World J Clin Cases. 2024 Nov 16;12(32):6538-6542. doi: 10.12998/wjcc.v12.i32.6538.

ABSTRACT

In this editorial, we comment on the article by Lei et al, with a specific focus on the timing of the initiation of the antifibrotic agent pirfenidone (PFD) in the management of idiopathic pulmonary fibrosis (IPF) and its impact on lung function of IPF patients. PFD is an antifibrotic agent that is widely used in the management of IPF in both early and advanced stages. It inhibits various pathways and has antifibrotic, anti-inflammatory, and antioxidant properties. Despite dosage lowering, PFD slowed IPF progression and maintained functional capacity. The 6-min walk distance test indicated that patients tolerated adverse events well, and PFD significantly reduced the incidence of progression episodes and death. Even when a single disease-progression event occurred, continuing PFD treatment had benefits.

PMID:39554893 | PMC:PMC11438636 | DOI:10.12998/wjcc.v12.i32.6538

J Thorac Dis. 2024 Oct 31;16(10):6799-6805. doi: 10.21037/jtd-24-392. Epub 2024 Oct 28.

ABSTRACT

BACKGROUND: The pathogenesis of idiopathic pulmonary fibrosis (IPF) is not well understood. Given the known role of hepatitis C virus (HCV) in inducing cirrhosis, the virus has also received attention in the study of IPF. An earlier retrospective study found an increased incidence of IPF in patients with HCV, supported by evidence in the alveolar lavage fluid of the patients, whereas another set of observational studies did not find an association, which prompted us to explore a causal relationship. It is well known that HCV and hepatitis B virus (HBV) have some similarities: both are RNA viruses, and both have a strong ability to induce cirrhosis, which in turn leads to poor prognosis and increased mortality in patients with viral hepatitis. This factor also inspired us to start exploring whether there is a causal relationship between HBV and IPF. Due to the inherent limitations of previous studies, causality between chronic HBV/HCV infection and IPF is yet to be established. Mendelian randomization (MR) uses genetic variation as exposure and can be used to determine the causal effect of exposure on outcomes. Therefore, we used a two-sample MR study to determine if there is a causal relationship between viral hepatitis and IPF risk.

METHODS: Single nucleotide polymorphisms (SNPs) were used as instrumental variables (IVs), with chronic HBV and HCV infections as exposure factors and IPF as the outcome variable. Three methods, inverse variance weighting (IVW), weighted median (WM), and MR-Egger regression, were employed for the bidirectional MR. Sensitivity analyses, including horizontal pleiotropy analysis, Cochran's Q test, and leave-one-out evaluation of result reliability, were conducted. Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) and MR-Egger regression tests were used to monitor potential horizontal pleiotropic effects. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to interpret the causal relationship between chronic HBV and HCV infections and IPF. Finally, reverse MR analysis was performed to validate the robustness of the results.

RESULTS: The results of the IVW suggested that there was no causal relationship between chronic HBV infection (OR =1.039, 95% CI: 0.935-1.154, P=0.48) and chronic HCV infection (OR =1.146, 95% CI: 0.834-1.576, P=0.40) and the risk of IPF. Sensitivity analysis showed no evidence of reverse causation, horizontal pleiotropy, and heterogeneity.

CONCLUSIONS: This study, using the bidirectional MR, provides preliminary evidence that chronic HBV and HCV infections are not causally related to IPF at the genetic level. However, this conclusion requires support from larger sample sizes in genome-wide association study (GWAS) databases for further MR analysis, and additional clinical studies and animal experiments are needed for validation.

PMID:39552846 | PMC:PMC11565300 | DOI:10.21037/jtd-24-392

Drugs. 2024 Nov 18. doi: 10.1007/s40265-024-02109-1. Online ahead of print.

