Ther Adv Respir Dis. 2024 Jan-Dec;18:17534666241287307. doi: 10.1177/17534666241287307.

ABSTRACT

What is this summary about?This plain language summary shares results from a clinical study called INTEGRIS-IPF that was published in the American Journal of Respiratory and Critical Care Medicine in 2024. This study looked at a medicine called bexotegrast (beck-so-teh-grast) as a possible treatment for idiopathic pulmonary fibrosis (i-dee-uh-pa-thick pul-muh-ner-ee fie-bro-sis; IPF). Bexotegrast is an investigational medicine, which means that it is being studied and has not yet been approved by the US Food and Drug Administration (FDA), for people with IPF to take as a treatment. IPF is a chronic, progressive lung disease that makes it hard to breathe and gets worse over time. There is no cure for IPF, treatment includes symptom management and consideration for the use of nintedanib or pirfenidone, which may decrease the pace of disease progression.The study compared bexotegrast to a placebo (a treatment that looks identical to the medicine but has no medicinal effect) to look at how well it works and how safe it is in treating people with IPF. Most people in the study also took one of two medicines that are already approved by the FDA for IPF, pirfenidone or nintedanib.

PMID:39512136 | DOI:10.1177/17534666241287307

Eur Respir J. 2024 Nov 7:2401484. doi: 10.1183/13993003.01484-2024. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) carries a high risk of lung cancer, but the effect of pirfenidone on lung cancer development remains uncertain. We investigated the association between pirfenidone use and lung cancer development in patients with IPF.

METHODS: We included 10 084 patients with IPF from the national claims database. Propensity score analysis with inverse probability of treatment weighting (IPTW) and landmark analyses were employed to evaluate lung cancer occurrence according to pirfenidone use. The association was evaluated using Cox regression models adjusted for clinical and socioeconomic variables. A single-center IPF clinical cohort (n=941) was used for validating the findings.

RESULTS: The mean patient age was 69.4 years, 73.8% were men, and 31.6% received pirfenidone. Lung cancer developed in 766 patients with IPF (7.6%; 21.9 cases per 1000 person-years) during a median follow-up of 3.0 years. After IPTW, the pirfenidone group showed lower incidence (10.4 versus 27.9 cases per 1000 person-years) than the no-pirfenidone group. Landmark analysis at 6 months after IPF diagnosis also showed lower incidence of lung cancer in the pirfenidone group than in the no-pirfenidone group. Pirfenidone use was independently associated with a reduced lung cancer risk (weighted adjusted hazard ratio [HR]: 0.347; 95% confidence interval [CI]: 0.258-0.466). A clinical cohort showed similar association (weighted adjusted HR: 0.716; 95% CI: 0.517-0.991). The association persisted across subgroups defined by age or sex.

CONCLUSION: Pirfenidone use may be associated with a reduced lung cancer risk in patients with IPF.

PMID:39510556 | DOI:10.1183/13993003.01484-2024

Chest. 2024 Nov 5:S0012-3692(24)05448-5. doi: 10.1016/j.chest.2024.10.038. Online ahead of print.

ABSTRACT

BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) may suffer from insomnia and use hypnotics. However, the effect of the use of hypnotics on their clinical course remains unclear.

RESEARCH QUESTION: Is the use of hypnotics associated with an increased risk of mortality in patients with IPF?

STUDY DESIGN AND PARTICIPANTS: This study included 99 and 123 patients with IPF from the Hamamatsu and Seirei hospital-based cohorts, respectively, and 30,218 patients with IPF from the national claims database of Japan (NDB cohort). To analyze the association of hypnotic use with outcomes avoiding immortal time bias, multivariable Cox models with time-dependent covariates and target trial emulation with a new user design were employed for the hospital- and NDB-based cohorts, respectively.

