality rates and irreversible progression without effective clinical interventions available at present. Previous studies have demonstrated that inhibition of heat shock protein 90 (HSP90) by an N-terminal inhibitor disrupts its interaction with TGFβRII, leading to the instability of TGFβRII, thus blocking the role of transforming growth factor-β1 (TGF-β1), which could potentially ameliorate IPF symptoms. However, given that the broad spectrum of HSP90 N-terminal inhibitors may lead to unanticipated side effects, we hypothesize that C-terminal inhibitors of HSP90 can interfere with TGFβRII while minimizing adverse reactions. In this study, silybin, a C-terminal inhibitor of HSP90, was separated into monomers, and silybin A was screened for its superior efficacy against TGFβRII. To facilitate targeted therapy for treating IPF, a cell membrane hybrid liposome loaded with silybin A (Cm-A-Lip) was developed to deliver silybin A to lung fibroblasts through pulmonary drug delivery. A bleomycin-induced IPF mouse model was used to evaluate the efficacy of Cm-A-Lip. By examination of lung hydroxyproline content, wet weight, histology, and inflammatory factor expression, the results showed that pulmonary delivery of Cm-A-Lip could increase the drug retention time in lung tissue compared with intravenous injection. Furthermore, Cm-A-Lip exhibited superior antifibrotic activity relative to conventional liposmomes loaded with silybin A (A-Lip) while concurrently mitigating systemic inflammatory responses associated with silybin A administration, thus enhancing the overall safety profile.

PMID:39698274 | PMC:PMC11651165 | DOI:10.1021/acsptsci.4c00524

Front Nutr. 2024 Dec 4;11:1440402. doi: 10.3389/fnut.2024.1440402. eCollection 2024.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease often complicated by sarcopenia, significantly impacting patient outcomes. This study investigates the prevalence and clinical implications of sarcopenia in IPF patients using morphofunctional assessment methods.

MATERIALS AND METHODS: Eighty-four IPF patients (predominantly male) were evaluated for sarcopenia using the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) criteria. Assessments included bioelectrical impedance vectorial analysis (Nutrilab, Akern), handgrip strength (HGS), Timed Up and Go test (TUG), and nutritional ultrasound (NU) measurements of rectus femoris and abdominal adipose tissue. Statistical analysis was performed (version 2.3.28 for macOS) to obtain sarcopenia cut-off points for the different techniques, and then the predictive capacity of these values for survival was analyzed using a Kaplan-Meier curve.

RESULTS: Sarcopenia was prevalent in 20.2% of the cohort. Sarcopenic patients exhibited significantly lower forced vital capacity (FVC) (2,142 mL vs. 2745.6 mL, p < 0.05), higher GAP stages (p < 0.05), and worse quality of life (SGRQ impact scores: 45.2 vs. 27.5, p < 0.05). The identified cutoff values were 2.94 cm2 for RFCSA, 9.19 s for TUG, and 1.08 cm for the RF-Y-axis and body cell mass (BCM) cutoff of 25.4 kg. Kaplan-Meier analysis indicated a higher hazard ratio (HR) for mortality in sarcopenic patients. Specifically, RFCSA sarcopenia patients had a 2.37 times higher risk of events (HR = 2.37, 95% CI: 1.02-5.48, p = 0.045), and TUG sarcopenia presented a 4.89 times higher risk of adverse events (HR = 4.89, 95% CI: 1.43-16.70, p = 0.011).

CONCLUSION: Sarcopenia is prevalent in IPF patients and is associated with greater disease severity and reduced quality of life. RFCSA, BCM, and TUG are good predictors of sarcopenia and 12-month mortality, improving the prognostic value of classical diagnostics based on EWGSOP2 criteria. Despite limitations such as a predominantly male sample and cross-sectional design, the findings emphasize the importance of early detection and targeted interventions. Future research should focus on longitudinal studies to better understand sarcopenia progression in IPF and evaluate the efficacy of various therapeutic approaches.