ABSTRACT

Axatilimab (NIKTIMVO™; axatilimab-csfr), an anti-colony-stimulating Factor 1 Receptor (CSF-1R) humanized IgG4 (κ light chain) monoclonal antibody, is being developed by Incyte Corporation and Syndax Pharmaceuticals for the treatment of chronic graft-versus-host disease (cGVHD) and other indications, including idiopathic pulmonary fibrosis (IPF). In August 2024, axatilimab was approved in the USA for the treatment of cGVHD after failure of at least two prior lines of systemic therapy in adult and paediatric patients weighing at least 40 kg. Axatilimab was added to the NCCN guidelines for cGVHD in August 2024. This article summarizes the development milestones leading to this first approval of axatilimab for the treatment of cGVHD.

PMID:39551906 | DOI:10.1007/s40265-024-02109-1

Int Immunopharmacol. 2024 Nov 15;143(Pt 3):113630. doi: 10.1016/j.intimp.2024.113630. Online ahead of print.

ABSTRACT

Liver injury induces an inflammatory response that activates hepatic stellate cells, which is the initial factor of liver fibrosis. Nintedanib, a multi-targeted tyrosine kinase inhibitor targeting the Src signalling pathway, has been approved for the treatment of idiopathic pulmonary fibrosis. However, it is still not known whether nintedanib ameliorates liver fibrosis by inhibiting inflammasome activation. Here, a carbon tetrachloride (CCl4)-induced liver fibrosis model was used to assess the anti-fibrotic efficacy of nintedanib in vivo. Lipopolysaccharide and ATP were used to activate nucleotide oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes in LX-2 cells, and the efficacy of nintedanib on NLRP3 inflammasome activation was evaluated. Moreover, we used Src-overexpressing and Src-downregulating lentiviruses to transfect LX-2 cells to explore the targets of nintedanib. Nintedanib attenuated inflammation and extracellular matrix accumulation in CCl4-induced fibrotic livers and reduced the expression of NLRP3, fibrotic makers, and the phosphorylation of Src, epidermal growth factor receptor (EGFR), AKT, ERK1/2 in LX-2 cells. Furthermore, nintedanib thwarted NLRP3 inflammasome activation by suppressing the phosphorylation of Src and its downstream signalling pathway and reducing reactive oxygen species production. Our study indicates that nintedanib effectively suppresses NLRP3 inflammasome activation and has the potential for the treatment of liver fibrosis.

PMID:39549551 | DOI:10.1016/j.intimp.2024.113630

Int Immunopharmacol. 2024 Nov 15;143(Pt 3):113587. doi: 10.1016/j.intimp.2024.113587. Online ahead of print.

ABSTRACT

One of the characteristic feature of idiopathic pulmonary fibrosis is an imbalanced fibrinolytic system. Plasminogen activator inhibitor-1 (PAI-1), an essential serine protease in the fibrinolytic system, has an anti-fibrotic tendency in some organs and a pro-fibrotic nature in others. Curcumin is reported to regulate the fibrinolytic system. In this study, we sought to determine how curcumin affected alterations in tissue remodelling mediated by PAI-1 in lung fibrosis. For in vitro studies, NIH3T3 fibroblasts were either exposed to TGF-β or overexpressed with PAI-1, and/or treated with curcumin. For in vivo studies, C57BL/6 mice were either instilled with bleomycin, overexpressed with PAI-1, and/or intervened with curcumin. Protein and gene expression studies were performed by western blotting and RT-PCR techniques, respectively. Curcumin intervention, in vitro and in vivo, could inhibit the the expression of collagen, fibronectin, MMP-2, and MMP-9, which was otherwise elevated by TGF-β or bleomycin. In conclusion, curcumin reduces pulmonary fibrosis by suppressing excessive basement membrane protein deposition and, likely, preventing the thickening of the alveolar septum.