RESULTS: In the cohorts studied, the 3-year cumulative incidence of new use of hypnotics after IPF diagnosis was 13.4%-24.1%. In both the hospital-based cohorts, the continuous use of hypnotics was associated with an increased risk of all-cause mortality and disease progression. In the NDB cohort, the continuous use of hypnotics was also associated with an increased risk of all-cause mortality. Subgroup analysis found associations between the continuous use of hypnotics and increased mortality regardless of sex and comorbidities, excluding certain subpopulations.

INTERPRETATION: This study found that continuous use of hypnotics was associated with an increased risk of mortality in patients with IPF. Given the relatively high cumulative incidence of hypnotic use in this population, there is an urgent need to reassess the appropriate use of hypnotics for patients with IPF.

PMID:39510406 | DOI:10.1016/j.chest.2024.10.038

Am J Physiol Cell Physiol. 2024 Nov 7. doi: 10.1152/ajpcell.00528.2024. Online ahead of print.

ABSTRACT

We aimed to study transcriptional and phenotypic changes in circulating immune cells associated with increased risk of mortality in COVID-19, resolution of pulmonary fibrosis in post-COVID-19-Interstitial Lung Disease (ILD) and persistence of Idiopathic Pulmonary Fibrosis. Whole blood and Peripheral Blood Mononuclear cells (PBMC) were obtained from 227 subjects with COVID-19, post-COVID-19 Interstitial Lung Disease (ILD), IPF and controls. We measured a 50-gene signature (nCounter, Nanostring) previously found to be predictive of IPF and COVID-19 mortality along with plasma levels of several biomarkers by Luminex. Additionally, we performed single-cell RNA sequencing in PBMC (10X Genomics) to determine the cellular source of the 50-gene signature. We identified the presence of three genomic risk profiles in COVID-19 based on the 50-gene signature associated with low, intermediate, or high-risk of mortality and with significant differences in pro-inflammatory and pro-fibrotic cytokines. COVID-19 patients in the high-risk group had increased expression of seven genes in CD14+HLA-DRlowCD163+Monocytic-Myeloid-Derived Suppressive cells (7Gene-M-MDSCs) and decreased expression of 43 genes in CD4 and CD8 T cell subsets. The loss of 7Gene-M-MDSC and increased expression of these 43 genes in T cells was seen in survivors with post-COVID-19-ILD. On the contrary, IPF patients had low expression of the 43 genes in CD4 and CD8 T cells. Collectively, we showed that a 50-gene, high-risk profile, predictive of IPF and COVID-19 mortality is characterized by a genomic imbalance in monocyte and T-cell subsets. This imbalance reverses in survivors with post-COVID-19-ILD highlighting genomic differences between post-COVID-19-ILD and IPF.

PMID:39510135 | DOI:10.1152/ajpcell.00528.2024

Respiration. 2024 Nov 7:1-12. doi: 10.1159/000541692. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) can occur at any age; however, studies on younger IPF patients are scarce because it primarily affects the elderly. This study aimed to investigate the clinical features and outcomes of younger IPF patients.

METHODS: We analyzed the National Korean Health Insurance Review and Assessment Service (HIRA) database from 2015 to 2021. Patients with IPF were identified using the International Classification of Diseases 10th Revision (ICD-10) codes and the Rare Intractable Diseases codes and were categorized into three age groups: <50, ≥50 and <65, and ≥65 years. The risk of acute exacerbation (AE) and mortality was analyzed.

RESULTS: Among 4,243 patients with IPF, 91 were under 50. These younger patients, who were predominantly female, exhibited less comorbidities and received more systemic steroids, whereas older group received more pirfenidone. Although AE risk increased with age, it was not statistically significant. Mortality and lung transplantation risks increased notably with age from the <50 group to the ≥50 and <65 group (hazard ratio [HR]: 1.52, 95% confidence interval [CI]: 0.93-2.49) and the ≥65 group (HR: 2.44, 95% CI: 1.51-3.93). These risks were influenced by factors such as age, comorbidities, previous AEs, and steroid use. Conversely, pirfenidone treatment reduced the risk.

