Tuberk Toraks. 2023 Dec;71(4):347-355. doi: 10.5578/tt.20239603.

ABSTRACT

INTRODUCTION: The aim of this study was to evaluate the real-life treatment and follow-up data of patients with idiopathic pulmonary fibrosis (IPF) in a singlecenter setting.

MATERIALS AND METHODS: The study included consecutive patients diagnosed with IPF who were followed up at the Akdeniz University, between January 1, 2014 and December 31, 2022. Patient information was obtained from the hospital automation system.

RESULT: A total of 227 patients with a mean age of 72.0 ± 8.2 years were included in the study. One hundred sixty-seven patients (73.6%) received pirfenidone while 60 patients (26.4%) received nintedanib treatment. Radiological findings were used to diagnose IPF in 79.3% (n= 180) of cases. Mean duration of antifibrotic treatment was 26.3 ± 19.9 months. Of the patients, 49.8% experienced hospital admissions during the treatment course, with respiratory reasons accounting for a majority of these admissions (33.6%). Disease exacerbation was detected in 26.6% of the patients during the treatment period. At least one side effect was observed in 126 patients (55.5%), with a significant portion of these side effects being mild to moderate (n= 79, 34.8%). Disease progression was observed in 21.6% of the patients under antifibrotic treatment. Dose reduction was necessary in 22.9% of the patients, with an average duration of dose reduction of 29 months. Antifibrotic treatment was switched to another medication in 24.2% of the patients. There were no statistically significant differences in baseline forced vital capacity (FVC) levels between the two groups (p= 0.314) while the diffusing capacity of the lungs for carbon monoxide (DLCO) level was higher in the nintedanib group (p= 0.024), and the six-minute walk distance was shorter (p= 0.049).

CONCLUSIONS: In this study evaluating patients with IPF under follow-up in our hospital, it was observed that the majority of patients consisted of elderly male individuals, frequent hospitalizations were due to respiratory reasons, and both antifibrotic medications were well tolerated with a similar side effect profile.

PMID:38152005 | DOI:10.5578/tt.20239603

Sci Rep. 2023 Dec 27;13(1):22977. doi: 10.1038/s41598-023-49180-4.

ABSTRACT

This study investigated the utility of periostin, a matricellular protein, as a prognostic biomarker in patients with idiopathic pulmonary fibrosis (IPF) who received nintedanib. Monomeric and total periostin levels were measured by enzyme-linked immunosorbent assay in 87 eligible patients who participated in a multicenter prospective study. Forty-three antifibrotic drug-naive patients with IPF described in previous studies were set as historical controls. Monomeric and total periostin levels were not significantly associated with the change in forced vital capacity (FVC) or diffusing capacity of the lungs for carbon monoxide (DLCO) during any follow-up period. Higher monomeric and total periostin levels were independent risk factors for overall survival in the Cox proportional hazard model. In the analysis of nintedanib effectiveness, higher binarized monomeric periostin levels were associated with more favorable suppressive effects on decreased vital capacity (VC) and DLCO in the treatment group compared with historical controls. Higher binarized levels of total periostin were associated with more favorable suppressive effects on decreased DLCO but not VC. In conclusion, higher periostin levels were independently associated with survival and better therapeutic effectiveness in patients with IPF treated with nintedanib. Periostin assessments may contribute to determining therapeutic strategies for patients with IPF.

PMID:38151520 | DOI:10.1038/s41598-023-49180-4

Aging (Albany NY). 2023 Dec 22;15(24):15382-15401. doi: 10.18632/aging.205355. Epub 2023 Dec 22.