PMID:39549545 | DOI:10.1016/j.intimp.2024.113587

Biomed Pharmacother. 2024 Nov 15;181:117680. doi: 10.1016/j.biopha.2024.117680. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) has a high incidence and prevalence among patients over 65 years old. While its exact etiology remains unknown, several risk factors have recently been identified. Hypoxia is associated with IPF due to the abnormal architecture of lung parenchyma and the accumulation of extracellular matrix produced by activated fibroblasts. Exosomes play a crucial role in intercellular communication during both physiological and pathological processes, including hypoxic diseases like IPF. Recent findings suggest that a hypoxic microenvironment influences the content of exosomes in various diseases, thereby altering cellular metabolism. Although the role of exosomes in IPF is an emerging area of research, the significance of hypoxic exosomes as inducers of metabolic reprogramming in fibroblasts is still underexplored. In this study, we analyze and discuss the relationship between hypoxia, exosomal cargo, and the metabolic reprogramming of fibroblasts in the progression of IPF.

PMID:39549361 | DOI:10.1016/j.biopha.2024.117680

Naunyn Schmiedebergs Arch Pharmacol. 2024 Nov 16. doi: 10.1007/s00210-024-03605-7. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a worsening fibrotic condition characterized by a short survival rate and limited treatment options. This study evaluates the potential anti-fibrotic properties of Schisandrin B (Sch B) through network pharmacology and experimental validation. A mouse model of bleomycin-induced pulmonary fibrosis was established, and the modeled mice were treated with Sch B at three doses (20 mg/kg/day, 40 mg/kg/day, and 80 mg/kg/day). A fibrotic model was developed in NIH/3T3 cells by treating them with TGF-β (10 ng/mL) and administering Sch B at various concentrations (10, 20, and 40 µM). The results revealed that Sch B treatment delayed the development of bleomycin-induced pulmonary fibrosis and substantially decreased the transcription levels of collagen I and α-SMA in TGF-β-induced fibroblasts. Core targets were screened with protein-protein interaction network analysis, molecular complex detection (MCODE), and CytoHubba plugin. The application of Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and molecular docking highlighted the significance of the HIF-1α signaling pathway in the potential mechanism of Sch B in IPF therapy. Western blot, PCR, and immunofluorescence were performed to validate the effects of Sch B on HIF-1α. In vivo and in vitro, Sch B administration reduced HIF-1α expression. These outcomes provide valuable insights into the potential mechanism by which Sch B delays IPF development, with HIF-1α potentially serving as a key target. However, further investigation is warranted to assess the safety and efficacy of Sch B in clinical settings.

PMID:39549058 | DOI:10.1007/s00210-024-03605-7

Biochim Biophys Acta Mol Basis Dis. 2024 Nov 13:167572. doi: 10.1016/j.bbadis.2024.167572. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a lethal progressive lung disease urgently needing new therapies. Current treatments only delay disease progression, leaving lung transplant as the sole remaining option. Recent studies support a model whereby IPF arises because alveolar epithelial type II (AT2) cells, which normally mediate distal lung regeneration, acquire airway and/or mesenchymal characteristics, preventing proper repair. Mechanisms driving this abnormal differentiation remain unclear. We performed integrated transcriptomic and epigenomic analysis of purified AT2 cells which revealed genome-wide alterations in IPF lungs. The most prominent epigenetic alteration was activation of an enhancer in thyroid receptor interactor 13 (TRIP13), although TRIP13 was not the most significantly transcriptionally upregulated gene. TRIP13 is broadly implicated in epithelial-mesenchymal plasticity. In cultured human AT2 cells and lung slices, small molecule TRIP13 inhibitor DCZ0415 prevented acquisition of the mesenchymal gene signature characteristic of IPF, suggesting TRIP13 inhibition as a potential therapeutic approach to fibrotic disease.

PMID:39547519 | DOI:10.1016/j.bbadis.2024.167572

Ecotoxicol Environ Saf. 2024 Nov 14;287:117333. doi: 10.1016/j.ecoenv.2024.117333. Online ahead of print.