PMID:39698245 | PMC:PMC11652176 | DOI:10.3389/fnut.2024.1440402

Stem Cell Res Ther. 2024 Dec 18;15(1):475. doi: 10.1186/s13287-024-04091-7.

ABSTRACT

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is a type of interstitial lung disease characterized by chronic inflammation due to persistent lung damage. Mesenchymal stem cells (MSCs), including those derived from the umbilical cord (UCMSCs) and placenta (PLMSCs), have been utilized in clinical trials for IPF treatment. However, the varying therapeutic effectiveness between these two MSC types remains unclear.

METHODS: In this study, we examined the therapeutic differences between UCMSCs and PLMSCs in treating lung damage using a bleomycin (BLM)-induced pulmonary injury mouse model.

RESULTS: We showed that UCMSCs had a superior therapeutic impact on lung damage compared to PLMSCs. Upon cytokine stimulation, UCMSCs expressed higher levels of inflammation-related genes and more effectively directed macrophage polarization towards the M2 phenotype than PLMSCs, both in vitro and in vivo. Furthermore, UCMSCs showed a preference for expressing CC motif ligation 2 (CCL2) and C-X-C motif chemokine ligand 1 (CXCL1) compared to PLMSCs. The expression of secreted phosphoprotein 1 (SPP1), triggering receptor expressed on myeloid cells 2 (Trem2), and CCAAT enhancer binding protein beta (Cebpb) in macrophages from mice with the disease treated with UCMSCs was significantly reduced compared to those treated with PLMSCs.

CONCLUSIONS: Therefore, UCMSCs demonstrated superior anti-fibrotic abilities in treating lung damage, potentially through inducing a more robust M2 polarization of macrophages than PLMSCs.

PMID:39696548 | DOI:10.1186/s13287-024-04091-7

BMC Genomics. 2024 Dec 18;25(1):1192. doi: 10.1186/s12864-024-11031-5.

ABSTRACT

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are debilitating diseases associated with divergent histopathological changes in the lungs. At present, due to cost and technical limitations, profiling cell types is not practical in large epidemiology cohorts (n > 1000). Here, we used computational deconvolution to identify cell types in COPD and IPF lungs whose abundances and cell type-specific gene expression are associated with disease diagnosis and severity.

RESULTS: We analyzed lung tissue RNA-seq data from 1026 subjects (COPD, n = 465; IPF, n = 213; control, n = 348) from the Lung Tissue Research Consortium. We performed RNA-seq deconvolution, querying thirty-eight discrete cell-type varieties in the lungs. We tested whether deconvoluted cell-type abundance and cell type-specific gene expression were associated with disease severity. The abundance score of twenty cell types significantly differed between IPF and control lungs. In IPF subjects, eleven and nine cell types were significantly associated with forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), respectively. Aberrant basaloid cells, a rare cells found in fibrotic lungs, were associated with worse FVC and DLCO in IPF subjects, indicating that this aberrant epithelial population increased with disease severity. Alveolar type 1 and vascular endothelial (VE) capillary A were decreased in COPD lungs compared to controls. An increase in macrophages and classical monocytes was associated with lower DLCO in IPF and COPD subjects. In both diseases, lower non-classical monocytes and VE capillary A cells were associated with increased disease severity. Alveolar type 2 cells and alveolar macrophages had the highest number of genes with cell type-specific differential expression by disease severity in COPD and IPF. In IPF, genes implicated in the pathogenesis of IPF, such as matrix metallopeptidase 7, growth differentiation factor 15, and eph receptor B2, were associated with disease severity in a cell type-specific manner.

CONCLUSIONS: Utilization of RNA-seq deconvolution enabled us to pinpoint cell types present in the lungs that are associated with the severity of COPD and IPF. This knowledge offers valuable insight into the alterations within tissues in more advanced illness, ultimately providing a better understanding of the underlying pathological processes that drive disease progression.