ABSTRACT

Aging usually causes lung-function decline and susceptibility to chronic lung diseases, such as pulmonary fibrosis. However, how aging affects the lung-fibrosis pathways and leads to the occurrence of pulmonary fibrosis is not completely understood. Here, mass spectrometry-based proteomics was used to chart the lung proteome of young and old mice. Micro computed tomography imaging, RNA immunoprecipitation, dual-fluorescence mRFP-GFP-LC3 adenovirus monitoring, transmission electron microscopy, and other experiments were performed to explore the screened differentially expressed proteins related to abnormal ferroptosis, autophagy, mitochondria, and mechanical force in vivo, in vitro, and in healthy people. Combined with our previous studies on pulmonary fibrosis, we further demonstrated that these biological processes and underlying molecular players were also involved in the aging process. Our work depicted a comprehensive cellular and molecular atlas of the aging lung and attempted to explain why aging is a risk factor for pulmonary fibrosis and the role that aging plays in the progression of pulmonary fibrosis. The abnormalities of aging triggered an increase in mechanical force and ferroptosis, autophagy blockade, and mitochondrial dysfunction, which often appear during pulmonary fibrogenesis. We hope that the elucidation of these anomalies will help to enhance our understanding of senescence-inducing pulmonary fibrosis, thereby guiding the use of anti-senescence as an entry point for early intervention in pulmonary fibrosis and age-related diseases.

PMID:38147026 | DOI:10.18632/aging.205355

Am J Med Sci. 2023 Dec 24:S0002-9629(23)01475-1. doi: 10.1016/j.amjms.2023.12.009. Online ahead of print.

ABSTRACT

BACKGROUND: Previous work has shown the ability of Fibresolve, a machine learning system, to non-invasively classify idiopathic pulmonary fibrosis (IPF) with a sensitivity of 41% and specificity of 87% versus other types of interstitial lung disease. Further external validation for the use of Fibresolve to classify IPF in patients with non-definite usual interstitial pneumonia (UIP) is needed. The aim of this study is to assess the sensitivity for Fibresolve to positively classify IPF in an external cohort of patients with a non-definite UIP radiographic pattern.

METHODS: This is a retrospective analysis of patients (n=193) enrolled in two prospective phase two clinical trials that enrolled patients with IPF. We retrospectively identified patients with non-definite UIP on HRCT (n=51), 47 of whom required surgical lung biopsy for diagnosis. Fibresolve was used to analyze the HRCT chest imaging which was obtained prior to invasive biopsy and sensitivity for final diagnosis of IPF was calculated.

RESULTS: The sensitivity of Fibresolve for the non-invasive classification of IPF in patients with a non-definite UIP radiographic pattern by HRCT was 76.5% (95% CI 66.5-83.7). For the subgroup of 47 patients who required surgical biopsy to aid in final diagnosis of IPF, Fibresolve had a sensitivity of 74.5% (95% CI 60.5-84.7).

CONCLUSION: In patients with suspected IPF with non-definite UIP on HRCT, Fibresolve can positively identify cases of IPF with high sensitivity. These results suggest that in combination with standard clinical assessment, Fibresolve has the potential to serve as a low-cost adjunct in the non-invasive diagnosis of IPF.

PMID:38147938 | DOI:10.1016/j.amjms.2023.12.009

Front Med (Lausanne). 2023 Dec 7;10:1280651. doi: 10.3389/fmed.2023.1280651. eCollection 2023.

ABSTRACT

BACKGROUND: Whether the airway is involved in the pathogenesis of interstitial lung abnormalities (ILA) is not well understood. Also the impact of ILA on lung function in COPD patients remains controversial. We aimed to assess the quantitative CT measurements of airway wall thickness (AWT) and lung function according to ILA status in COPD patients.

METHODS: 157 COPD patients discharged from our hospital from August 1, 2019 through August 31, 2022 who underwent chest CT imagings and pulmonary function tests were retrospectively enrolled. Linear regression analysis and multiple models were used to analyze associations between quantitative assessment of airway wall changes and the presence of ILA.

RESULTS: In 157 COPD patients, 23 patients (14.6%) had equivocal ILA, 42 patients (26.8%) had definite ILA. The definite ILA group had the highest measurements of Pi10 (square root of theoretical airway wall area with a lumen perimeter of 10 mm), segmental AWT and segmental WA% (percentage of wall area), whereas the no ILA group had the lowest measurements of Pi10, segmental AWT and segmental WA%. In the adjusted analyses (adjusted by age, sex, body mass index, smoking intensity, COPD GOLD stage, lung function, slice thickness and scanner type), compared to COPD patients without ILA, the measurements of Pi10, segmental AWT and segmental WA% were higher in definite ILA group with differences of 0.225 mm (p = 0.012), 0.152 mm (p < 0.001), 4.8% (p < 0.001) respectively. COPD patients with definite ILA tended to have higher FEV1% predicted, FVC% predicted and lower MMEF75/25% predicted, but there were no statistically differences among the three groups.