ABSTRACT

Inhalation toxicity assessment is a crucial tool for the identification and classification of hazardous materials like volatile organic carbons, aerosols, and particulate matter. Unlike traditional acute inhalation toxicity studies that use mortality as an endpoint, the Fixed Concentration Procedure (FCP) emphasizes "evident toxicity" by monitoring behavior, weight, and food intake. This reduces reliance on mortality but doesn't directly address respiratory system impact. The present study introduced a respirometer-based inhalation toxicity and respiratory status assessment method. The toxicity evaluation system integrated a respirometric system with an animal exposure chamber, enabling real-time monitoring of oxygen consumption. The ICR mice were exposed to various concentrations of benzene (10, 20, 40, and 80 mg/L of air), toluene (7.5, 15, 30, and 60 mg/L of air), and xylene (7.5, 15, 30, and 60 mg/L of air). The respiration rate decreased by 70 % and 69 % for benzene (80 mg/L of air) and toluene (60 mg/L of air), respectively, with EC50 values of 32.5 mg/l and 21.2 mg/L based on oxygen consumption. Xylene did not exhibit EC50 values at the tested concentrations. However, the oxygen consumption rate significantly decreased (46 %) at high concentrations (60 mg/L of air), indicating sub-lethal toxicological effects. Furthermore, the present study was also validated in the bleomycin-induced idiopathic pulmonary fibrosis (IPF) model, demonstrating its reliability as a respiratory impairment marker. The results exhibited a strong correlation between weight loss and less oxygen consumption in the BLM group (bleomycin-induced) as compared to the SHAM group (control), which was confirmed by histological examination and protein marker analysis. The results suggest the potential use of oxygen consumption as an endpoint measurement in inhalation toxicity assessment tests without animal sacrifice, and the present study could be useful for providing valuable insights into disease progression and pharmacological interventions.

PMID:39547059 | DOI:10.1016/j.ecoenv.2024.117333

Br J Pharmacol. 2024 Nov 15. doi: 10.1111/bph.17390. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: Pneumoconiosis, especially silicosis, is a prevalent occupational disease with substantial global economic implications and lacks a definitive cure. Both pneumoconiosis and idiopathic pulmonary fibrosis (IPF) are interstitial lung diseases, which share many common physiological characteristics. Because pirfenidone and nintedanib are approved to treat IPF, their potential efficacy as antifibrotic agents in advanced silicosis deserves further exploration. Thus, we aimed to evaluate the individual and combined effects of pirfenidone and nintedanib in treating advanced silicosis mice and elucidate the underlying mechanisms of their therapeutic actions via multiomics.

EXPERIMENTAL APPROACH: We administered monotherapy or combined therapy of pirfenidone and nintedanib, with low and high doses, in silicosis established after 6 weeks and evaluated lung function, inflammatory responses and fibrotic status. Additionally, we employed transcriptomic and metabolomic analyses to uncover the mechanisms underlying different therapeutic strategies.

KEY RESULTS: Both pirfenidone and nintedanib were effective in treating advanced silicosis, with superior outcomes observed in combination therapy. Transcriptomic and metabolomic analyses revealed that pirfenidone and nintedanib primarily exerted their therapeutic effects by modulating immune responses, signalling cascades and metabolic processes involving lipids, nucleotides and carbohydrates. Furthermore, we experimentally validated both monotherapy and combined therapy yielded therapeutic benefits through two common signalling pathways: steroid biosynthesis and purine metabolism.

CONCLUSION AND IMPLICATIONS: In conclusion, pirfenidone and nintedanib, either individually or in combination, demonstrate substantial potential in advanced silicosis. Furthermore, combined therapy outperformed monotherapy, even at low doses. These therapeutic benefits are attributed to their influence on diverse signalling pathways and metabolic processes.