PMID:39695952 | DOI:10.1186/s12864-024-11031-5

Respir Res. 2024 Dec 18;25(1):433. doi: 10.1186/s12931-024-03063-y.

ABSTRACT

BACKGROUND: Patients with familial fibrotic interstitial lung disease (ILD) experience worse survival than patients with sporadic disease. Current guidelines do not consider family aggregation or genetic information in the diagnostic algorithm for idiopathic pulmonary fibrosis or other fibrotic ILDs. Better characterizing familial cases could help in diagnostic and treatment decision-making.

METHODS: This retrospective cohort study included 222 patients with fibrotic ILD (104 familial and 118 sporadic) from Bellvitge University Hospital. Clinical, radiological, pulmonary functional tests (PFT), and histological evaluations were performed at diagnosis and follow-up. Telomere shortening and disease-associated variants (DAVs) in telomerase-related genes were analysed in familial patients and sporadic patients with telomeric clinical signs. Primary outcomes were the presence of a UIP histological pattern and disease progression.

RESULTS: Patients with idiopathic pulmonary fibrosis (IPF) (52%), fibrotic hypersensitivity pneumonitis (23%), and other fibrotic ILDs (25%) were included. 42% of patients underwent lung biopsy. Patients with family aggregation were younger and less frequently associated comorbidities, male sex, and smoking history. However, usual interstitial pneumonia (UIP) was more frequent on pathology (p = 0.005; OR 3.37), especially in patients with indeterminate or non-UIP radiological patterns. Despite similar PFT results at diagnosis, familial patients were more likely to present with progressive disease (p = 0.001; OR 3.75). Carrying a DAV increased the risk of fibrotic progression in familial and sporadic patients (p = 0.029, OR 5.01).

DISCUSSION: Familial patients diagnosed with different fibrotic ILDs were more likely to exhibit a histological UIP pattern and disease progression than sporadic patients, independent of radiological findings and pulmonary function at diagnosis.

CONCLUSION: Considering the diagnostic likelihood of the histological UIP pattern and disease outcome, the presence of family aggregation would be useful in the decision making of multidisciplinary committees.

PMID:39695595 | DOI:10.1186/s12931-024-03063-y

Respir Investig. 2024 Dec 17;63(1):127-137. doi: 10.1016/j.resinv.2024.12.009. Online ahead of print.

ABSTRACT

Idiopathic pleuroparenchymal fibroelastosis (iPPFE) is characterized by upper lobe-dominant fibrosis involving the pleura and subpleural lung parenchyma. Pathologically, it is characterized by parenchymal intra-alveolar fibrosis with marked deposition of elastic fibers and dense thickening of the visceral pleura. Since iPPFE was categorized as a rare idiopathic interstitial pneumonia (IIP) by the America Thoracic Society/European Respiratory Society, several studies have been conducted, revealing an overall picture of iPPFE in terms of epidemiology, clinical manifestations, and mortality, in addition to its radiological and histological characteristics. Subsequently, several clinical diagnostic criteria that were not necessary for pathological analyses were proposed. Further, the underlying diseases responsible for secondary PPFE and PPFE-like lesions and their clinical implications were delineated. Typically, patients with iPPFE exhibit lean body stature together with platythorax, as well as relatively severe impairment of pulmonary function. In addition to upper-lobe PPFE lesions, lower-lobe interstitial lung disease (ILD) is commonly observed in patients with iPPFE, with the usual interstitial pneumonia pattern being most frequent. These distinct features of iPPFE were mostly associated with mortality, resulting in a poor prognosis relative to fibrotic ILD. Despite increased knowledge regarding the clinical characteristics of iPPFE, no effective therapy has been established other than lung transplantation. The efficacy of antifibrotic therapy, nutrition intervention, and pulmonary rehabilitation has not been determined. This article reviews previous studies and discusses the etiology, clinical manifestations, mortality risk, and treatment of iPPFE.