CONCLUSION: While younger IPF patients had a lower risk of mortality and lung transplantation, with no significant differences in the risk of AEs, they were less likely to receive antifibrotic therapy and more often treated with steroids, which may affect outcomes. Early, targeted treatment strategies, including antifibrotic use, are crucial for improving their prognosis.

PMID:39510056 | DOI:10.1159/000541692

Ann Am Thorac Soc. 2024 Nov 5. doi: 10.1513/AnnalsATS.202409-969OC. Online ahead of print.

ABSTRACT

Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease characterized by dyspnea and loss of lung function. Transforming growth factor-beta (TGF-β) activation mediated by αv integrins is central to the pathogenesis of IPF. Bexotegrast (PLN 74809) is an oral, once-daily, dual-selective inhibitor of αvβ6 and αvβ1 integrins under investigation for the treatment of IPF. Positron emission tomography (PET) using an αvβ6-specific PET tracer could confirm target engagement of bexotegrast in the lungs of participants with IPF. Objectives: This Phase 2 study (NCT04072315) evaluated αvβ6 receptor occupancy in the lung, as assessed by changes from baseline in αvβ6 PET tracer uptake, following single dose administration of bexotegrast to participants with IPF. Methods: In this open-label, single-center, single-arm study, adults with IPF received up to 2 single doses of bexotegrast, ranging from 60 to 320 mg with or without background IPF therapy (pirfenidone or nintedanib). At baseline and approximately 4 hours after each orally administered bexotegrast dose, a 60-minute dynamic PET/CT scan was conducted following administration of an αvβ6-specific PET probe ([18F]FP-R01-MG-F2). αvβ6 receptor occupancy by bexotegrast was estimated from the changes in PET tracer uptake following bexotegrast. Pharmacokinetics, safety, and tolerability of bexotegrast were also assessed. Results: Eight participants completed the study. Total and unbound plasma bexotegrast concentrations increased in a dose-dependent manner, and regional PET volume of distribution (VT) values decreased in a dose- and concentration-dependent manner. The VT data fit a simple saturation model, producing an unbound bexotegrast EC50 estimate of 3.32 ng/mL. Estimated maximum receptor occupancy was 35%, 53%, 71%, 88%, and 92% following single 60, 80, 120, 240, and 320-mg doses of bexotegrast, respectively. No treatment-emergent adverse events related to bexotegrast were reported. Conclusions: Dose- and concentration-dependent αvβ6 receptor occupancy by bexotegrast was observed by PET imaging, supporting once-daily 160 to 320 mg dosing to evaluate efficacy in clinical trials of IPF. Trial registration number: NCT04072315 Primary source of funding: Pliant Therapeutics, Inc. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PMID:39499805 | DOI:10.1513/AnnalsATS.202409-969OC

Am J Manag Care. 2024 Oct;30(7 Suppl):S122-S130. doi: 10.37765/ajmc.2024.89634.

ABSTRACT

The term "progressive pulmonary fibrosis" or "PPF" is generally used to describe progressive lung fibrosis in an individual with an interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis (IPF). Several sets of criteria have been proposed for the identification of PPF, most of which are based on a combination of a decline in forced vital capacity, worsening of respiratory symptoms, and increase in the extent of fibrosis on radiology. Although some risk factors for faster progression of fibrosing ILD have been identified, it remains challenging to predict which individuals will develop PPF. Close monitoring, including regular pulmonary function tests, is required to detect the earliest signs of worsening disease. PPF is associated with high rates of hospitalization and death. Management of PPF requires a multidisciplinary and multimodal approach, including pharmacological therapy and supportive care. Discussions about palliative care should begin at an early stage, individualized to the needs of the patient.

