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In patients with a progressive interstitial lung disease, 62% of whom had a CT pattern of usual interstitial pneumonia, those who received nintedanib had a lower annual rate of decline in the forced vital capacity than those who received placebo at 52 weeks.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by irreversible scarring of lung tissue, leading to death. Despite recent advancements in understanding its pathophysiology, IPF remains elusive, and therapeutic options are limited and non-curative. This review aims to synthesize the latest research developments, focusing on the molecular mechanisms driving the disease and on the related emerging treatments. Unfortunately, several phase 2 studies showing promising preliminary results did not meet the primary endpoints in the subsequent phase 3, underlying the complexity of the disease and the need for new integrated endpoints. IPF remains a challenging condition with a complex interplay of genetic, epigenetic, and pathophysiological factors. Ongoing research into the molecular keystones of IPF is critical for the development of targeted therapies that could potentially stop the progression of the disease. Future directions include personalized medicine approaches, artificial intelligence integration, growth in genetic insights, and novel drug targets.

Background The antifibrotic therapies, pirfenidone and nintedanib, have been approved since 2014 for idiopathic pulmonary fibrosis (IPF), but in the United States only a quarter of people living with IPF have ever been exposed to an antifibrotic. Understanding the burden and consequences of the disease and its treatment from the perspective of people living with IPF may facilitate improved education and outreach for them and their providers. Methods Qualitative interviews with people living with IPF explored perspectives on the diagnosis and management of IPF. Transcripts were analyzed to derive themes and topics, and illustrative quotes were selected for presentation. Data were developed into a 74-item on-line survey taken by additional people living with IPF. Quantitative survey data were analyzed with 95% confidence intervals and Z tests. Results Sixteen people living with IPF underwent qualitative interviews. Direct quotes were used to derive and support themes, and survey stimuli are presented. Ninety additional people living with IPF responded to the on-line survey. 52% of survey participants were male, 54% used supplemental oxygen, and 34% had never been exposed to an antifibrotic. Top sources of information about their IPF diagnosis were their healthcare provider, the internet, and support groups. Most participants had one or more of shortness of breath, fatigue, or cough and over 40% described these symptoms as very burdensome. The most common reason for not starting an antifibrotic was, “I am waiting to start treatment until my symptoms worsen.” For those treated with antifibrotics, (78%) agreed with a statement that their antifibrotic gives them hope even though around 90% had at least one side effect. Conclusions Most individuals living with IPF experienced significant challenges due to their disease and its treatment, that substantially impacted their quality of life. A better understanding of these challenges can facilitate patient-centered and shared decision-making, ultimately enhancing outcomes and satisfaction for people living with IPF.

Objective To identify potential therapeutic targets and evaluate the safety profiles for Idiopathic Pulmonary Fibrosis (IPF) using a comprehensive multi-omics approach. Method We integrated genomic and transcriptomic data to identify therapeutic targets for IPF. First, we conducted a transcriptome-wide association study (TWAS) using the Omnibus Transcriptome Test using Expression Reference Summary data (OTTERS) framework, combining plasma expression quantitative trait loci (eQTL) data with IPF Genome-Wide Association Studies (GWAS) summary statistics from the Global Biobank (discovery) and Finngen (duplication). We then applied Mendelian randomization (MR) to explore causal relationships. RNA-seq co-expression analysis (bulk, single-cell and spatial transcriptomics) was used to identify critical genes, followed by molecular docking to evaluate their druggability. Finally, phenome-wide MR (PheW-MR) using GWAS data from 679 diseases in the UK Biobank assessed the potential adverse effects of the identified genes. Result We identified 696 genes associated with IPF in the discovery dataset and 986 genes in the duplication dataset, with 126 overlapping genes through TWAS. MR analysis revealed 29 causal genes in the discovery dataset, with 13 linked to increased and 16 to decreased IPF risk. Summary data-based MR (SMR) confirmed six essential genes: ANO9, BRCA1, CCDC200, EZH1, FAM13A, and SFR1. Bulk RNA-seq showed FAM13A upregulation and SFR1 and EZH1 downregulation in IPF. Single-cell RNA-seq revealed gene expression changes across cell types. Molecular docking identified binding solid affinities for essential genes with respiratory drugs, and PheW-MR highlighted potential side effects. Conclusion We identified six key genes—ANO9, BRCA1, CCDC200, EZH1, FAM13A, and SFR1—as potential drug targets for IPF. Molecular docking revealed strong drug affinities, while PheW-MR analysis highlighted therapeutic potential and associated risks. These findings offer new insights for IPF treatment and further investigation of potential side effects.