PMID:39546810 | DOI:10.1111/bph.17390

J Med Chem. 2024 Nov 15. doi: 10.1021/acs.jmedchem.4c01533. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no ideal drugs. Our previous research demonstrated that phosphodiesterase 1 (PDE1) could be a promising target for the treatment of IPF. However, only a few selective PDE1 inhibitors are available, and the mechanism of recognition between inhibitors and the PDE1 protein is not fully understood. This study carried out a step-by-step optimization of a dihydropyrimidine hit Z94555858. By targeting the metal pocket of PDE1, a lead compound 3f was obtained, exhibiting an IC50 value of 11 nM against PDE1, moderate selectivity over other PDEs, and significant anti-fibrotic effects in bleomycin-induced pulmonary fibrosis rats. The structure-activity relationship study aided by molecular docking revealed that forming halogen bonds with water in the metal pocket greatly enhanced the PDE1 inhibition, providing a novel strategy for further rational design of PDE1 inhibitors.

PMID:39546471 | DOI:10.1021/acs.jmedchem.4c01533

J Allergy Clin Immunol. 2024 Nov 12:S0091-6749(24)01184-9. doi: 10.1016/j.jaci.2024.11.006. Online ahead of print.

ABSTRACT

Asthma is a common respiratory condition with various phenotypes, non-specific symptoms and variable clinical course. The occurrence of other respiratory conditions with asthma, respiratory co-morbidities (RCs), is not unusual. A literature search was performed for asthma and a variety of respiratory co-morbidities using Pub-Med for the years 2019-2024. The 5 conditions with the largest number of references, other than rhinitis and rhinosinusitis addressed in another paper in this issue, or which are the most problematic in the authors' clinical experience are summarized. Others are briefly discussed. The diagnosis and treatment of both asthma and RCs are complicated by the overlap of symptoms and signs. Recognizing RCs is especially problematic in adult onset, non-type 2 asthma as there are no biomarkers to assist in confirming non-type 2 asthma. Treatment decisions in subjects with suspected asthma and RCs are complicated by the potential similarities between the symptoms or signs of the RC and asthma, the absence of a sine quo non for the diagnosis of asthma, the likelihood that many RCs improve with systemic corticosteroids, and the possibility that the manifestations of the RCs are misattributed to asthma or vice versa. Recognition of RCs is critical to the effective management of asthma, particularly severe or difficult to treat asthma.

PMID:39542142 | DOI:10.1016/j.jaci.2024.11.006

Tuberc Respir Dis (Seoul). 2024 Nov 14. doi: 10.4046/trd.2024.0116. Online ahead of print.

ABSTRACT

This review article explores the multifaceted relationship between air pollution and interstitial lung diseases (ILDs), particularly focusing on idiopathic pulmonary fibrosis (IPF), the most severe form of fibrotic ILD. Air pollutants are mainly composed of particulate matter (PM), ozone (O3), nitrogen dioxide (NO2), carbon monoxide (CO), and sulfur dioxide (SO2). They are recognized as risk factors for several respiratory diseases. However, their specific effects on ILDs and related mechanisms have not been thoroughly studied yet. Emerging evidence suggests that air pollutants may contribute to the development and acute exacerbation of ILDs. Longitudinal studies have indicated that air pollution can adversely affect the prognosis of disease by decreasing lung function and increasing mortality. Lots of in vitro, in vivo, and epidemiologic studies have proposed possible mechanisms linking ILDs to air pollution, including inflammation and oxidative stress induced by exposure to air pollutants, which may induce mitochondrial dysfunction, promote cellular senescence, and disrupt normal epithelial repair processes. Despite these findings, effective interventions to mitigate effects of air pollution on ILD are not well established yet. This review emphasizes the urgent need to address air pollution as a key environmental risk factor for ILDs and calls for further studies to clarify its effects and develop preventive and therapeutic strategies.

PMID:39542009 | DOI:10.4046/trd.2024.0116

Cell Commun Signal. 2024 Nov 13;22(1):542. doi: 10.1186/s12964-024-01925-y.