PMID:39495032 | DOI:10.37765/ajmc.2024.89634

Am J Manag Care. 2024 Oct;30(7 Suppl):S107-S113. doi: 10.37765/ajmc.2024.89632.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is characterized by a progressive decline in lung function, worsening quality of life, and high mortality. However, the rate and pattern of progression of IPF are variable. Real-world studies, which include a broader population of patients than clinical trials and collect data over longer periods, have provided important information on the clinical course of IPF and further insights into the efficacy and safety of antifibrotic therapies. They also highlight the worsening of patients' quality of life as lung function is lost, the high frequency of hospitalizations, and the impact of acute exacerbations on mortality in patients with IPF. Data from patient registries and analyses of claims data suggest that antifibrotic therapy is more likely to be used in patients who have worse lung function and that its use is associated with an improvement in life expectancy. The safety profile of antifibrotic therapies in real-world populations is consistent with that observed in clinical trials. Further real-world studies are needed to improve understanding of the course and impact of IPF in specific groups of patients and how the care provided to these patients might be improved.

PMID:39495030 | DOI:10.37765/ajmc.2024.89632

Sci Rep. 2024 Nov 2;14(1):26470. doi: 10.1038/s41598-024-77469-5.

ABSTRACT

Fibrosing interstitial lung diseases (ILDs) encompass a diverse range of scarring disorders that lead to progressive lung failure. Previous gene expression profiling studies focused on idiopathic pulmonary fibrosis (IPF) and bulk tissue samples. We employed digital spatial profiling to gain new insights into the spatial resolution of gene expression across distinct lung microenvironments (LMEs) in IPF, chronic hypersensitivity pneumonitis (CHP) and non-specific interstitial pneumonia (NSIP). We identified differentially expressed genes between LMEs within each condition, and across histologically similar regions between conditions. Uninvolved regions in IPF and CHP were distinct from normal controls, and displayed potential therapeutic targets. Hallmark LMEs of each condition retained distinct gene signatures, but these could not be reproduced in matched lung tissue samples. Based on these profiles and unsupervised clustering, we grouped previously unclassified ILD cases into NSIP or CHP. Overall, our work uniquely dissects gene expression profiles between LMEs within and across different types of fibrosing ILDs.

PMID:39488596 | DOI:10.1038/s41598-024-77469-5

medRxiv [Preprint]. 2024 Oct 15:2024.10.12.24315151. doi: 10.1101/2024.10.12.24315151.

ABSTRACT

BACKGROUND: The clinical course of idiopathic pulmonary fibrosis (IPF) is highly variable and unpredictable, with multiple genetic variants influencing IPF outcomes. Notably, rare pathogenic variants in telomere-related genes are associated with poorer clinical outcomes in these patients. Here we assessed whether rare qualifying variants (QVs) in monogenic adult-onset pulmonary fibrosis (PF) genes are associated with IPF survival. Using polygenic risk scores (PRS), we also evaluated the influence of common IPF risk variants in individuals carrying these QVs.

METHODS: We identified QVs in telomere and non-telomere genes linked to monogenic PF forms using whole-genome sequences (WGS) from 888 Pulmonary Fibrosis Foundation Patient Registry (PFFPR) individuals. We also derived a PRS for IPF (PRS-IPF) from 19 previously published common sentinel IPF variants. Using regression models, we then examined the mutual relationships of QVs and PRS-IPF and their association with survival. Validation of results was sought in WGS from an independent IPF study (PROFILE, n=472), and results from the two cohorts were meta-analyzed.

RESULTS: Carriers of QVs in monogenic adult-onset PF genes, representing nearly 1 out of 6 IPF patients, were associated with lower PRS-IPF (Odds Ratio [OR]: 1.79; 95% Confidence Interval [CI]: 1.15-2.81; p=0.010) and shorter survival (Hazard Ratio [HR]: 1.53; 95% CI: 1.12-2.10; p=7.3×10 -3 ). Notably, carriers of pathogenic variants at telomere genes showed the strongest association with survival (HR: 1.76; 95% CI: 1.13-2.76; p=0.013). The meta-analysis of the results showed a consistent direction of effect across both cohorts.