Background Recent studies have demonstrated that airway basal stem cells (BCs) transplantation can ameliorate bleomycin-induced idiopathic pulmonary fibrosis (IPF) through lung regeneration promotion. However, BCs under oxidative stress in the alveolar microenvironment are poor in survival, causing unsatisfied efficacy of BCs transplantation. In this study, we investigated whether Coenzyme Q10(CoQ10) counteracts oxidative stress in the alveolar microenvironment, thus improved the efficacy of BCs transplantation for IPF treatment. Methods The protective effects of CoQ10 on H 2 O 2 -induced BCs apoptosis and cytoplasmic reactive oxygen species (ROS) level were tested by flow cytometry in vitro. The therapeutic effects of BCs combined with CoQ10 were compared to a single BCs transplantation protocol in IPF treatment after 2 weeks and were evaluated by parameters including changes of body weight and survival rate, as well as various levels of pulmonary inflammation, α-SMA expression and hydroxyproline (HYP) in IPF mouse lung tissues. Results CoQ10 preincubation with BCs (10 mM, 24 h) significantly reduced the late apoptosis of BCs and the number of oxidative stressful BCs as a result of H 2 O 2 stimulation (1 mM, 6 h) in vitro. IPF mouse model was constructed through bleomycin (5 mg/kg) intratracheal instillation. Bleomycin-induced IPF mice showed weight loss continuously and mortality increased progressively during modeling. Serious pulmonary inflammatory cell infiltration, collagen fiber proliferation, and collagen protein deposition were observed in lung tissues of IPF mice. Though BCs transplantation alone improved indicators above in bleomycin-induced IPF mice to some extent, the combination with CoQ10 improved the transplantation efficacy and obtained better therapeutic effects. Conclusion CoQ10 blocked H 2 O 2 -induced apoptosis of BCs and ROS production in vitro, and enhanced the efficacy of BCs transplantation against bleomycin-induced IPF in mice.

Endotoxin removal therapy with polymyxin B immobilized fiber column (PMX) has been clinically applied for sepsis and septic shock patients since 1994. The effectiveness and usefulness of this therapy have been demonstrated for more than a quarter of a century. However, a documented survival benefit has not yet been demonstrable in a large, multicenter, randomized and controlled trial. Following the findings derived from a large sepsis clinical trial with PMX in North America, a new trial is ongoing to determine if PMX has a long-term survival benefit when administered to septic patients. Another approach to support a survival benefit from intervention with PMX is to utilize a detailed analysis available from a large clinical data base. The endotoxin adsorption capacity of PMX columns in vitro and the effectiveness of PMX columns can be further demonstrable in animal models. The capability of PMX and details of its mechanism of action to intervene in the sepsis cascade and impede organ dysfunction in septic patients is not fully understood. The surface antigen expression in monocytes and neutrophils are improved after PMX therapy. Immunomodulatory effects as a result of endotoxin removal and/or other mechanisms of action have been suggested. These effects and other potential immune effects may explain some of the improved effects upon organ dysfunction of sepsis and septic shock patients. Endotoxemia may be involved in the pathophysiology of other diseases than sepsis. A rapid diagnostic method to detect and target endotoxemia could allow us to practice precision medicine and expand the clinical indications of endotoxin removal therapy.

ObjectivesIdiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease (ILD) and the most common idiopathic interstitial pneumonia. The UK IPF Registry was established in 2013 to collect data pertaining to clinical features, therapeutic approaches and outcomes. From February 2023, the Registry expanded to include any ILD with evidence of fibrosis.DesignThe UK IPF Registry is a national, multicentre observational registry, including both prospective and retrospective data of patients with IPF in secondary or tertiary care. Cases eligible for inclusion were those with a diagnosis of IPF, presenting at participating centres from January 2013.ResultsBetween January 2013 and February 2023, 5052 IPF cases were registered from 64 participating centres. There was a male preponderance (77.8%) with mean±SD age of 74±8.1 years, 66% were ex-smokers and 76% had at least one comorbidity. Over a third (36.7%) experienced symptoms for more than 24 months prior to their first clinic visit. The majority of cases were discussed at a multidisciplinary team (MDT) meeting and the most common radiological patterns at presentation were probable (54.6%) and definite (42.7%) usual interstitial pneumonia. There was a reduction in surgical lung biopsies from 14% in 2013 to 5.5% in 2022. Antifibrotic therapy prescription rose from 36.0% in 2013 to 55.9% in 2023. The use of nintedanib (approved by National Institute of Clinical Excellence in January 2016) rose from 6.7% in 2013 to 31.5% in 2022 and pirfenidone (approved in April 2013) was initially used in around a third of cases before dropping to between 16.8% and 24.9% after nintedanib was approved.ConclusionThese data reflect clinical practice across the UK and it is intended the data will have a role in informing the future of IPF care and providing a model for benchmarking, ultimately increasing knowledge and improving clinical care for this devastating disease.

Acute exacerbation of idiopathic pulmonary fibrosis has been defined as an acute, clinically significant, respiratory deterioration of unidentifiable cause. The objective of this international working group report on acute exacerbation of idiopathic pulmonary fibrosis was to provide a comprehensive update on the topic. A literature review was conducted to identify all relevant English text publications and abstracts. Evidence-based updates on the epidemiology, etiology, risk factors, prognosis, and management of acute exacerbations of idiopathic pulmonary fibrosis are provided. Finally, to better reflect the current state of knowledge and improve the feasibility of future research into its etiology and treatment, the working group proposes a new conceptual framework for acute respiratory deterioration in idiopathic pulmonary fibrosis and a revised definition and diagnostic criteria for acute exacerbation of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal and incurable form of interstitial lung disease in which persistent injury results in scar tissue formation. As fibrosis thickens, the lung tissue loses the ability to facilitate gas exchange and provide cells with needed oxygen. Currently, IPF has few treatment options and no effective therapies, aside from lung transplant. Here we present a series of studies utilizing lung spheroid cell-secretome (LSC-Sec) and exosomes (LSC-Exo) by inhalation to treat different models of lung injury and fibrosis. Analysis reveals that LSC-Sec and LSC-Exo treatments could attenuate and resolve bleomycin- and silica-induced fibrosis by reestablishing normal alveolar structure and decreasing both collagen accumulation and myofibroblast proliferation. Additionally, LSC-Sec and LSC-Exo exhibit superior therapeutic benefits than their counterparts derived from mesenchymal stem cells in some measures. We showed that an inhalation treatment of secretome and exosome exhibited therapeutic potential for lung regeneration in two experimental models of pulmonary fibrosis. Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease and adult lung spheroid cells have been shown to promote regeneration in animal models of IPF. Here the authors show that the secretome and exosomes of lung spheroid cells is effective as inhalation treatment in rodent models of lung injury and fibrosis and superior to the counterparts derived from mesenchymal stem cells.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by progressive lung scarring and the histological picture of usual interstitial pneumonia (UIP). It is associated with increasing cough and dyspnoea and impaired quality of life. IPF affects ∼3 million people worldwide, with incidence increasing dramatically with age. The diagnostic approach includes the exclusion of other interstitial lung diseases or overlapping conditions and depends on the identification of the UIP pattern, usually with high-resolution CT; lung biopsy might be required in some patients. The UIP pattern is predominantly bilateral, peripheral and with a basal distribution of reticular changes associated with traction bronchiectasis and clusters of subpleural cystic airspaces. The biological processes underlying IPF are thought to reflect an aberrant reparative response to repetitive alveolar epithelial injury in a genetically susceptible ageing individual, although many questions remain on how to define susceptibility. Substantial progress has been made in the understanding of the clinical management of IPF, with the availability of two pharmacotherapeutic agents, pirfenidone and nintedanib, that decrease physiological progression and likely improve progression-free survival. Current efforts are directed at identifying IPF early, potentially relying on combinations of biomarkers that include circulating factors, demographics and imaging data. Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by progressive lung scarring that is thought to occur in a genetically susceptible, ageing individual through aberrant reparative responses to repeated injury to the alveolar epithelium. This Primer summarizes the processes thought to underlie the development of IPF and clinical challenges faced in treating patients with this irreversible condition.