ABSTRACT

Despite the tremendous advancements in the knowledge of the pathophysiology and clinical aspects of SARS-CoV-2 infection, still many issues remain unanswered, especially in the long-term effects. Mounting evidence suggests that pulmonary fibrosis (PF) is one of the most severe complications associated with COVID-19. Therefore, understanding the molecular mechanisms behind its development is helpful to develop successful therapeutic strategies. Epithelial to mesenchymal transition (EMT) and its cell specific variants endothelial to mesenchymal transition (EndMT) and mesothelial to mesenchymal transition (MMT) are physio-pathologic cellular reprogramming processes induced by several infectious, inflammatory and biomechanical stimuli. Cells undergoing EMT acquire invasive, profibrogenic and proinflammatory activities by secreting several extracellular mediators. Their activity has been implicated in the pathogenesis of PF in a variety of lung disorders, including idiopathic pulmonary fibrosis (IPF) and COVID-19. Aim of this article is to provide an updated survey of the cellular and molecular mechanisms, with emphasis on EMT-related processes, implicated in the genesis of PF in IFP and COVID-19.

PMID:39538298 | DOI:10.1186/s12964-024-01925-y

Eur Respir Rev. 2024 Nov 13;33(174):240129. doi: 10.1183/16000617.0129-2024. Print 2024 Oct.

ABSTRACT

Air pollution is one of the leading causes of early deaths worldwide, with particulate matter (PM) as an emerging factor contributing to this trend. PM is classified based on its physical size, which ranges from PM10 (diameter ≤10 μm) to PM2.5 (≤2.5 μm) and PM0.5 (≤0.5 μm). Smaller-sized PM can move freely through the air and readily infiltrate deep into the lungs, intensifying existing health issues and exacerbating complications. Lung complications are the most common issues arising from PM exposure due to the primary site of deposition in the respiratory system. Conditions such as asthma, COPD, idiopathic pulmonary fibrosis, lung cancer and various lung infections are all susceptible to worsening due to PM exposure. PM can epigenetically modify specific target sites, further complicating its impact on these conditions. Understanding these epigenetic mechanisms holds promise for addressing these complications in cases of PM exposure. This involves studying the effect of PM on different gene expressions and regulation through epigenetic modifications, including DNA methylation, histone modifications and microRNAs. Targeting and manipulating these epigenetic modifications and their mechanisms could be promising strategies for future treatments of lung complications. This review mainly focuses on different epigenetic modifications due to PM2.5 exposure in the various lung complications mentioned above.

PMID:39537244 | DOI:10.1183/16000617.0129-2024

Chron Respir Dis. 2024 Jan-Dec;21:14799731241299443. doi: 10.1177/14799731241299443.

ABSTRACT

OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive fibrosis of the lung parenchyma, resulting in respiratory failure. This study analysed differences in patient characteristics and antifibrotic treatment strategies during the first years after IPF diagnosis.

METHODS: Data from patients with IPF was extracted from the Swedish IPF registry. Patients were defined as treated (either as fully- or reduced treated) or non-treated with antifibrotic drugs. Differences in clinical parameters and side effects were defined.

RESULTS: Among 532 patients, 371 received treatment with antifibrotic drugs. Treated patients were younger, had worse lung function, higher body mass index (BMI), higher Gender-Age-Physiology stage, and were more often on oxygen treatment. Non-treated patients displayed a stable BMI, whereas patients treated with antifibrotics declined in BMI during follow-up. More than half (56%) of treated patients had reduced antifibrotic treatment. Sixty per cent reported side effects, with diarrhoea, nausea, and skin rash as the most common.

CONCLUSIONS: Patients prescribed antifibrotic treatment had more advanced disease compared to patients not prescribed antifibrotics. A considerable proportion of the patients had reduced treatment, probably due to more side effects in this group. This indicates that individuals starting treatment at IPF diagnosis are considered to be in greater need of antifibrotic drug treatment by the prescriber, compared to individuals with less severe disease.