CONCLUSION: Our study demonstrates the higher AWT measures in COPD patients with ILA compared to the patients without ILA. These findings suggest that the airway may be involved in the pathogenesis of ILA.

PMID:38146423 | PMC:PMC10749311 | DOI:10.3389/fmed.2023.1280651

Oxf Med Case Reports. 2023 Dec 19;2023(12):omad091. doi: 10.1093/omcr/omad091. eCollection 2023 Dec.

ABSTRACT

Idiopathic pulmonary hemosiderosis (IPH) is a rare entity with no known underlying etiology. It can be complicated by lung fibrosis. Emphysema is rarely reported as a consequence of IPH. We present a case of a 30-year-old female who presented with recurrent hemoptysis and shortness of breath. Radiographs revealed advanced emphysematous changes of the lower lobes. The diagnosis of IPH was established with an open lung biopsy. She was treated with systemic steroids, underwent bullectomy and was subsequently maintained on inhaled steroids.

PMID:38145263 | PMC:PMC10735625 | DOI:10.1093/omcr/omad091

Avicenna J Med. 2023 Nov 1;13(4):230-236. doi: 10.1055/s-0043-1776063. eCollection 2023 Oct.

ABSTRACT

Background Decisions on the management of interstitial lung diseases (ILD) and prognostication require an accurate diagnosis. It has been proposed that multidisciplinary team (MDT) meetings for ILD (ILD-MDT) improve these decisions in challenging cases of ILD. However, most studies in this field have been based on the decisions of individual clinicians and there are few reports on the outcomes of the ILD-MDT approach. We therefore describe the experience of the ILD-MDT meetings at our institution. Methods A single-center retrospective review of the electronic health care records of patients discussed in the ILD-MDT meetings at our institution from February 2016 to January 2021 was performed. At out institution, at each ILD-MDT meeting, the referring pulmonologist presents the clinical history and the results of all relevant investigations including serology, blood gas analyses, lung function tests, bronchoscopy, and bronchoalveolar lavage. A radiologist then describes the imaging including serial computed tomography (CT) scans. When available, the findings on lung biopsy are presented by a pathologist. Subsequent discussions lead to a consensus on the diagnosis and further management. Results The study included 121 patients, comprising 71 (57%) males and 76 nonsmokers (62.8%), with a mean age of 65 years (range: 25-93 years). The average number of comorbidities was 2.4 (range: 0-7). Imaging-based diagnoses were usual interstitial pneumonia (UIP)/chronic hypersensitivity pneumonitis (CHP) in 32 (26%) patients, UIP in 20 (17%) patients, probable UIP in 27 (22%) patients, nonspecific interstitial pneumonia in 11 (9%) patients, and indeterminate interstitial lung abnormalities (ILA) in 10 (8%) patients. The most common consensus clinical diagnosis after an ILD-MDT discussion was chronic hypersensitivity pneumonitis/idiopathic pulmonary fibrosis in 17 patients (14%), followed by idiopathic pulmonary fibrosis and connective tissue disease associated interstitial lung disease in 16 patients (13%), CHP in 11 patients (9.1%), and ILA in 10 patients (8.4%). Only a 42 patients (35%) required surgical lung biopsy for confirmation of the diagnosis. Conclusion This study describes the characteristics of the patients discussed in the ILD-MDT meetings with emphasis on their clinical, radiological, and laboratory data to reach a diagnosis and management plan. The decisions on commencement of antifibrotics or immunosuppressive therapy for patients with various ILDs are also made during these ILD-MDT meetings. This descriptive study could help other health care professionals regarding the structure of their ILD-MDT meetings and with discussions about diagnostic and care decisions for diffused parenchymal lung disease patients.

PMID:38144909 | PMC:PMC10736212 | DOI:10.1055/s-0043-1776063

Reprod Toxicol. 2023 Dec 21:108526. doi: 10.1016/j.reprotox.2023.108526. Online ahead of print.