CONCLUSIONS: We revealed the opposite effects of QVs and PRS-IPF on IPF survival. Thus, a distinct IPF molecular subtype might be defined by QVs in monogenic adult-onset PF genes. Assessing the carrier status for QVs and modelling PRS-IPF promises to further contribute to predicting disease progression among IPF patients.

PMID:39484282 | PMC:PMC11527076 | DOI:10.1101/2024.10.12.24315151

Monaldi Arch Chest Dis. 2024 Oct 29. doi: 10.4081/monaldi.2024.2952. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) has been widely hypothesized to occur as a result of an interplay between a nexus of environmental and genetic risk factors. However, not much is known about the genetic aspect of this disease. The objective of this review was to identify the genetic polymorphisms associated with the risk of developing IPF. We searched PubMed, EBSCO CINAHL Plus, Web of Science, and Wiley Cochrane Library databases for studies on risk factors of IPF published between March 2000 and November 2023. Studies with an IPF diagnosis based only on the American Thoracic Society and the European Respiratory Society guidelines were included. Thirty-one case-control studies were included with 3997 IPF and 20,925 non-IPF subjects. Two of the studies enrolled biopsy-proven IPF patients; 13 studies diagnosed IPF on the basis of clinical and high-resolution computed tomography (HRCT) findings; and 14 studies diagnosed based on both biopsy and clinical and HRCT findings. 16 studies with MUC5B rs35705950, IL-4 rs2243250, IL-4 rs2070874, and tumor necrosis factor α (TNFα)-308 were eligible for meta-analysis. The allele contrast model (T versus G) for MUC5B rs35705950 revealed statistically significant association of T allele with the risk of IPF [odds ratio (OR) 3.84, 95% confidence interval (CI) 3.20 to 4.61, adjusted p<0.0001), as was the allele contrast model for Asian (OR 2.83, 95% CI 1.51 to 5.32, adjusted p=0.009) and Caucasian (OR 4.11, 95% CI 3.56 to 4.75, adjusted p<0.0001). The allele contrast models for IL-4 rs2243250, IL-4 rs2070874, and TNFα-308 did not demonstrate any significant association with IPF. This review suggests an association of MUC5B rs35705950 T allele with the risk of developing IPF. To our knowledge, this study is the first to aggregate several genetic polymorphisms associated with IPF.

PMID:39480160 | DOI:10.4081/monaldi.2024.2952

Front Cell Dev Biol. 2024 Oct 16;12:1470875. doi: 10.3389/fcell.2024.1470875. eCollection 2024.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a prevalent chronic pulmonary fibrosis disease characterized by alveolar epithelial cell damage, fibroblast proliferation and activation, excessive extracellular matrix deposition, and abnormal epithelial-mesenchymal transition (EMT), resulting in tissue remodeling and irreversible structural distortion. The mortality rate of IPF is very high, with a median survival time of 2-3 years after diagnosis. The exact cause of IPF remains unknown, but increasing evidence supports the central role of epigenetic changes, particularly microRNA (miRNA), in IPF. Approximately 10% of miRNAs in IPF lung tissue exhibit differential expression compared to normal lung tissue. Diverse miRNA phenotypes exert either a pro-fibrotic or anti-fibrotic influence on the progression of IPF. In the context of IPF, epigenetic factors such as DNA methylation and long non-coding RNAs (lncRNAs) regulate differentially expressed miRNAs, which in turn modulate various signaling pathways implicated in this process, including transforming growth factor-β1 (TGF-β1)/Smad, mitogen-activated protein kinase (MAPK), and phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathways. Therefore, this review presents the epidemiology of IPF, discusses the multifaceted regulatory roles of miRNAs in IPF, and explores the impact of miRNAs on IPF through various pathways, particularly the TGF-β1/Smad pathway and its constituent structures. Consequently, we investigate the potential for targeting miRNAs as a treatment for IPF, thereby contributing to advancements in IPF research.

PMID:39479511 | PMC:PMC11521927 | DOI:10.3389/fcell.2024.1470875

Cureus. 2024 Sep 30;16(9):e70497. doi: 10.7759/cureus.70497. eCollection 2024 Sep.

