Ann Am Thorac Soc. 2024 Nov 20. doi: 10.1513/AnnalsATS.202404-419OC. Online ahead of print.

ABSTRACT

RATIONALE: In the United States (U.S.), ambulatory oxygen is recommended for patients with idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) who experience symptomatic exertional hypoxemia. Ambulatory oxygen need is often determined by submaximal hall walk testing; however, this may fail to accurately characterize exertional hypoxemia in some patients.

OBJECTIVES: Assess for differences in ambulatory oxygen needs between IPF and COPD patients who completed a ramped treadmill protocol exercise test (RTPET) and correlate oxygen flow rates determined at highest level exertion with lung function and exercise parameters. Oxygen "need" is defined as flow rate needed to maintain oxygen saturation >90% in patients who desaturate to <88%.

METHODS: We conducted a retrospective review of RTPET results for IPF and COPD patients who also recently completed spirometry. The RTPET has three phases: rest, submaximal usual pace walking at 0% treadmill grade for 3 minutes, and highest level walking at the UP walk speed with increasing treadmill grade by 2% every 2 minutes. IPF patients were part of a clinical registry while COPD patients were identified based on diagnosis coding and spirometry (FEV1/FVC <0.70). The RTPET for both groups was completed based on a pulmonologist's referral.

MEASUREMENTS AND MAIN RESULTS: We included 329 IPF and 2,343 COPD patients. A greater proportion of IPF patients required ambulatory oxygen to maintain saturation >90%. After adjusting for demographic covariates and exercise parameters, IPF patients required higher ambulatory oxygen flow rates compared to COPD subjects with similar DLCO values. Of patients who did not require oxygen with submaximal usual pace testing, 49% with IPF and 24% with COPD required oxygen at highest level exertion.

CONCLUSIONS: The RTPET identified higher oxygen flow needs at highest level exertion in IPF versus COPD patients; however, in both diseases, there was a significant proportion of patients who were only found to have exertional desaturation at highest level exertion. Current oxygen policies and reliance on submaximal testing may fail to meet the needs of patients with IPF and COPD. Further studies are needed to determine if oxygen prescriptions targeting highest level desaturation improve clinical outcomes, symptoms, or quality-of-life.

PMID:39565187 | DOI:10.1513/AnnalsATS.202404-419OC

AJR Am J Roentgenol. 2024 Nov 20. doi: 10.2214/AJR.24.32053. Online ahead of print.

ABSTRACT

High-resolution CT (HRCT) plays an important role in diagnosing and monitoring interstitial lung diseases (ILDs). Despite advances, predicting disease progression and treatment response remains challenging. HRCT enables noninvasive visualization and classification of patterns of lung injury and assessment of disease extent. Visual estimation of CT extent of fibrotic lung disease is an independent predictor of mortality and progression, but is subjective, with only modest interobserver agreement for radiologic interpretation of ILD. Machine learning-based textural analysis of fibrosis extent on baseline and serial HRCT scans shows robust correlations with physiologic measures and strong association with risk of disease progression or mortality across various fibrosing ILDs. In idiopathic pulmonary fibrosis, quantitative CT (QCT) assessment is associated with physiologic impairment and risk of progression and death, and increasing severity of fibrosis on longitudinal evaluation is associated with increased risk of progression and death. Similar results have been noted for fibrotic hypersensitivity pneumonitis and connective tissue disease. This review focuses on QCT techniques for ILDs. We describe the clinical need for quantification of lung disease and illustrate the role of conventional visual evaluation and of QCT approaches in defining disease severity, prognosis, and longitudinal progression, both in established disease and in preclinical interstitial abnormality.

PMID:39564907 | DOI:10.2214/AJR.24.32053

ACS Med Chem Lett. 2024 Oct 16;15(11):1804-1805. doi: 10.1021/acsmedchemlett.4c00473. eCollection 2024 Nov 14.

ABSTRACT

Provided herein are novel substituted benzimidazole compounds as TLR9 inhibitors, pharmaceutical compositions, use of such compounds in treating fibrotic diseases, particularly idiopathic pulmonary fibrosis, and processes for preparing such compounds.

PMID:39563824 | PMC:PMC11571016 | DOI:10.1021/acsmedchemlett.4c00473

Mol Biol Rep. 2024 Nov 19;51(1):1166. doi: 10.1007/s11033-024-10104-8.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and highly fatal disease characterized by excessive accumulation of extracellular matrix (ECM), foci of myofibroblasts, and a usual pattern of interstitial pneumonia. As suggested by international guidelines, the treatment for this disease involves supportive therapies, as there is currently no effective treatment. Plant-derived nanovesicles have emerged as a new treatment for various diseases and have been tested in cellular and murine models.

METHODS AND RESULTS: This research aimed to test the use of Allium sativum nanovesicles (AS-NV) in a murine model of IPF induced by bleomycin. AS-NV reduced the amount of collagen and restored lung architecture in the mouse model. AS-NV was tested on human lung fibroblasts, which do not affect the viability of healthy cells. AS-NV treatment decreases the mRNA levels of genes related to fibrosis, inflammation, and ECM deposition (Mmp2,Timp-2,Vegf,Pcna,Col1a1,Tgf-β,α-Sma,IL-1β,and Hif1a) in bleomycin-induced idiopathic pulmonary fibrosis.

CONCLUSIONS: This research highlights the anti-inflammatory and antifibrotic activity of AS-NV, which contributes to plant nanovesicle mechanisms in IPF; however, more AS-NV studies are needed to identify alternative treatments for idiopathic pulmonary fibrosis.

PMID:39560703 | DOI:10.1007/s11033-024-10104-8

Clin Epigenetics. 2024 Nov 18;16(1):161. doi: 10.1186/s13148-024-01776-x.