PMID:39532288 | DOI:10.1177/14799731241299443

Ann Am Thorac Soc. 2024 Nov 12. doi: 10.1513/AnnalsATS.202404-382OC. Online ahead of print.

ABSTRACT

RATIONALE: While exposure to air pollution is a known risk factor for adverse pulmonary outcomes, its impact in individuals with idiopathic pulmonary fibrosis (IPF) is less well understood.

OBJECTIVE: To investigate the effects of long-term exposure to air pollution on disease severity and progression in patients with IPF and to determine whether genomic factors, such as MUC5B promoter polymorphism or telomere length, modify these associations.

METHODS: We performed analyses at enrollment and after one year of follow-up in the IPF-PRO Registry, a prospective observational registry that enrolled individuals with IPF at 46 US sites from June 2014 to October 2018. Five-year average pollution exposures (PM2.5, NO2, O3) prior to enrollment date were estimated at participants' residential addresses with validated national spatio-temporal models. Multivariable regression models estimated associations between pollution exposure and physiologic measurements (FVC, DLCO, supplemental oxygen use at rest) and quality of life measurements (St. George's Respiratory Questionnaire [SGRQ], EuroQoL, Cough and Sputum Assessment Questionnaire) at enrollment. Cox proportional hazard models estimated associations between pollutants and a composite outcome of death, lung transplant, or >10% absolute decline in FVC % predicted in the year after enrollment. Models were adjusted for individual-level and spatial confounders, including proxies for disease onset. Gene-environment interactions with MUC5B and telomere length were assessed.

RESULTS: Of 835 participants, 94% were non-Hispanic Whites, 76% were male, mean (SD) age was 70 (7.7) years. In fully adjusted analyses, higher PM2.5 exposure was associated with worse quality of life per SGRQ activity score (3.48 [95% confidence interval (CI) 0.64, 6.32] per 2µg/m3 PM2.5) and EuroQoL scores (-0.04 [95%CI -0.06, -0.01] per 2µg/m3 PM2.5), and lower FVC % predicted and lower DLCO% predicted at enrollment. Each 3 parts per billion difference in O3 exposure was associated with a 1.57% [95% CI 0.15, 2.98] higher FVC % predicted at enrollment, although this effect was attenuated in multi-pollutant models. There was no association between NO2 and enrollment measures, between pollution exposure and one-year outcomes, or evidence for gene-environment interactions.

CONCLUSION: In the IPF-PRO Registry, long-term exposure to PM2.5 was associated with worse quality of life and lung function at enrollment, but not with short-term disease progression or mortality. There was no evidence of effect modification by interaction of genomic factors with pollution. The reason for the unexpected relationship between O3 exposure and higher FVC is unclear.

PMID:39531618 | DOI:10.1513/AnnalsATS.202404-382OC

Adv Mater. 2024 Nov 12:e2407661. doi: 10.1002/adma.202407661. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is exacerbated by injurious mechanical forces that destabilize the pulmonary mechanical microenvironment homeostasis, leading to alveolar dysfunction and exacerbating disease severity. However, given the inherent mechanosensitivity of fibrotic lungs, where type II alveolar epithelial cells (AEC IIs) are subjected to persistent stretching and overactivated myofibroblasts experience malignant interactions during mechanotransduction, it becomes imperative to develop effective strategies to modulate the pulmonary mechanical microenvironment. Herein, cyclo (RGDfC) peptide-decorated zeolitic imidazolate framework-8 nanoparticles (named ZDFPR NPs) are constructed to target and repair the aberrant mechanical force levels in pathological lungs. Specifically, reduces mechanical tension in AEC IIs by pH-responsive ZDFPR NPs that release zinc ions and 7, 8-dihydroxyflavone to promote alveolar repair and differentiation. Meanwhile, malignant interactions between myofibroblast contractility and extracellular matrix stiffness during mechanotransduction are disrupted by the fasudil inhibition ROCK signaling pathway. The results show that ZDFPR NPs successfully restored pulmonary mechanical homeostasis and terminated the fibrosis process in bleomycin-induced fibrotic mice. This study not only presents a promising strategy for modulating pulmonary mechanical microenvironment but also pioneers a novel avenue for IPF treatment.

