Respir Res. 2024 Dec 24;25(1):442. doi: 10.1186/s12931-024-03075-8.

ABSTRACT

BACKGROUND: The composite physiologic index (CPI) was developed to estimate the extent of interstitial lung disease (ILD) in idiopathic pulmonary fibrosis (IPF) patients based on pulmonary function tests (PFTs). The CALIPER-revised version of the CPI (CALIPER-CPI) was also developed to estimate the volume fraction of ILD measured by CALIPER, an automated quantitative CT postprocessing software. Recently, artificial intelligence-based quantitative CT image analysis software (AIQCT), which can be used to quantify the bronchial volume separately from the ILD volume, was developed and validated in IPF. The aim of this study was to develop AIQCT-derived CPI formulas to quantify CT abnormalities in IPF and to investigate the associations of these CPI formulas with survival.

METHODS: The first cohort included 116 patients with IPF. In this cohort, ILD, bronchial, and hyperlucent volumes on CT were quantified using AIQCT. New CPI formulas were developed based on PFTs to estimate the volume fraction of ILD (ILD-CPI), the sum of the ILD and bronchial volume fractions (ILDB-CPI), and the sum of the ILD, bronchial and hyperlucent volume fractions (ILDBH-CPI). The associations of the original CPI, the CALIPER-CPI and the AIQCT-derived CPIs with survival were analyzed in the first cohort and in a second cohort of patients with IPF (n = 72).

RESULTS: In the first cohort, over a median observation time of 92.8 months, 79 patients (68.1%) died, and one patient (0.9%) underwent living-donor lung transplantation. The original CPI, the CALIPER-CPI, and all AIQCT-derived CPIs were associated with overall survival (hazard ratios: 1.07-1.22). The C-index of the ILDB-CPI (0.759) was the highest among all AIQCT-derived CPIs and was comparable to that of the original CPI (0.765) and the CALIPER-CPI (0.749). The C-index of the ILDBH-CPI (0.729) was lower than that of the other CPI variables. The second cohort yielded similar C-indices as the first cohort for the original CPI (0.738), CALIPER-CPI (0.757) and ILDB-CPI (0.749).

CONCLUSIONS: The ILDB-CPI can predict the outcomes of IPF patients with a similar performance to that of the original CPI and the CALIPER-CPI. Adding the hyperlucent volume to the CPI formula did not improve its predictive accuracy for mortality.

TRIAL REGISTRATION: None (no health care interventions were performed).

PMID:39719582 | DOI:10.1186/s12931-024-03075-8

RMD Open. 2024 Dec 23;10(4):e004704. doi: 10.1136/rmdopen-2024-004704.

ABSTRACT

Interstitial lung disease (ILD) associated with rheumatoid arthritis or with connective tissue diseases such as systemic sclerosis can be collectively named systemic autoimmune rheumatic disease-associated ILDs (SARD-ILDs) or rheumatic musculoskeletal disorder-associated ILDs. SARD-ILDs result in substantial morbidity and mortality, and there is a high medical need for effective therapies that target both fibrotic and inflammatory pathways in SARD-ILD. Phosphodiesterase 4 (PDE4) hydrolyses cyclic AMP, which regulates multiple pathways involved in inflammatory processes. PDE4 is overexpressed in peripheral blood monocytes from patients with inflammatory diseases. However, clinical data on pan-PDE4 inhibition in fibrotic conditions are lacking. The PDE4B subtype is highly expressed in the brain, lungs, heart, skeletal muscle and immune cells. As such, inhibition of PDE4B may be a novel approach for fibrosing ILDs such as idiopathic pulmonary fibrosis (IPF) and SARD-ILD. Preclinical data for PDE4B inhibition have provided initial evidence of both anti-inflammatory and antifibrotic activity, with reduced potential for gastrointestinal toxicity compared with pan-PDE4 inhibitors. In a proof-of-concept phase II trial in patients with IPF, nerandomilast (BI 1015550), the only PDE4B inhibitor currently in clinical development, prevented a decline in lung function over 12 weeks compared with placebo. The potential clinical benefit of PDE4B inhibition is now being investigated in the phase III setting, with two trials evaluating nerandomilast in patients with IPF (FIBRONEER-IPF) or with progressive pulmonary fibrosis other than IPF (FIBRONEER-ILD). Here, we review the preclinical and clinical data that provide rationale for PDE4B inhibition as a treatment strategy in patients with SARD-ILD.