PMID:39693846 | DOI:10.1016/j.resinv.2024.12.009

Respir Investig. 2024 Dec 17;63(1):138-145. doi: 10.1016/j.resinv.2024.12.011. Online ahead of print.

ABSTRACT

BACKGROUND: Progressive pulmonary fibrosis (PPF) is a critical concern in interstitial lung disease (ILD) management. The HAL score, which incorporates honeycombing (H), age >75 years (A), and serum lactate dehydrogenase >222 U/L (L), can predict acute exacerbations in patients with idiopathic interstitial pneumonia (IIP). This study aims to evaluate the predictive utility of the HAL score for PPF development.

METHODS: This study was a post-hoc analysis of a multicenter prospective cohort study involving patients with IIP. PPF was diagnosed if at least two of the following three criteria were met: worsening respiratory symptoms, radiological progression, and physiological progression.

RESULTS: Among the 144 patients, 29 (22.3%) developed PPF during the observation period. Among the three criteria for PPF, a higher HAL score significantly correlated with worsening respiratory symptoms (p = 0.001) and radiological progression (p = 0.022), but not with physiological progression (p = 0.717). Therefore, a higher HAL score significantly correlated with an increased PPF risk (12.5% for a score of 0, 25.9% for a score of 1, and 33.3% for a score of ≥2; p = 0.032). The HAL score also correlated with overall survival (p < 0.001). For the 92 patients (70.8%) with non-idiopathic pulmonary fibrosis (IPF), the HAL score was significantly associated with PPF development (p = 0.021), while not for the 38 patients (29.2%) with IPF (p = 0.872).

CONCLUSION: In patients with non-IPF, the HAL score correlated with PPF development and could be useful to monitor those patients and to avoid missed treatment opportunities.

PMID:39693847 | DOI:10.1016/j.resinv.2024.12.011

Respir Investig. 2024 Dec 16;63(1):109-117. doi: 10.1016/j.resinv.2024.12.005. Online ahead of print.

ABSTRACT

BACKGROUND: The prognostic factors in mild fibrosing interstitial lung disease (FILD) have not been established.

METHODS: We retrospectively attempted to identify predictive factors of annual progression in mild FILD with gender-age-physiology (GAP) score of 3 or less using logistic regression analysis. Annual FILD progression was defined as meeting any two or more of the following conditions: 1, more than 10% decrease in forced vital capacity (FVC) or 15% decrease in diffusing capacity of the lungs for carbon monoxide (DLCO); 2, worsening of dyspnea; 3, worsening of fibrotic change on CT at 1 year after admission.

RESULTS: Univariate analysis showed that diagnosis of connective tissue disease-associated ILD, CT-definite usual interstitial pneumonia (UIP) pattern, composite physiologic index, FVC, DLCO, lowest SpO2 and decrease in SpO2, and walk distance in the 6-minutes walk test (6MWT), chronic pulmonary emphysema assessment test (CAT) score, and some variables in Short-Form 36 were significantly associated with incidence of annual progression. Multivariate analysis showed that independent predictive factors were diagnosis of idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (HP), CT-definite UIP pattern, lowest SpO2 and decrease in SpO2 in the 6MWT, and CAT score. In logistic regression analysis among 63 patients with non-IPF-ILD, diagnosis with fibrotic HP, lowest SpO2 and decrease in SpO2 in the 6MWT, and CAT score were also independent risk factors for annual FILD progression.

CONCLUSIONS: Exercise-induced hypoxia, patient-reported outcome, radiological UIP pattern, and diagnosis with fibrotic HP are independent predictors of annual progression in mild FILD.