PMID:39529565 | DOI:10.1002/adma.202407661

Respir Res. 2024 Nov 11;25(1):405. doi: 10.1186/s12931-024-03014-7.

ABSTRACT

BACKGROUND: The receptor for advanced glycation end product (RAGE) is a transmembrane receptor accelerating a pro-inflammatory signal. RAGE signalling is promoted by decreased soluble isoform of RAGE (sRAGE), which is a decoy receptor for RAGE ligands, and RAGE SNP rs2070600 minor allele. In Caucasian and Japanese cohorts, low circulatory sRAGE levels and presence of the minor allele are associated with poor survival of idiopathic pulmonary fibrosis (IPF) and increased disease susceptibility to interstitial lung disease, respectively. However, whether sRAGE and RAGE SNP rs2070600 are associated with acute exacerbation of IPF (AE-IPF) is unclear.

METHODS: This retrospective cohort study evaluated the association between the onset of AE-IPF and serum sRAGE levels in 69 German and 102 Japanese patients with IPF. The association of AE-IPF with RAGE SNP rs2070600 in 51 German and 84 Japanese patients, whose DNA samples were stored, was also investigated.

RESULTS: In each cohort, the incidence of AE-IPF was significantly and reproducibly higher in the patients with sRAGE < 467.1 pg/mL. In a pooled exploratory analysis, the incidence of AE-IPF was lowest in the patients with higher sRAGE levels and rs2070600 minor allele, although no significant difference in the incidence was observed between the patients with and without the rs2070600 minor allele.

CONCLUSIONS: Low sRAGE levels were associated with increased incidence of AE-IPF in two independent cohorts of different ethnicities. The combination of rs2070600 and sRAGE levels may stratify patients with IPF for the risk of AE.

PMID:39529063 | DOI:10.1186/s12931-024-03014-7

Signal Transduct Target Ther. 2024 Nov 11;9(1):306. doi: 10.1038/s41392-024-02011-y.

ABSTRACT

Fibroblast activation plays an important role in the occurrence and development of idiopathic pulmonary fibrosis (IPF), which is a progressive, incurable, and fibrotic lung disease. However, the underlying mechanism of fibroblast activation in IPF remains elusive. Here, we showed that the expression levels of STX11 and SNAP25 were downregulated in the lung tissues from patients with IPF and mice with bleomycin (BLM)-induced lung fibrosis as well as in the activated fibroblasts. Upregulation of STX11 or SNAP25 suppressed TGF-β1-induced activation of human lung fibroblasts (HLFs) via promoting autophagy. However, they failed to suppress fibroblast actviation when autophagy was blocked with the use of chloroquine (CQ). In addition, STX11 or SNAP25 could inhibit TGF-β1-induced fibroblast proliferation and migration. In vivo, overexpression of STX11 exerted its protective role in the mice with BLM-induced lung fibrosis. STX11 and SNAP25 mutually promoted expression of each other. Co-IP assay indicated that STX11 has an interaction with SNAP25. Mechanistically, STX11-SNAP25 interaction activated fibroblast autophagy and further inhibited fibroblast activation via blocking the PI3K/AKT/mTOR pathway. Overall, the results suggested that STX11-SNAP25 interaction significantly inhibited lung fibrosis by promoting fibroblast autophagy and suppressing fibroblast activation via blocking the PI3K/ATK/mTOR signaling pathway. Therefore, STX11 serves as a promising therapeutic target in IPF.

PMID:39523374 | DOI:10.1038/s41392-024-02011-y