PMID:39719300 | DOI:10.1136/rmdopen-2024-004704

Naunyn Schmiedebergs Arch Pharmacol. 2024 Dec 24. doi: 10.1007/s00210-024-03744-x. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a severe and progressive lung disorder with an average survival rate of 3 to 5 years. IPF presents a significant challenge in clinical management, necessitating novel therapeutic approaches. Nanostructured lipid carriers (NLCs) have proven to be promising vehicles for targeted drug delivery to the lung tissues. This research focuses on formulating and evaluating umbelliferone (UMB)-loaded NLCs for the treatment of IPF. UMB-NLC was formulated using the hot emulsion ultrasonication method and was characterized. The formulation was then tested for its efficacy in a bleomycin-induced IPF mice model. Leukocyte infiltration and interleukin-6 were estimated in the bronchoalveolar lavage fluid (BALF). Various antioxidant activities were also assessed for the formulation, followed by histopathological analysis. Furthermore, an in silico mechanistic approach using network pharmacology was carried out to obtain genes of interest. Particle size analysis revealed a mean size of 174.9 ± 3.66 nm for UMB-NLC, ideal for lung tissue targeting. Zeta potential measurements indicated good stability (-34.3 ± 1.35 mV) for long-term storage. Fourier transform infrared spectroscopy (FTIR) confirmed the successful encapsulation of UMB within the lipid matrix of NLCs. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) demonstrated the amorphous state of UMB-NLC, indicating enhanced solubility and bioavailability. Field emission scanning electron microscopy (FESEM) revealed uniform, spherical particles in the nanometer range. Drug entrapment efficiency (EE%) and loading capacity (DL%) were found to be 85.03 ± 2.36% and 17.01 ± 0.48%, respectively, indicating efficient drug incorporation. In vitro release study showed uniform sustained drug release over 48 h, indicating the potential for prolonged therapeutic effect. In vivo studies using UMB-NLC demonstrated significant improvements in bleomycin-induced IPF. A restoration in body weight and lung/body-weight (L/B) ratio was observed compared to disease controls. BALF analysis revealed reduced leukocyte infiltration and decreased inflammatory cytokine IL-6 levels (**p < 0.01). Biochemical assays showed enhanced antioxidant status and reduced oxidative stress in lung tissues. Hydroxyproline content (HPO, **p < 0.01), malondialdehyde (MDA, ***p < 0.001), and total protein content (**p < 0.01) were significantly reduced, while glutathione (GSH, ***p < 0.001), superoxide dismutase (SOD, **p < 0.01), and catalase (CAT, **p < 0.01) were elevated. Histopathological analysis confirmed the attenuation of lung fibrosis with maintained alveolar architecture and reduced fibrotic deposition. Furthermore, network pharmacology identified UMB targets and IPF-related genes with a Venn diagram, and cytoHubba analysis revealed key hub genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment demonstrated UMB's involvement in IPF-related pathways, highlighting its therapeutic potential. Therefore, UMB-NLC may exhibit promising therapeutic potential in the treatment of IPF, offering targeted drug delivery, enhanced bioavailability, and improved efficacy in alleviating pulmonary inflammation and fibrosis.

PMID:39718612 | DOI:10.1007/s00210-024-03744-x

Adv Ther. 2024 Dec 23. doi: 10.1007/s12325-024-03079-2. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial pneumonia, which is characterised by progressive worsening of dyspnoea and lung function. Nintedanib treatment is recommended to slow IPF disease progression. The aim of this post-marketing surveillance (PMS) study was to evaluate the safety and effectiveness of nintedanib over 24 months in patients with IPF in a real-world setting in Japan.

METHODS: This prospective, non-interventional, all-case PMS study of nintedanib included Japanese patients with IPF who started nintedanib between 7 October 2015 and 2 May 2023. The primary outcome was to determine the proportion of patients with adverse drug reactions (ADRs), and the secondary outcome was the adjusted absolute change from baseline in forced vital capacity (FVC) at 24 months.

RESULTS: In total, 5717 patients from 1013 institutions were included in the safety analysis (mean ± standard deviation age 71.7 ± 8.1 years, 78.1% male, 70.8% current or former smokers). Most patients (83.9%) had initiated nintedanib at a dose of 150 mg capsules twice daily. At 24 months, 2841 patients (64.8%) had discontinued nintedanib, mainly due to adverse events (44.0%), ADRs (24.1%) or insufficient effectiveness (5.7%). The most common ADRs were diarrhoea (35.5%), hepatic function abnormal (14.4%), decreased appetite (9.9%), liver disorders (7.8%) and nausea (5.8%). The adjusted absolute mean change in FVC from baseline to 24 months was - 212.3 mL (95% confidence interval - 235.3, - 189.3).

CONCLUSION: This is the largest prospective study to investigate patients with IPF who were treated with nintedanib. The safety and effectiveness of nintedanib treatment in this real-world setting of Japanese patients with IPF was similar to that reported in previous studies. Nintedanib effectively slowed the progression of IPF. No new safety concerns were identified, and the need for appropriate management of hepatic disorders and diarrhoea (as per the approved product information) was confirmed.

STUDY REGISTRATION: ClinicalTrials.gov (NCT02607722)/European Union electronic register of Post-Authorisation Studies (EUPAS10891).

PMID:39714546 | DOI:10.1007/s12325-024-03079-2

Clin Radiol. 2024 Nov 29;81:106759. doi: 10.1016/j.crad.2024.106759. Online ahead of print.

ABSTRACT

AIM: Idiopathic pulmonary fibrosis (IPF) is a debilitating and fatal lung disease. Changes in body composition potentially correlate with outcomes in patients with IPF.

MATERIALS AND METHODS: Patients with IPF on antifibrotic treatment attending a single institution were identified and retrospectively evaluated (n=84). Three groups were formed based on antifibrotic treatment: pirfenidone group, nintedanib group and pirfenidone-nintedanib switch group. Morphomic analysis of muscle quantity (cross-sectional area in cm2) and quality (density in Hounsfield Units) on thoracic computed tomography (CT) was performed using a web-based morphomic segmentation tool. Bilateral erector spinae and pectoralis muscles were measured at pre-defined vertebral levels.

RESULTS: All three treatment groups showed a statistically significant decline in forced vital capacity (FVC), diffusion capacity of the lung for carbon monoxide (DLCO), pectoral muscle cross sectional area (PMA), and erector spinae muscle cross-sectional area (ESMA). Muscle density did not change significantly. Differences existed in analytic morphomics between treatment groups. Patients with a pretreatment body mass index (BMI) below 30 were found to have a significantly greater loss of PMA when treated with nintedanib instead of pirfenidone. FVC and DLCO did not differ between treatment groups.

CONCLUSION: There were no direct correlations between pulmonary function and morphomic parameters in our entire group of IPF patients. However, between different treatment groups, the rate of muscle bulk loss differed. This is an important consideration for clinicians when deciding on an antifibrotic agent of choice.

PMID:39709732 | DOI:10.1016/j.crad.2024.106759

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