PMID:39689588 | DOI:10.1016/j.resinv.2024.12.005

Trends Mol Med. 2024 Dec 16:S1471-4914(24)00312-5. doi: 10.1016/j.molmed.2024.11.012. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating lung disease characterized by excessive extracellular matrix deposition and tissue scarring. The median survival of patients with IPF is only 4.5 years following diagnosis, and effective treatment options are scarce. Recent studies found aberrant translation of specific mRNAs in various fibrosing diseases, highlighting the role of key translational regulators, including RNA binding proteins (RBPs), microRNAs, long noncoding RNAs, and transcript modifications. Notably, when inhibited, 10 profibrotic RBPs cause a significant attenuation of fibrosis, illuminating potential therapeutic targets. In this review, we describe translational regulation in fibrosis and highlight a model where a conserved evolutionary mechanism may explain this regulation.

PMID:39690057 | DOI:10.1016/j.molmed.2024.11.012

Respirology. 2024 Dec 17. doi: 10.1111/resp.14874. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Digital technologies offer opportunities for remote monitoring, increased patient engagement and incorporation of patient-reported outcome measures (PROMs) into interstitial lung disease (ILD) care and research. This study evaluated the usability and patient experience of the RE-BUILD (Registry for Better Understanding of ILD) application, an ILD-specific smartphone app.

METHODS: Patients with ILD aged ≥18 years were recruited from three tertiary ILD centres to use the RE-BUILD app for 6 months. The mHealth App Usability Questionnaire (MAUQ) was evaluated at 1, 3 and 6 months and patients received monthly prompts to enter clinical and PROM data. Qualitative interviews regarding patient experience were performed in a subset of 10.

RESULTS: Fifty patients, with mean age 66.9 ± 10.3 years, 25 (50%) female were included. Participants used the app for a median of 48 (IQR 21-178.3) sessions, equivalent to 8 sessions (IQR 3.5-29.71) per month. Median number of days that the app was accessed was 37 (IQR 14-96.8), with 13 (26%) patients using the app >30 times per month. The most accessed app feature was physical activity, followed by 'air quality'. Participants agreed or strongly agreed that the app was easy to use (76.0%) easy to learn to use (79.8%) and well-organized with accessible information (74.8%). The median overall MAUQ score for usability was 5.69 (IQR 5.03-6.19). There was also a high rate of engagement with app functionalities.

CONCLUSION: RE-BUILD is a usable and intuitive platform for self-monitoring and data collection in ILD. Patients report a high degree of satisfaction and have provided valuable feedback for its further development.

PMID:39689971 | DOI:10.1111/resp.14874

Biofabrication. 2024 Dec 17. doi: 10.1088/1758-5090/ada092. Online ahead of print.

ABSTRACT

Recent studies have shown promising results using decellularized extracellular matrix (dECM) matrikines-based hydrogel as attractive strategies for preventing and alleviating fibrosis.&#xD;Methods & Results: Porcine lung decellularization and pepsin digestion were used to prepare the lung dECM hydrogel. Proteomic analysis revealed that the lung dECM hydrogel was enriched in glycoproteins, collagens, laminins, fibrinogen, held receptors, and bound growth factors. With porous structures and good mechanical properties and stability, the lung dECM hydrogel showed low cytotoxicity and good biocompatibility both in vitro and in vivo. The lung dECM hydrogel was further administered to verify the safety and effectiveness of reversing pulmonary fibrosis in a bleomycin induced rat model. The results revealed a relatively complete alveolar structure with less inflammatory infiltration and a reduced amount of collagen fiber deposition. TMT quantification proteomic analyses revealed significant downregulation of proteins, pathways, and interactions involved in the regulation of ECM components, tissue remodeling, inflammation, and the cytoskeleton and indicated that fibrosis-related proteins were obviously downregulated and inflammation-related proteins were significantly changed, particularly in macrophages, after administration of the lung dECM hydrogel. Multiplex immunohistochemical (mIHC) staining of lung tissue revealed that the inflammatory response was regulated by the lung dECM hydrogel, as indicated by a decrease in the number of CD3+ T cells and macrophages and the suppression of M2 macrophage polarization. Gene set enrichment analysis revealed that downregulated ficolin signaling was enriched in macrophages after lung dECM hydrogel administration, and the findings were verified in lung tissue by mIHC. Additionally, the effects of ficolin B proteins on macrophage polarization were proved in vitro.&#xD;Conclusion: This study suggested that the lung dECM hydrogel can reverse pulmonary fibrosis by suppressing M2 macrophage polarization through downregulation of the ficolin signaling pathway. Thus, the dECM hydrogel represent a promising class of biological materials for use in regenerative medicine.

PMID:39689433 | DOI:10.1088/1758-5090/ada092

ERJ Open Res. 2024 Dec 16;10(6):00558-2023. doi: 10.1183/23120541.00558-2023. eCollection 2024 Nov.

ABSTRACT

BACKGROUND: Biomarkers that change in response to nintedanib in subjects with idiopathic pulmonary fibrosis (IPF) would be valuable. We investigated the effects of nintedanib on circulating biomarkers in subjects with IPF in the INMARK trial.

METHODS: Subjects with IPF were randomised 1:2 to receive nintedanib 150 mg twice daily or placebo for 12 weeks, after which all patients received open-label nintedanib for 40 weeks. Fold changes in adjusted mean levels of circulating biomarkers were analysed using a linear mixed model for repeated measures.

RESULTS: 346 subjects were treated (116 randomised to nintedanib, 230 to placebo). Surfactant protein D (SP-D) and cancer antigen 125 (CA-125), markers of epithelial injury, decreased in subjects treated with nintedanib versus placebo. Fold changes from baseline in SP-D at week 12 corresponded to a 4% decrease and 3% increase in the nintedanib and placebo groups, respectively (ratio 0.94, 95% CI 0.89-0.99; p=0.024). Fold changes in CA-125 at week 12 corresponded to a 22% decrease and 4% increase in the nintedanib and placebo groups, respectively (ratio 0.75, 95% CI 0.71-0.81; p<0.0001). A mediation analysis suggested that 42.1% of the effect of nintedanib on change in forced vital capacity over 12 weeks was attributable to the change in CA-125. A small increase in C3A (collagen 3 degraded by ADAMTS-1/4/8) and a small decrease in C3M (collagen 3 degraded by matrix metalloproteinase-9), markers of extracellular matrix turnover, were observed in subjects treated with nintedanib versus placebo.

CONCLUSIONS: Effects of nintedanib on circulating markers of epithelial dysfunction and collagen degradation, most notably CA-125, were observed in patients with IPF.

PMID:39687396 | PMC:PMC11647937 | DOI:10.1183/23120541.00558-2023

ERJ Open Res. 2024 Dec 16;10(6):00192-2024. doi: 10.1183/23120541.00192-2024. eCollection 2024 Nov.

ABSTRACT

BACKGROUND: Idiopathic interstitial pneumonias (IIPs), such as idiopathic pulmonary fibrosis and interstitial pneumonia with autoimmune features, present diagnostic and therapeutic challenges due to their heterogeneous nature. This study aimed to identify intrinsic molecular signatures within the lung microenvironment of these IIPs through proteomic analysis of bronchoalveolar lavage fluid (BALF).

METHODS: Patients with IIP (n=23) underwent comprehensive clinical evaluation including pre-treatment bronchoscopy and were compared with controls without lung disease (n=5). Proteomic profiling of BALF was conducted using label-free quantitative methods. Unsupervised cluster analyses identified protein expression profiles that were then analysed to predict survival outcomes and investigate associated pathways.

RESULTS: Proteomic profiling successfully differentiated IIP from controls. k-means clustering based on protein expression revealed three distinct IIP clusters, which were not associated with age, smoking history, or baseline pulmonary function. These clusters had unique survival trajectories and provided more accurate survival predictions than the Gender Age Physiology index (concordance index 0.794 versus 0.709). The cluster with the worst prognosis featured decreased inflammatory signalling and complement activation, with pathway analysis highlighting altered immune response pathways related to immunoglobulin production and B-cell-mediated immunity.