ABSTRACT

Zinpentraxin alfa is a recombinant human pentraxin-2 (PTX-2) developed for the treatment of various fibrotic diseases with the hypothesis that supplementing endogenous PTX-2 levels through intravenous administration should increase its regulatory capacity in circulation and at the site of disease, thereby promoting healing and reducing fibrosis. Zinpentraxin alfa has been studied in various clinical trials, particularly in patients with idiopathic pulmonary fibrosis, where it has demonstrated efficacy in slowing decline in lung function in a phase 2 study. In the present investigation, we summarize findings from 14-day repeat-dose toxicity studies in rats and cynomolgus monkeys supporting early clinical development of zinpentraxin alfa. In addition, we also describe the findings from the embryo-fetal developmental (EFD) studies conducted in rats and rabbits, since the intended fibrosis patient population may include patients of childbearing potential. Zinpentraxin alfa was well tolerated by rats and monkeys in general toxicity studies with no treatment-related adverse effects, as well as by pregnant rats over the same dose range in a definitive EFD study. In contrast, substantial toxicity was observed in a rabbit dose-range-finder EFD study. Zinpentraxin alfa was poorly tolerated by pregnant rabbits and effects on the dams correlated with post-implantation fetal losses. The disparate effects of zinpentraxin alfa on embryo-fetal development between the two species suggests a potential unknown biological function of PTX-2 in pregnancy in the rabbit, which may be relevant to humans. Our findings warrant the consideration for highly effective contraceptive measures to avoid pregnancy in patients enrolled in clinical studies with zinpentraxin alfa.

PMID:38141866 | DOI:10.1016/j.reprotox.2023.108526

Respir Med Res. 2023 Nov 2;85:101058. doi: 10.1016/j.resmer.2023.101058. Online ahead of print.

ABSTRACT

BACKGROUND: Computational advances in artificial intelligence have led to the recent emergence of U-Net convolutional neural networks (CNNs) applied to medical imaging. Our objectives were to assess the progression of fibrotic interstitial lung disease (ILD) using routine CT scans processed by a U-Net CNN developed by our research team, and to identify a progression threshold indicative of poor prognosis.

METHODS: CT scans and clinical history of 32 patients with idiopathic fibrotic ILDs were retrospectively reviewed. Successive CT scans were processed by the U-Net CNN and ILD quantification was obtained. Correlation between ILD and FVC changes was assessed. ROC curve was used to define a threshold of ILD progression rate (PR) to predict poor prognostic (mortality or lung transplantation). The PR threshold was used to compare the cohort survival with Kaplan Mayer curves and log-rank test.

RESULTS: The follow-up was 3.8 ± 1.5 years encompassing 105 CT scans, with 3.3 ± 1.1 CT scans per patient. A significant correlation between ILD and FVC changes was obtained (p = 0.004, ρ = -0.30 [95% CI: -0.16 to -0.45]). Sixteen patients (50%) experienced unfavorable outcome including 13 deaths and 3 lung transplantations. ROC curve analysis showed an aera under curve of 0.83 (p < 0.001), with an optimal cut-off PR value of 4%/year. Patients exhibiting a PR ≥ 4%/year during the first two years had a poorer prognosis (p = 0.001).

CONCLUSIONS: Applying a U-Net CNN to routine CT scan allowed identifying patients with a rapid progression and unfavorable outcome.

PMID:38141579 | DOI:10.1016/j.resmer.2023.101058

J Clin Med. 2023 Dec 8;12(24):7589. doi: 10.3390/jcm12247589.

ABSTRACT

Neutrophil activation can release neutrophil extracellular traps (NETs) in acute inflammation. NETs result in the release of human neutrophil elastase (HNE) and calprotectin, where the former can degrade the latter and generate protein fragments associated with neutrophil activity. We investigated this in chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) using the novel neoepitope biomarker CPa9-HNE, quantifying a specific HNE-mediated fragment of calprotectin in serum. CPa9-HNE was compared to total calprotectin. Initially, CPa9-HNE was measured in healthy (n = 39), COPD (n = 67), and IPF (n = 16) serum using a neoepitope-specific competitive enzyme-linked immunosorbent assay. Then, a head-to-head comparison of CPa9-HNE and total calprotectin, a non-neoepitope, was conducted in healthy (n = 19), COPD (n = 25), and IPF (n = 19) participants. CPa9-HNE levels were significantly increased in COPD (p < 0.0001) and IPF subjects (p = 0.0001) when compared to healthy participants. Additionally, CPa9-HNE distinguished IPF (p < 0.0001) and COPD (p < 0.0001) from healthy participants more effectively than total calprotectin for IPF (p = 0.0051) and COPD (p = 0.0069). Here, CPa9-HNE also distinguished IPF from COPD (p = 0.045) participants, which was not observed for total calprotectin (p = 0.98). Neutrophil activity was significantly higher, as assessed via serum CPa9-HNE, for COPD and IPF compared to healthy participants. Additionally, CPa9-HNE exceeded the ability of non-neoepitope calprotectin serum measurements to separate healthy from lung disease and even COPD from IPF participants, indicating that neutrophil activity is essential for both COPD and IPF.