ABSTRACT

BACKGROUND: DNA methylation is a critical regulatory mechanism of gene expression, influencing various human diseases and traits. While traditional expression quantitative trait loci (eQTL) studies have helped elucidate the genetic regulation of gene expression, there is a growing need to explore environmental influences on gene expression. Existing methods such as PrediXcan and FUSION focus on genotype-based associations but overlook the impact of environmental factors. To address this gap, we present MOSES (methylation-based gene association), a novel approach that utilizes DNA methylation to identify environmentally regulated genes associated with traits or diseases without relying on measured gene expression.

RESULTS: MOSES involves training, imputation, and association testing. It employs elastic-net penalized regression models to estimate the influence of CpGs and SNPs (if available) on gene expression. We developed and compared four MOSES versions incorporating different methylation and genetic data: (1) cis-DNA methylation within 1 Mb of promoter regions, (2) both cis-SNPs and cis-CpGs, 3) both cis- and a part of trans- CpGs (±5Mb away) from promoter regions), and 4) long-range DNA methylation (±10 Mb away) from promoter regions. Our analysis using nasal epithelium and white blood cell data from the Epigenetic Variation and Childhood Asthma in Puerto Ricans (EVA-PR) study demonstrated that MOSES, particularly the version incorporating long-range CpGs (MOSES-DNAm 10 M), significantly outperformed existing methods like PrediXcan, MethylXcan, and Biomethyl in predicting gene expression. MOSES-DNAm 10 M identified more differentially expressed genes (DEGs) associated with atopic asthma, particularly those involved in immune pathways, highlighting its superior performance in uncovering environmentally regulated genes. Further application of MOSES to lung tissue data from idiopathic pulmonary fibrosis (IPF) patients confirmed its robustness and versatility across different diseases and tissues.

CONCLUSION: MOSES represents an innovative advancement in gene association studies, leveraging DNA methylation to capture the influence of environmental factors on gene expression. By incorporating long-range CpGs, MOSES-DNAm 10 M provides superior predictive accuracy and gene association capabilities compared to traditional genotype-based methods. This novel approach offers valuable insights into the complex interplay between genetics and the environment, enhancing our understanding of disease mechanisms and potentially guiding therapeutic strategies. The user-friendly MOSES R package is publicly available to advance studies in various diseases, including immune-related conditions like asthma.

PMID:39558360 | DOI:10.1186/s13148-024-01776-x

BMC Pulm Med. 2024 Nov 18;24(1):572. doi: 10.1186/s12890-024-03389-9.

ABSTRACT

BACKGROUND AND AIMS: Interstitial lung diseases (ILDs), encompassing both pediatric and adult cases, present a diverse spectrum of chronic conditions with variable prognosis. Despite limited therapeutic options beyond antifibrotic drugs and immunosuppressants, accurate diagnosis is challenging, often necessitating invasive procedures that may not be feasible for certain patients. Drawn against this background, experts across pediatric and adult ILD fields have joined forces in the RARE-ILD initiative to pioneer novel non-invasive diagnostic algorithms and biomarkers. Collaborating with the RARE-ILD consortium, the eurILDreg aims to comprehensively describe different ILDs, analyze genetically defined forms across age groups, create innovative diagnostic and therapeutic biomarkers, and employ artificial intelligence for data analysis.

METHODS: The foundation of eurILDreg is built on a comprehensive parameter list developed and adopted by clinical experts, encompassing over 1,800 distinct parameters related to patient history, clinical examinations, diagnosis, lung function and biospecimen collection. This robust dataset is further enriched with daily assessments captured through the patientMpower app, including handheld spirometry and exercise tests, conducted on approximately 350 patients over the course of a year. This approach involves app-based daily assessments of quality of life, symptom tracking, handheld spirometry, saturation measurement, and the 1-min sit-to-stand test (1-STST). Additionally, pediatric data from the ChILD-EU registry will be integrated into the RARE-ILD Data Warehouse, with the ultimate goal of including a total of 4.000 ILD patients and over 100.000 biospecimen.

DISCUSSION: The collaborative efforts within the consortium are poised to streamline research endeavors significantly, promising to advance patient-centered care, foster innovation, and shape the future landscape of interstitial lung disease research and healthcare practices.

TRIAL REGISTRATION: EurILDreg is registered in the German Clinical Trials Register (DRKS 00028968, 26.07.2022), and eurIPFreg is registered in ClinicalTrials.gov (NCT02951416).

PMID:39558302 | DOI:10.1186/s12890-024-03389-9

J Allergy Clin Immunol Pract. 2024 Nov 16:S2213-2198(24)01168-1. doi: 10.1016/j.jaip.2024.10.046. Online ahead of print.

ABSTRACT

Cough reflex hypersensitivity is emerging as a key treatable trait in chronic cough and other cough-associated respiratory conditions. This review examines the neurological basis of cough, highlighting the complex interplay between peripheral and central mechanisms. The concept of cough hypersensitivity aims to address unmet clinical needs by recognizing chronic cough as a distinct disorder rather than merely a symptom. Evidence from clinical trials supports cough hypersensitivity as a treatable trait in chronic cough, with opiates, gabapentinoids, and novel P2X3 antagonists showing efficacy. Cough hypersensitivity is also relevant in conditions presenting with persistent cough, like asthma, bronchiectasis, and idiopathic pulmonary fibrosis, though more research is needed. Recognizing cough reflex hypersensitivity as a treatable trait offers new avenues for management, particularly for patients with persistent cough despite etiology-targeted therapies. We propose redefining chronic cough as a distinct disease entity in which cough hypersensitivity is a common feature and key therapeutic target, potentially leading to better patient care and the development of novel therapies.

PMID:39557291 | DOI:10.1016/j.jaip.2024.10.046

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