CONCLUSIONS: The unsupervised clustering of BALF proteomics provided a novel stratification of IIP patients, with potential implications for prognostic and therapeutic targeting. The identified molecular phenotypes underscore the diversity within the IIP classification and the potential importance of personalised treatments for these conditions. Future validation in larger, multi-ethnic cohorts is essential to confirm these findings and to explore their utility in clinical decision-making for patients with IIP.

PMID:39687393 | PMC:PMC11647942 | DOI:10.1183/23120541.00192-2024

J Clin Med. 2024 Nov 26;13(23):7170. doi: 10.3390/jcm13237170.

ABSTRACT

Background: Both a probable usual interstitial pneumonia (UIP) pattern (p-UIP) and a definite UIP pattern (d-UIP) on high-resolution computed tomography (HRCT) are sufficient to establish a diagnosis of idiopathic pulmonary fibrosis (IPF) without the need for a surgical lung biopsy, according to the 2022 IPF guidelines. However, it remains unknown whether patients with p-UIP and d-UIP have similar disease behaviors and clinical courses. Material and Methods: We retrospectively collected clinical data of patients with IPF and divided the patients into two groups according to their HRCT patterns: a p-UIP group and a d-UIP group. The baseline characteristics, survival rates, and pulmonary function tests were compared between the two groups. The risk factors for mortality were determined by Cox regression in p-UIP and d-UIP separately. Results: There were 304 patients in the p-UIP group and 480 patients in the d-UIP group. Patients in the d-UIP group were more likely to have smoking histories (p < 0.001) and had lower baseline FVC% (74% vs. 77%, p = 0.021) and DLCO% (50% vs. 58%, p < 0.001). Survival rates were higher in p-UIP compared with d-UIP (p = 0.004). There were no differences in changes in FVC% or DLCO% between the two groups. Baseline DLCO% was the only independent risk factor for mortality in p-UIP. Baseline FVC% was independently associated with mortality in d-UIP. Symptom of cough was a risk factor for disease progression (OR = 1.2, p = 0.002) in p-UIP, while symptom of dyspnea might be associated with disease progression in d-UIP (OR = 2.7, p = 0.065). Male patients (OR = 1.88, p = 0.002) with a smoking history (OR = 1.16, p = 0.002) were at higher risk of developing d-UIP. Conclusions: We observed the different disease trajectories between p-UIP and d-UIP. P-UIP on HRCT might identify a subgroup of IPF patients who are in the early stage with a better prognosis.

PMID:39685629 | DOI:10.3390/jcm13237170

Int J Mol Sci. 2024 Dec 4;25(23):13026. doi: 10.3390/ijms252313026.

ABSTRACT

Alterations to post-translational crosslinking modifications in the extracellular matrix (ECM) are known to drive the pathogenesis of fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). Thus, the methodology for measuring crosslinking dynamics is valuable for understanding disease progression. The existing crosslinking analysis sample preparation and liquid chromatography tandem mass spectrometry (LC-MS/MS) methods are typically labor-intensive and time-consuming which limits throughput. We, therefore, developed a rapid approach minimizing specialized equipment and hands-on time. The LC-MS/MS sample analysis time was reduced to two minutes per sample. We then improved the analytical integrity of the method by developing a novel surrogate matrix approach for the dihydroxylysinonorleucine (DHLNL) crosslink. By modifying sample preparation, we prepared a tissue-based surrogate matrix with undetectable levels of endogenous DHLNL, providing a strategy for quantifying this crosslink with a more relevant standard matrix. We then applied this rapid methodology to evaluating crosslinking in lung fibrosis. We showed an increase in DHLNL in human IPF lung relative to healthy donors, as well as in a fibrotic mouse model. Finally, we demonstrated that this increase in DHLNL could be mitigated with an anti-fibrotic compound, suggesting that this assay has potential for evaluating pharmaceutical compound efficacy.

PMID:39684739 | DOI:10.3390/ijms252313026