PMID:38137658 | DOI:10.3390/jcm12247589

Biomedicines. 2023 Dec 8;11(12):3257. doi: 10.3390/biomedicines11123257.

ABSTRACT

Interstitial lung diseases (ILDs) constitute a group of more than 200 disorders, with idiopathic pulmonary fibrosis (IPF) being one of the most frequent. Telomere length (TL) shortening causes loss of function of the lung parenchyma. However, little is known about its role as a prognostic factor in ILD patients. With the aim of investigating the role of TL and telomerase activity in the prognosis of patients affected by ILDs, we analysed lung tissue samples from 61 patients. We measured relative TL and telomerase activity by conventional procedures. Both clinical and molecular parameters were associated with overall survival by the Kaplan-Meier method. Patients with IPF had poorer prognosis than patients with other ILDs (p = 0.034). When patients were classified according to TL, those with shortened telomeres reported lower overall survival (p = 0.085); differences reached statistical significance after excluding ILD patients who developed cancer (p = 0.021). In a Cox regression analysis, TL behaved as a risk-modifying variable for death associated with rheumatic disease (RD) co-occurrence (p = 0.029). Also, in patients without cancer, ferritin was significantly increased in cases with RD and IPF co-occurrence (p = 0.032). In relation to telomerase activity, no significant differences were detected. In conclusion, TL in lung tissue emerges as a prognostic factor in ILD patients. Specifically, in cases with RD and IPF co-occurrence, TL can be considered as a risk-modifying variable for death.

PMID:38137478 | DOI:10.3390/biomedicines11123257

Biomedicines. 2023 Dec 5;11(12):3220. doi: 10.3390/biomedicines11123220.

ABSTRACT

Keloids are common benign cutaneous pathological fibrous proliferation diseases, which are difficult to cure and easily recur. Studies have shown that fibroblast growth factor receptor-1 (FGFR1) was enhanced in pathological fibrous proliferation diseases, such as cirrhosis and idiopathic pulmonary fibrosis (IPF), suggesting the FGFR1 pathway has potential for keloid treatment. Derazantinib is a selective FGFR inhibitor with antiproliferative activity in in vitro and in vivo models. The present study determined the effects of derazantinib on human keloid fibroblasts (KFs). Cell viability assay, migration assay, invasion assay, immunofluorescence staining, quantitative polymerase chain reaction, Western blot analysis, HE staining, Masson staining, and immunohistochemical analysis were used to analyze the KFs and keloid xenografts. In this study, we found that derazantinib inhibited the proliferation, migration, invasion, and collagen production of KFs in vitro. The transcription and expression of plasminogen activator inhibitor-1 (PAI-1), which is closely related to collagen deposition and tissue fibrosis, was significantly inhibited. Also, derazantinib inhibited the expression of FGFR1 and PAI-1 and reduced the weight of the implanted keloid from the xenograft mice model. These findings suggest that derazantinib may be a potent therapy for keloids via FGFR signaling.