ABSTRACT

Pirfenidone is a groundbreaking antifibrotic agent that has become a cornerstone in managing fibrotic interstitial lung diseases (ILDs), particularly idiopathic pulmonary fibrosis (IPF). This review comprehensively analyzes pirfenidone's mechanisms of action, clinical efficacy, safety profile, and emerging applications beyond IPF. Pirfenidone exerts its therapeutic effects by inhibiting key pathways involved in fibrosis, including transforming growth factor-beta (TGF-β) and other pro-fibrotic cytokines. It also reduces oxidative stress and inflammation. Clinical trials have consistently demonstrated pirfenidone's ability to slow the decline in lung function, reduce disease progression, and improve survival rates in IPF patients. Furthermore, emerging evidence supports its potential use in other fibrotic ILDs and non-pulmonary fibrotic conditions, such as liver and kidney fibrosis. Despite its proven benefits, pirfenidone's safety and tolerability profiles require careful monitoring, with gastrointestinal and photosensitivity reactions being the most common adverse effects. Future research is poised to explore combination therapies, personalized treatment approaches, and novel applications of pirfenidone in a broader range of fibrotic disorders. As the field of antifibrotic therapy advances, pirfenidone remains a pivotal agent with the potential to significantly impact the management of fibrotic diseases across multiple organ systems. This review aims to provide clinicians and researchers with a detailed understanding of pirfenidone's current role and prospects in treating fibrosis.

PMID:39479105 | PMC:PMC11524648 | DOI:10.7759/cureus.70497

Front Med (Lausanne). 2024 Oct 16;11:1503195. doi: 10.3389/fmed.2024.1503195. eCollection 2024.

ABSTRACT

[This corrects the article DOI: 10.3389/fmed.2024.1356825.].

PMID:39478828 | PMC:PMC11523292 | DOI:10.3389/fmed.2024.1503195

Respir Res. 2024 Oct 30;25(1):393. doi: 10.1186/s12931-024-03006-7.

ABSTRACT

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF), prevalently affecting individuals over 60 years of age, has been mainly studied in young mouse models. The limited efficacy of current treatments underscores the need for animal models that better mimic an aged patient population. We addressed this by inducing pulmonary fibrosis in aged mice, using longitudinal micro-CT imaging as primary readout, with special attention to animal welfare.

METHODS: A double bleomycin dose was administered to 18-24 months-old male C57Bl/6j mice to induce pulmonary fibrosis. Bleomycin dosage was reduced to as low as 75% compared to that commonly administered to young (8-12 weeks-old) mice, resulting in long-term lung fibrosis without mortality, complying with animal welfare guidelines. After fibrosis induction, animals received Nintedanib once-daily for two weeks and longitudinally monitored by micro-CT, which provided structural and functional biomarkers, followed by post-mortem histological analysis as terminal endpoint.

RESULTS: Compared to young mice, aged animals displayed increased volume, reduced tissue density and function, and marked inflammation. This increased vulnerability imposed a bleomycin dosage reduction to the lowest tested level (2.5 µg/mouse), inducing a milder, yet persistent, fibrosis, while preserving animal welfare. Nintedanib treatment reduced fibrotic lesions and improved pulmonary function.

CONCLUSIONS: Our data identify a downsized bleomycin treatment that allows to achieve the best trade-off between fibrosis induction and animal welfare, a requirement for antifibrotic drug testing in aged lungs. Nintedanib displayed significant efficacy in this lower-severity disease model, suggesting potential patient stratification strategies. Lung pathology was quantitatively assessed by micro-CT, pointing to the value of longitudinal endpoints in clinical trials.

PMID:39478545 | DOI:10.1186/s12931-024-03006-7

Respir Investig. 2024 Oct 29;62(6):1204-1208. doi: 10.1016/j.resinv.2024.10.010. Online ahead of print.

