Mol Med. 2024 Nov 22;30(1):225. doi: 10.1186/s10020-024-00961-1.

ABSTRACT

Smad5 (small mothers against decapentaplegic 5) protein is a receptor-regulated member of the Smad family proteins, mainly participating in the bone morphogenetic protein (BMP) signaling pathway in its phosphorylated form. This article will provide a detailed review of Smad5, focusing on its gene characteristics, protein structure, and subcellular localization properties. We will also explore the related signaling pathways and the mechanisms of Smad5 in respiratory diseases, including chronic obstructive pulmonary disease (COPD), bronchial asthma, pulmonary arterial hypertension(PAH), lung cancer, and idiopathic pulmonary fibrosis (IPF). Additionally, the review will cover aspects such as proliferation, differentiation, apoptosis, anti-fibrosis, and mitochondrial function metabolism. In addition, the review will cover aspects of proliferation, differentiation, apoptosis, anti-fibrosis and functional mitochondrial metabolism related to the above topics. Numerous studies suggest that Smad5 may play a unique and important role in the pathogenesis of respiratory system diseases. However, in previous research, Smad5 was mainly used to broadly determine the activation of the BMP signaling pathway, and its own function has not been given much attention. It is worth noting that Smad5 has distinct nuclear-cytoplasmic distribution characteristics different from Smad1 and Smad8. It can undergo significant nuclear-cytoplasmic shuttling when intracellular pH (pHi) changes, playing important roles in both the classical BMP signaling pathway and non-BMP signaling pathways. Given that Smad5 can move intracellularly in response to changes in physicochemical properties, its cellular localization may play a crucial role in the development of respiratory diseases. This article will explore the possibility that its distribution characteristics may be an important factor that is easily overlooked and not adequately considered in disease research.

PMID:39578779 | DOI:10.1186/s10020-024-00961-1

Mol Med. 2024 Nov 23;30(1):227. doi: 10.1186/s10020-024-00990-w.

ABSTRACT

Impaired interaction of fibroblasts with pneumocytes contributes to the progression of chronic lung disease such as idiopathic pulmonary fibrosis (IPF). Mucin 5B (MUC5B) is associated with IPF. Here we analyzed the interaction of primary fibroblasts and alveolar type 2 (AT2) pneumocytes in the organoid model. Single-cell analysis, histology, and qRT-PCR revealed that fibroblasts expressing high levels of fibrosis markers regulate STAT3 signaling in AT2 cells, which is accompanied by cystic organoid growth and MUC5B expression. Cystic growth and MUC5B expression were also caused by the cytokine IL-6. The PI3K-Akt signaling pathway was activated in fibroblasts. The drug dasatinib prevented the formation of MUC5B-expressing cystic organoids. MUC5B associated with AT2 cells in samples obtained from IPF patients. Our model shows that fibrotic primary fibroblasts induce impaired differentiation of AT2 cells via STAT3 signaling pathways, as observed in IPF patients. It can be used for mechanistic studies and drug development.

PMID:39578767 | DOI:10.1186/s10020-024-00990-w

Chemosphere. 2024 Nov 20:143785. doi: 10.1016/j.chemosphere.2024.143785. Online ahead of print.

ABSTRACT

Polyhexamethylene guanidine (PHMG) is widely utilized in personal hygiene products due to its bactericidal, non-volatile, and hydrophilic properties. However, the long-term toxic effects and underlying mechanisms associated with respiratory exposure to the commonly used form, PHMG phosphate (PHMG-p), are still insufficiently understood. This study aims to elucidate the types of pulmonary lesions and the incidence of lung cancer associated with varying concentrations of PHMG-p and observation periods, along with the molecular mechanisms underlying this relationship. To assess these effects, CT scans and pathological analyses were conducted for up to 54 weeks following initial exposure to PHMG-p. Furthermore, to investigate the underlying causes of pulmonary toxicity, TGF-beta-activated kinase 1 was identified as a PHMG-p-binding protein, and its associated signaling pathways, including necroptosis, apoptosis, and MKK7, were explored. Somatic mutational signature, and gene ontology (GO) analyses were performed to investigate the genetic characteristics of PHMG-p-induced lung carcinogenesis. PHMG-p exposure led to somatic mutations in lung cancer-related genes, including TP53, SOS1, KMT2D, MDM2, ERBB2, SETD2, MET, and ARID1A, as well as in genes such as RAB31, WASHC1, and DDX11. The mutated genes were primarily associated with impaired DNA repair mechanisms. GO analysis highlighted the activation of pathways related to cell cycle checkpoints, necroptosis, MAPK, and idiopathic pulmonary fibrosis, while also revealing the suppression of signaling pathways associated with natural killer cells, GADD45, LXR/RXR activation, and IL-15 production. Gain-of-function experiments confirmed the oncogenic roles of PLAU and HMGA2, as well as the tumor-suppressive functions of TBX4 and GPX3. These findings suggest that PHMG-p activates necroptosis and MAPK signaling, increases the frequency of somatic mutations, and inhibits apoptosis, thus fostering an environment conducive to carcinogenesis. This underscores the importance of understanding the potential health risks associated with PHMG-p exposure and provides insights for future research and regulatory considerations regarding the safety of personal hygiene products.