PMID:38137441 | DOI:10.3390/biomedicines11123220

Biomedicines. 2023 Nov 21;11(12):3109. doi: 10.3390/biomedicines11123109.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with reduced quality of life and earlier mortality, but its pathogenesis and key genes are still unclear. In this investigation, bioinformatics was used to deeply analyze the pathogenesis of IPF and related key genes, so as to investigate the potential molecular pathogenesis of IPF and provide guidance for clinical treatment. Next-generation sequencing dataset GSE213001 was obtained from Gene Expression Omnibus (GEO), and the differentially expressed genes (DEGs) were identified between IPF and normal control group. The DEGs between IPF and normal control group were screened with the DESeq2 package of R language. The Gene Ontology (GO) and REACTOME pathway enrichment analyses of the DEGs were performed. Using the g:Profiler, the function and pathway enrichment analyses of DEGs were performed. Then, a protein-protein interaction (PPI) network was constructed via the Integrated Interactions Database (IID) database. Cytoscape with Network Analyzer was used to identify the hub genes. miRNet and NetworkAnalyst databaseswereused to construct the targeted microRNAs (miRNAs), transcription factors (TFs), and small drug molecules. Finally, receiver operating characteristic (ROC) curve analysis was used to validate the hub genes. A total of 958 DEGs were screened out in this study, including 479 up regulated genes and 479 down regulated genes. Most of the DEGs were significantly enriched in response to stimulus, GPCR ligand binding, microtubule-based process, and defective GALNT3 causes HFTC. In combination with the results of the PPI network, miRNA-hub gene regulatory network and TF-hub gene regulatory network, hub genes including LRRK2, BMI1, EBP, MNDA, KBTBD7, KRT15, OTX1, TEKT4, SPAG8, and EFHC2 were selected. Cyclothiazide and rotigotinethe are predicted small drug molecules for IPF treatment. Our findings will contribute to identification of potential biomarkers and novel strategies for the treatment of IPF, and provide a novel strategy for clinical therapy.

PMID:38137330 | DOI:10.3390/biomedicines11123109

Antioxidants (Basel). 2023 Nov 21;12(12):2024. doi: 10.3390/antiox12122024.

ABSTRACT

Unfolded protein response (UPR) signaling and endoplasmic reticulum (ER) stress have been linked to pulmonary fibrosis. However, the relationship between UPR status and pulmonary function and prognosis in idiopathic pulmonary fibrosis (IPF) patients remains largely unknown. Through a series of bioinformatics analyses, we established a correlation between UPR status and pulmonary function in IPF patients. Furthermore, thrombospondin-1 (TSP-1) was identified as a potential biomarker for prognostic evaluation in IPF patients. By utilizing both bulk RNA profiling and single-cell RNA sequencing data, we demonstrated the upregulation of TSP-1 in lung fibroblasts during pulmonary fibrosis. Gene set enrichment analysis (GSEA) results indicated a positive association between TSP-1 expression and gene sets related to the reactive oxygen species (ROS) pathway in lung fibroblasts. TSP-1 overexpression alone induced mild ER stress and pulmonary fibrosis, and it even exacerbated bleomycin-induced ER stress and pulmonary fibrosis. Mechanistically, TSP-1 promoted ER stress and fibroblast activation through CD47-dependent ROS production. Treatment with either TSP-1 inhibitor or CD47 inhibitor significantly attenuated BLM-induced ER stress and pulmonary fibrosis. Collectively, these findings suggest that the elevation of TSP-1 during pulmonary fibrosis is not merely a biomarker but likely plays a pathogenic role in the fibrotic changes in the lung.

PMID:38136144 | DOI:10.3390/antiox12122024

Antioxidants (Basel). 2023 Nov 21;12(12):2022. doi: 10.3390/antiox12122022.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive fatal lung disease with a limited therapeutic strategy. Mitochondrial oxidative stress in macrophages is directly linked to IPF. Elamipretide(SS-31) is a mitochondrion-targeted peptide that has been shown to be safe and beneficial for multiple diseases. However, whether SS-31 alleviates IPF is unclear. In the present study, we used a bleomycin (BLM)-induced mouse model followed by SS-31 injection every other day to investigate its role in IPF and explore the possible mechanism. Our results showed that SS-31 treatment significantly suppressed BLM-induced pulmonary fibrosis and inflammation, with improved histological change, and decreased extracellular matrix deposition and inflammatory cytokines release. Impressively, the expression percentage of IL-1β and IL-18 was downregulated to lower than half with SS-31 treatment. Mechanistically, SS-31 inhibited IL-33- or lipopolysaccharide(LPS)/IL-4-induced production of IL-1β and IL-18 in macrophages by suppressing NOD-like receptor thermal protein domain associated protein 3(NLRP3) inflammasome activation. Nuclear factor erythroid 2-related factor 2(Nrf2) was dramatically upregulated along with improved mitochondrial function after SS-31 treatment in activated macrophages and BLM-induced mice. Conversely, there was no significant change after SS-31 treatment in Nrf2-/- mice and macrophages. These findings indicated that SS-31 protected against pulmonary fibrosis and inflammation by inhibiting the Nrf2-mediated NLRP3 inflammasome in macrophages. Our data provide initial evidence for the therapeutic efficacy of SS-31 in IPF.