ABSTRACT

BACKGROUND: Constipation is associated with the prognosis of several chronic diseases. However, the effect of constipation on the prognosis of idiopathic interstitial pneumonias (IIPs) remains unclear. This study aimed to investigate the association between constipation and the prognosis of patients with IIPs.

METHODS: In this single-center, observational study, the association between constipation and survival of patients with IIPs was retrospectively investigated using a marginal structural model (MSM) analysis with weighting of age, sex, body mass index, treatment (corticosteroids, immunosuppressants, and antifibrotic agents), and pulmonary function (percent predicted forced vital capacity and diffusing capacity of the lungs for carbon monoxide).

RESULTS: A total of 433 patients with IIPs (148 and 285 patients with idiopathic pulmonary fibrosis [IPF] and those without IPF) were included in the study. During the observation period, 238 patients developed constipation. The MSM analysis showed that constipation was significantly associated with shorter overall survival (hazard ratio [HR], 2.374; 95% confidence interval, 1.924-2.928, p < 0.001). When the use of antifibrotic agents was weighted separately as nintedanib or pirfenidone, constipation was significantly associated with shorter survival (HR, 2.427; 95% CI, 1.972-2.988, p < 0.001; and HR, 2.395; 95% CI, 1.940-2.957, p < 0.001, respectively). Furthermore, a subgroup analysis showed that constipation was associated with worse survival in patients with IPF and in those without IPF, regardless of the disease severity.

CONCLUSIONS: This study shows that constipation is an independent prognostic factor for patients with IIPs, suggesting its potential clinical utility.

PMID:39476439 | DOI:10.1016/j.resinv.2024.10.010

Br J Hosp Med (Lond). 2024 Oct 30;85(10):1-7. doi: 10.12968/hmed.2024.0180. Epub 2024 Oct 27.

ABSTRACT

A 26-year-old female presented with a 3-month history of dry cough, unintentional weight loss, night sweats and fatigue. Her background history was significant for ulcerative colitis, managed with Adalimumab for almost 2 years. Clinical examination was unremarkable, apart from some mild pallor. Abnormal chest x-ray findings prompted a computerised tomography (CT) thorax which demonstrated multifocal peri-bronchial consolidation. The differential diagnosis was multifocal organising pneumonia and tuberculosis (TB). Extensive investigations, including invasive bronchial imaging and biopsy, ultimately ruled out TB. This paper reports a case of Adalimumab-induced organising pneumonia and discusses its clinical implications.

PMID:39475044 | DOI:10.12968/hmed.2024.0180

Adv Sci (Weinh). 2024 Oct 30:e2405406. doi: 10.1002/advs.202405406. Online ahead of print.

ABSTRACT

Mitochondrial permeability transition pore (mPTP) opening is a key hallmark of injured type II alveolar epithelial cells (AECIIs) in idiopathic pulmonary fibrosis (IPF). Inhibiting mPTP opening in AECIIs is considered a potential IPF treatment. Herein, a "double braking" strategy on mPTP by cyclosporin A (CsA) derived ionizable lipid with 3D structure (3D-lipid) binding cyclophilin D (CypD) and siRNA downregulating mitochondrial calcium uniporter (MCU) expression is proposed for treating IPF. 3D-lipid and MCU targeting siRNA (siMCU) are co-assembled to form stable 3D-LNP/siMCU nanoparticles (NPs), along with helper lipids. In vitro results demonstrated that these NPs effectively inhibit mPTP opening by 3D-lipid binding with CypD and siRNA downregulating MCU expression, thereby decreasing damage-associated molecular patterns (DAMPs) release and suppressing epithelial-to-mesenchymal transition (EMT) process in bleomycin-induced A549 cells. In vivo results revealed that 3D-LNP/siMCU NPs effectively ameliorated collagen deposition, pro-fibrotic factors secretion, and fibroblast activation in bleomycin-induced pulmonary fibrosis (PF) mouse models. Moreover, compared to the commercial MC3-based formulation, optimized Opt-MC3/siRNA NPs with incorporating 3D-lipid as the fifth component, showed superior therapeutic efficacy against PF due to their enhanced stability and higher gene silencing efficiency. Overall, the nanomedicine containing 3D-lipid and siMCU will be a promising and potential approach for IPF treatment.