PMID:39577803 | DOI:10.1016/j.chemosphere.2024.143785

bioRxiv [Preprint]. 2024 Nov 6:2024.11.03.621735. doi: 10.1101/2024.11.03.621735.

ABSTRACT

In single-cell studies, cells can be characterized with multiple sources of heterogeneity such as cell type, developmental stage, cell cycle phase, activation state, and so on. In some studies, many nuisance sources of heterogeneity (SOH) are of no interest, but may confound the identification of the SOH of interest, and thus affect the accurate annotate the corresponding cell subpopulations. In this paper, we develop B-Lightning, a novel and robust method designed to identify marker genes and cell subpopulations correponding to a SOH (e.g., cell activation status), isolating it from other sources of heterogeneity (e.g., cell type, cell cycle phase). B-Lightning uses an iterative approach to enrich a small set of trustworthy marker genes to more reliable marker genes and boost the signals of the SOH of interest. Multiple numerical and experimental studies showed that B-Lightning outperforms existing methods in terms of sensitivity and robustness in identifying marker genes. Moreover, it increases the power to differentiate cell subpopulations of interest from other heterogeneous cohorts. B-Lightning successfully identified new senescence markers in ciliated cells from human idiopathic pulmonary fibrosis (IPF) lung tissues, new T cell memory and effector markers in the context of SARS-COV-2 infections, and their synchronized patterns which were previously neglected. This paper highlights B-Lightning's potential as a powerful tool for single-cell data analysis, particularly in complex data sets where sources of heterogeneity of interest are entangled with numerous nuisance factors.

PMID:39574750 | PMC:PMC11580937 | DOI:10.1101/2024.11.03.621735

J Transl Med. 2024 Nov 21;22(1):1051. doi: 10.1186/s12967-024-05894-1.

ABSTRACT

BACKGROUND: Ficolins were originally identified as proteins that bind to transforming growth factor-β1 (TGF-β1). They are capable of activating the complement system through lectin pathway for immune system protection. Ficolin-2 and 3 have been identified in patients with interstitial lung diseases (ILD) and their function in these diseases is currently being explored. In contrast, the functional role of ficolin-1 in pulmonary fibrosis is still elusive and remains to be elucidated.

METHODS: The expression of ficolin-1 in the plasma of idiopathic pulmonary fibrosis (IPF) and connective tissue disease (CTD)-ILD patients was first determined. As the orthologue of human ficolin-1, ficolin-B knockout and ficolin-B overexpression were used to establish bleomycin (BLM)-induced pulmonary fibrosis mouse model. Co-immunoprecipitation, immunofluorescence and RNA sequencing were utilized to explore and expound on the expression and the functional mechanism of ficolin-1 in pulmonary fibrosis.

RESULTS: Compared with healthy controls, plasma ficolin-1 was significantly decreased in patients with IPF and CTD-ILD. In the bleomycin (BLM)-induced mice model, ficolin-B deficiency aggravated lung injury and fibrosis. There was also observed increase in TGF-β1 levels and enhanced downstream signaling. However, the overexpression of ficolin-B showed preventative and therapeutic efficacy against lung fibrosis. Furthermore, coimmunoprecipitation studies revealed the direct interaction between ficolin-1 and TGF-β1 in human plasma, which was further confirmed by the colocalization of ficolin-1 and TGF-β1 in lung tissues.

CONCLUSIONS: Ficolin-1 inhibits pulmonary fibrosis by directly binding to the key profibrogenic factor TGF-β1, marking it as a potential target for therapy in the treatment of fibrotic lung diseases.

PMID:39574172 | DOI:10.1186/s12967-024-05894-1

Respir Med. 2024 Nov 19:107862. doi: 10.1016/j.rmed.2024.107862. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a fatal progressive fibrosing lung disease. A decreased 6-minute walk distance (6MWD) and exercise-induced oxygen desaturation measured during the 6-minute walk test (6MWT), are known predictors of mortality in patients with IPF. However, the use of antifibrotic drugs showed a survival benefit in IPF. Therefore, this study aimed to evaluate to what extend 6MWT-derived attributes are associated with two-year survival when antifibrotic drugs were introduced as part of standard IPF-care.

METHODS: This real-world data-study included patients with IPF with a 6MWT between 2015-2020, and used composite outcome: mortality or lung transplantation within 2 years of follow-up. Data were collected systematically, including demographics, pulmonary function tests, comorbidities, medications and 6MWT-derived attributes. The prediction attributes of 6MWT were studied with a Cox Proportional-Hazards model and Kaplan-Meier survival curves. The best discriminating attribute to predict mortality was added to the prediction model Gender-Age-Physiology (GAP).