PMID:38136142 | DOI:10.3390/antiox12122022

Eur Respir J. 2023 Dec 22:2300752. doi: 10.1183/13993003.00752-2023. Online ahead of print.

ABSTRACT

Dyspnoea and cough can have a profound impact on the lives of patients with pulmonary fibrosis. We investigated the effects of nintedanib on the symptoms and impact of pulmonary fibrosis in patients with progressive pulmonary fibrosis (PPF) in the INBUILD trial using the Living with Pulmonary Fibrosis (L-PF) questionnaire.Patients had a fibrosing interstitial lung disease (ILD) (other than idiopathic pulmonary fibrosis) of >10% extent on HRCT and met criteria for ILD progression within the prior 24 months. Patients were randomised 1:1 to receive nintedanib or placebo. Changes in L-PF questionnaire scores from baseline to week 52 were assessed using mixed models for repeated measures.A total of 663 patients were treated. Compared with placebo, there were significantly smaller increases (worsenings) in adjusted mean L-PF questionnaire total (0.5 versus 5.1), symptoms (1.3 versus 5.3), dyspnoea (4.3 versus 7.8), and fatigue (0.7 versus 4.0) scores in the nintedanib group at week 52. L-PF questionnaire cough score decreased in the nintedanib group and increased in the placebo group (-1.8 versus 4.3). L-PF questionnaire impacts score decreased slightly in the nintedanib group and increased in the placebo group (-0.2 versus 4.6). Similar findings were observed in patients with a usual interstitial pneumonia (UIP)-like fibrotic pattern on HRCT and in patients with other fibrotic patterns on HRCT.Based on changes in L-PF questionnaire scores, nintedanib reduced worsening of dyspnoea, fatigue and cough and impacts of ILD over 52 weeks in patients with PPF.

PMID:38135442 | DOI:10.1183/13993003.00752-2023

Ann Am Thorac Soc. 2023 Dec 22. doi: 10.1513/AnnalsATS.202305-491OC. Online ahead of print.

ABSTRACT

RATIONALE: Hospital readmission within 30 days poses challenges for healthcare providers, policymakers, and patients due to its impact on care quality, costs, and outcomes. Interstitial lung disease (ILD) patients are particularly affected by readmission, which is associated with increased morbidity, mortality, and reduced quality of life. While small sample sizes have hindered previous studies, this study seeks to address this gap in knowledge by examining a large-scale dataset.

OBJECTIVE: To determine the rate and probability of 30-day all-cause readmission and secondary outcomes in COVID-19 or ILD patients admitted to the hospital.

METHODS: This study is a nested cohort study using the PearlDiver patient records database. Adult patients (≥18 years) who were admitted to hospitals in 28 states of the US with COVID-19 or ILD diagnoses were included. We defined and analyzed two separate cohorts in this study. The first cohort consisted of COVID-19 patients, that later formed two groups with or without ILD history and the second cohort compromised ILD patients which later formed groups of with COVID-19 or with non-COVID-19 Pneumonia diagnosis at admission. We also studied two other sub cohorts of idiopathic pulmonary fibrosis (IPF) and non-IPF under the second cohort. Propensity score matching (PSM) was employed to match confounders between groups. The Kaplan Meier log rank test was applied to compare the probability of outcomes.

RESULTS: We assessed the data of 2,286,775 patients with COVID-19 and 118892 patients with ILD. We found that COVID-19 patients with pre-existing ILD had an odds ratio of 1.6 for 30-day all-cause readmission rates. Similarly, an odds ratio of 2.42 in readmission rates was observed among hospitalized individuals with ILD who contracted COVID-19 compared to those who have hospitalized for non-COVID-19 pneumonia. . Our study also found a significantly higher probability of ICU admission among patients in both cohorts.