PMID:39475000 | DOI:10.1002/advs.202405406

Turk J Med Sci. 2024 May 27;54(5):900-907. doi: 10.55730/1300-0144.5866. eCollection 2024.

ABSTRACT

BACKGROUND/AIM: Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) are two entities categorized as fibrotic lung diseases. With a similar clinical presentation and treatment modalities in many cases, the line differentiating these two diseases may not be evident. Hence, it was aimed herein to evaluate the effectiveness of antifibrotic treatment and the course of fibrotic lung diseases.

MATERIALS AND METHODS: The study included patients diagnosed with IPF and PPF who were given antifibrotic treatment and followed-up for 12 months at our clinic. At the final follow-up, treatment response and radiological evaluation were investigated via high-resolution computed tomography.

RESULTS: Eighty-seven patients were included in the study (57 with IPF and 30 with PPF). Under antifibrotic treatment, there were no statistically significant decreases in the six-minute walking test, forced vital capacity, and diffusing capacity of the lungs for carbon monoxide values at 6 and 12 months posttreatment. The most common side effects were photosensitivity for patients under the pirfenidone regimen, while diarrhea was predominantly observed in the PPF group. Radiological progression was observed in 22.9% of the patients at 12 months posttreatment. Hospitalization requirements were more evident in the PPF group, with at least one hospitalization history present in 60% (n = 18) of the PPF patients compared to 12.3% (n = 7) of the IPF patients.

CONCLUSION: A personalized approach is preferred with similar clinical profiles for both treatment modalities, with specific side effects considered.

PMID:39473748 | PMC:PMC11518374 | DOI:10.55730/1300-0144.5866

Sci Rep. 2024 Oct 30;14(1):26044. doi: 10.1038/s41598-024-74570-7.

ABSTRACT

The role and detailed mechanisms of lncRNAs in idiopathic pulmonary fibrosis (IPF) are not fully understood. qPCR was conducted to verify lncRNA FEZF1-AS1 expression in the transforming growth factor-beta 1 (TGF-β1)-stimulated human lung fibroblasts (HLF) and A549. The EMT-related proteins were performed by western blotting. Cell proliferation, migration, and transition were detected by CCK-8, colony formation, wound-healing and transwell assays. A dual-luciferase reporter assay was conducted to validate the target relationship of FEZF1-AS1 and miR-200c-3p. FEZF1-AS1 is highly expressed in the fibrotic A549 and HLF. in vitro experiments revealed that FEZF1-AS1 facilitates cell proliferation, migration and invasion. Knockdown of FEZF1-AS1 attenuated TGF-b1-induced fibrogenesis both in vitro. Moreover, silencing FEZF1-AS1 inhibited fibrogenesis through modulation of miR-200c-3p. In addition, inhibition of miR-200c-3p promoted fibrogenesis by regulation of Zinc finger E-box binding homeobox 1 (ZEB1). Mechanistically, FEZF1-AS1 promoted lung fibrosis by acting as a competing endogenous RNA (ceRNA) for miR-200c-3p. FEZF1-AS1 silencing increased the expression and activity of miR-200c-3p to inhibit ZEB1 and alleviate lung fibrogenesis in A549 and HLF. In addition, our study showed that FEZF1-AS1 can regulate enhancer of zeste homolog2 (EZH2) to upregulate fibrosis-related proteins and promote lung fibrosis. In summary, the results of our study revealed the pulmonary fibrogenic effect of FEZF1-AS1 in cellular experiments, demonstrating the potential roles and mechanisms of the FEZF1-AS1/miR-200c-3p/ZEB1 and FEZF1-AS1/EZH2 pathways, which provides a novel and potential therapeutic target to lung fibrosis.

PMID:39472569 | DOI:10.1038/s41598-024-74570-7