RESULTS: In 216 patients, 2-year transplant-free survival cut-off points were identified for the 6MWD (≥413 m), 6MWD %predicted (≥83%), SpO2-nadir (≥86%) and distance-saturation-product (≥374 m%), with the best discriminative value for SpO2-nadir (area under the curve: 0.761). 2-Year survival percentage of patients with SpO2-nadir below or above threshold (86%) was 37.1% and 80.0%, respectively. Exercise-induced oxygen desaturation added to the GAP model showed an improvement in its predictive power.

CONCLUSION: Patients with IPF who have an exercise-induced oxygen desaturation have worse prognosis. Addition of SpO2-nadir to the GAP model seems promising for use in clinical care of IPF patients.

PMID:39571824 | DOI:10.1016/j.rmed.2024.107862

J Med Chem. 2024 Nov 21. doi: 10.1021/acs.jmedchem.4c02090. Online ahead of print.

ABSTRACT

We describe the discovery and preclinical characterization of a potent and selective lysophosphatidic acid receptor 1 (LPAR1) antagonist with a direct-acting antifibrotic mechanism. 18a was initially identified as a potent non-carboxylic acid LPAR1 antagonist in an LPA-induced myocardin-related transcription factor A (MRTF-A) nuclear translocation assay. Modifications to the aromatic elements in the structure allowed for improvements in metabolic stability and the mitigation of GSH adduct formation, but in vitro to in vivo clearance disconnects were observed with several potent sulfonamides (e.g., 27b) across preclinical species. Through modification of the sulfonamide, 42 (GS-2278) emerged as a potent LPAR1 antagonist with a suitable in vitro profile and desirable pharmacokinetic properties for oral QD dosing. GS-2278 dose-dependently blocked LPA-induced histamine release and demonstrated efficacy in an interventional model of bleomycin-induced lung fibrosis. However, CNS-related toxicity was observed in dogs, and based on these findings, the clinical development of GS-2278 for IPF was halted.

PMID:39570661 | DOI:10.1021/acs.jmedchem.4c02090

Sci Rep. 2024 Nov 20;14(1):28743. doi: 10.1038/s41598-024-80023-y.

ABSTRACT

Changes in lung and gut microbial communities have been associated with idiopathic pulmonary fibrosis (IPF). This study aimed to investigate correlations between microbial changes in the lung and gut and host physiological indices in an IPF model, exploring potential mechanisms of the lung-gut axis in IPF pathogenesis. IPF model rats were established via trans-tracheal injection of bleomycin, with assessments of hematological indices, serum cytokines, lung histopathology, and microbiome alterations. Significant differences in microbial structure and composition were observed in the IPF model compared to controls, with 14 lung and 7 gut microbial genera showing significant abundance changes. Further analysis revealed 20 significant correlations between pulmonary and gut genera. Notably, 11 pairs of correlated genera were linked to the same IPF-related physiological indices, such as hydroxyproline, mean corpuscular volume (MCV), and red cell distribution width-standard deviation (RDW-SD). We identified 24 instances where a lung and a gut genus were each associated with the same physiological index, forming "lung genus-index-gut genus" relationships. Mediation analysis showed that indices like hydroxyproline, MCV, and RDW-SD mediated correlations between 10 lung genera (e.g., Cetobacterium, Clostridium XVIII ) and the gut genus Allobaculum. This study first describes gut-lung microbial interactions in pulmonary fibrosis. Mediation analysis suggests pathways underlying "lung genus-host index-gut genus" and "gut genus-host index-lung genus" correlations, thus providing clues to further elucidate the mechanisms of the "gut-lung axis" in IPF pathogenesis.

PMID:39567656 | DOI:10.1038/s41598-024-80023-y

Life Sci Alliance. 2024 Nov 20;8(2):e202402805. doi: 10.26508/lsa.202402805. Print 2025 Feb.

ABSTRACT

Idiopathic pulmonary fibrosis is a progressive and lethal interstitial lung disease with an unclear etiology and limited treatment options. Fatty acid synthase (FASN) plays various roles in metabolic-related diseases. This study demonstrates that FASN expression is increased in fibroblasts from the lung tissues of patients with idiopathic pulmonary fibrosis and in bleomycin-treated mice. In MRC-5 cells, the inhibition of FASN using shRNA or the pharmacological inhibitor C75 resulted in the increased mRNA and protein expression of glycogen synthase kinase 3β and Axin1, both negative regulators of the Wnt/β-catenin signaling pathway, and promoted autophagy. This outcome led to a decrease in β-catenin protein and mRNA levels, effectively inhibiting the proliferation, migration, and differentiation of lung fibroblasts into myofibroblasts, while inducing the differentiation of fibroblasts into adipofibroblasts. In vivo experiments showed that C75 alleviated bleomycin-induced lung fibrosis in mice by inhibiting β-catenin. In conclusion, these findings suggest that inhibiting FASN in fibroblasts may diminish the activity of the Wnt/β-catenin signaling pathway, providing a potential therapeutic avenue for pulmonary fibrosis.

PMID:39567194 | DOI:10.26508/lsa.202402805

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