CONCLUSIONS: ILD patients face heightened rates of hospital readmissions, particularly when combined with COVID-19, resulting in adverse outcomes such as decreased quality of life and increased healthcare expenses. It is imperative to prioritize preventive measures against COVID-19 and establish effective post-discharge care strategies for ILD patients.

PMID:38134434 | DOI:10.1513/AnnalsATS.202305-491OC

Cells. 2023 Dec 8;12(24):2795. doi: 10.3390/cells12242795.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic and refractory interstitial lung disease. Although there is no cure for IPF, the development of drugs with improved efficacy in the treatment of IPF is required. Daphnetin, a natural coumarin derivative, has immunosuppressive, anti-inflammatory, and antioxidant activities. However, its antifibrotic effects have not yet been elucidated. In this study, we investigated the antifibrotic effects of daphnetin on pulmonary fibrosis and the associated molecular mechanism. We examined the effects of daphnetin on splenocytes cultured in Th17 conditions, lung epithelial cells, and a mouse model of bleomycin (BLM)-induced pulmonary fibrosis. We identified that daphnetin inhibited IL-17A production in developing Th17 cells. We also found that daphnetin suppressed epithelial-to-mesenchymal transition (EMT) in TGF-β-treated BEAS2B cells through the regulation of AKT phosphorylation. In BLM-treated mice, the oral administration of daphnetin attenuated lung histopathology and improved lung mechanical functions. Our findings clearly demonstrated that daphnetin inhibited IL-17A and EMT both in vitro and in vivo, thereby protecting against BLM-induced pulmonary fibrosis. Taken together, these results suggest that daphnetin has potent therapeutic effects on lung fibrosis by modulating both Th17 differentiation and the TGF-β signaling pathway, and we thus expect daphnetin to be a drug candidate for the treatment of IPF.

PMID:38132116 | DOI:10.3390/cells12242795

BMC Pulm Med. 2023 Dec 21;23(1):517. doi: 10.1186/s12890-023-02788-8.

ABSTRACT

BACKGROUND: The relationship between gastroesophageal reflux disease (GERD) and the susceptibility as well as the prognosis of idiopathic pulmonary fibrosis (IPF) has been previously suggested, with the potential confounding factor of smoking not adequately addressed. In light of this, we conducted a Mendelian randomization (MR) study to investigate the causal effects of GERD on the susceptibility and prognosis of IPF while excluding smoking.

METHODS: We chose GERD as the exposure variable and employed genome-wide association data to examine its association with susceptibility, forced vital capacity (FVC), diffusing capacity of the lung for carbon monoxide (DLco), and transplant-free survival (TFS) in patients with IPF as the outcome variables. MR analyses were performed using the inverse variance weighted (IVW) method, and sensitivity analyses were conducted using the MR-PRESSO outlier test, Cochran's Q test, MR-Egger intercept test, and leave-one-out sensitivity analysis. Additionally, to mitigate the potential effects of smoking on our MR estimates, we conducted a multivariable MR (MVMR) analysis by adjusting for smoking.

RESULTS: The univariable MR analysis demonstrated no causal effect of GERD on FVC (βIVW = 26.63, SE = 48.23, P = 0.581), DLco (βIVW = 0.12, SE = 0.12, P = 0.319), and TFS (HRIVW = 0.87, 95% CI = 0.56 to 1.35, P = 0.533) in patients with IPF. Furthermore, sensitivity analysis revealed no evidence of heterogeneity, horizontal pleiotropy, or outlier single nucleotide polymorphisms. The MVMR analysis showed no causal effect of GERD on susceptibility to IPF after adjusting for smoking (ORIVW = 1.30, 95% CI = 0.93 to 1.68, P = 0.071). These findings were consistent in the replication cohort.

CONCLUSIONS: The link between GERD and its potential impact on susceptibility to IPF may not be of a direct causal nature and could be influenced by factors such as smoking. Our findings did not reveal any evidence of a causal relationship between GERD and the FVC, DLco, and TFS of patients with IPF.

PMID:38129814 | DOI:10.1186/s12890-023-02788-8

Eur Respir J. 2023 Dec 21;62(6):2301878. doi: 10.1183/13993003.01878-2023. Print 2023 Dec.

NO ABSTRACT

PMID:38128953 | DOI:10.1183/13993003.01878-2023