Genes (Basel). 2023 Nov 16;14(11):2084. doi: 10.3390/genes14112084.

ABSTRACT

Interstitial lung disease and airway disease (AD) are often complicated with rheumatoid arthritis (RA) and have a poor prognosis. Several studies reported genetic associations with interstitial lung disease in RA. However, few genetic studies have examined the susceptibility to AD in RA patients. Here, we investigated whether single nucleotide variants susceptible to idiopathic pulmonary fibrosis might be associated with interstitial lung disease or AD in Japanese RA patients. Genotyping of rs2736100 [C/A] in TERT and rs1278769 [G/A] in ATP11A was conducted in 98 RA patients with usual interstitial pneumonia, 120 with nonspecific interstitial pneumonia (NSIP), 227 with AD, and 422 without chronic lung disease using TaqMan assays. An association with AD in RA was found for rs2736100 (p = 0.0043, Pc = 0.0129, odds ratio [OR] 1.40, 95% confidence interval [CI] 1.11-1.77). ATP11A rs1278769 was significantly associated with NSIP in older RA patients (>65 years, p = 0.0010, OR 2.15, 95% CI 1.35-3.40). This study first reported an association of rs2736100 with AD in RA patients and ATP11A rs1278769 with NSIP in older RA patients.

PMID:38003027 | DOI:10.3390/genes14112084

J Clin Med. 2023 Nov 11;12(22):7041. doi: 10.3390/jcm12227041.

ABSTRACT

BACKGROUND: The INBUILD study demonstrated the efficacy of nintedanib in the treatment of progressive fibrosing interstitial lung disease different to idiopathic pulmonary fibrosis, including rheumatoid arthritis (RA)-related ILD. Nevertheless, the prevalence of RA-ILD patients that may potentially benefit from nintedanib remains unknown.

OBJECTIVES AND METHODS: The aim of the present multicentre study was to investigate the prevalence and possible associated factors of fibrosing progressive patterns in a cross-sectional cohort of RA-ILD patients.

RESULTS: One hundred and thirty-four RA-ILD patients with a diagnosis of RA-ILD, who were confirmed at high-resolution computed tomography and with a follow-up of at least 24 months, were enrolled. The patients were defined as having a progressive fibrosing ILD in case of a relative decline in forced vital capacity > 10% predicted and/or an increased extent of fibrotic changes on chest imaging in a 24-month period. Respiratory symptoms were excluded to reduce possible bias due to the retrospective interpretation of cough and dyspnea. According to radiologic features, ILD was classified as usual interstitial pneumonia (UIP) in 50.7% of patients, nonspecific interstitial pneumonia in 19.4%, and other patterns in 29.8%. Globally, a fibrosing progressive pattern was recorded in 36.6% of patients (48.5% of patients with a fibrosing pattern) with a significant association to the UIP pattern.

CONCLUSION: We observed that more than a third of RA-ILD patients showed a fibrosing progressive pattern and might benefit from antifibrotic treatment. This study shows some limitations, such as the retrospective design. The exclusion of respiratory symptoms' evaluation might underestimate the prevalence of progressive lung disease but increases the value of results.

PMID:38002655 | DOI:10.3390/jcm12227041

Lipids Health Dis. 2023 Nov 24;22(1):201. doi: 10.1186/s12944-023-01964-3.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is considered an age-related disease. Age-related changes, along with other factors such as obesity, hormonal imbalances, and various metabolic disorders, lead to ectopic fat deposition (EFD). This accumulation of fat outside of its normal storage sites is associated with detrimental effects such as lipotoxicity, oxidative stress, inflammation, and insulin resistance. This narrative review provides an overview of the connection between ectopic and visceral fat deposition in aging, obesity, and IPF. It also elucidates the mechanism by which ectopic fat deposition in the airways and lungs, pericardium, skeletal muscles, and pancreas contributes to lung injury and fibrosis in patients with IPF, directly or indirectly. Moreover, the review discusses the impact of EFD on the severity of the disease, quality of life, presence of comorbidities, and overall prognosis in IPF patients. The review provides detailed information on recent research regarding representative lipid-lowering drugs, hypoglycemic drugs, and lipid-targeting drugs in animal experiments and clinical studies. This may offer new therapeutic directions for patients with IPF.

PMID:38001499 | DOI:10.1186/s12944-023-01964-3

Curr Opin Cell Biol. 2023 Nov 23;86:102282. doi: 10.1016/j.ceb.2023.102282. Online ahead of print.

ABSTRACT

Keratin (K) intermediate filaments are attached to desmosomes and constitute the orchestrators of epithelial cell and tissue architecture. While their relevance in the epidermis is well recognized, our review focuses on their emerging importance in internal epithelia. The significance of keratin-desmosome scaffolds (KDSs) in the intestine is highlighted by transgenic mouse models and individuals with inflammatory bowel disease who display profound KDS alterations. In lung, high K8 expression defines a transitional cell subset during regeneration, and K8 variants are associated with idiopathic pulmonary fibrosis. Inherited variants in desmosomal proteins are overrepresented in idiopathic lung fibrosis, and familiar eosinophilic esophagitis. K18 serum fragments are established hepatocellular injury markers that correlate with the extent of histological inflammation. K17 expression is modified in multiple tumors, and K17 levels might be of prognostic relevance. These data should spur further studies on biological roles of these versatile tissue protectors and efforts on their therapeutic targeting.

PMID:38000362 | DOI:10.1016/j.ceb.2023.102282

Mol Aspects Med. 2023 Nov 23;94:101227. doi: 10.1016/j.mam.2023.101227. Online ahead of print.

ABSTRACT

Fibrosis is the concluding pathological outcome and major cause of morbidity and mortality in a number of common chronic inflammatory, immune-mediated and metabolic diseases. The progressive deposition of a collagen-rich extracellular matrix (ECM) represents the cornerstone of the fibrotic response and culminates in organ failure and premature death. Idiopathic pulmonary fibrosis (IPF) represents the most rapidly progressive and lethal of all fibrotic diseases with a dismal median survival of 3.5 years from diagnosis. Although the approval of the antifibrotic agents, pirfenidone and nintedanib, for the treatment of IPF signalled a watershed moment for the development of anti-fibrotic therapeutics, these agents slow but do not halt disease progression or improve quality of life. There therefore remains a pressing need for the development of effective therapeutic strategies. In this article, we review emerging therapeutic strategies for IPF as well as the pre-clinical and translational approaches that will underpin a greater understanding of the key pathomechanisms involved in order to transform the way we diagnose and treat pulmonary fibrosis.

PMID:38000335 | DOI:10.1016/j.mam.2023.101227

Healthcare (Basel). 2023 Nov 8;11(22):2925. doi: 10.3390/healthcare11222925.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is one of the most deleterious diseases of the pulmonary fibrosis spectrum. Its clinical presentation includes irreversible loss of lung function, and increasing cough, dyspnea and impaired quality of life. Chest physiotherapy can improve ventilation capacity, gas exchange, dyspnea, exercise capacity and quality of life. The aim of this study was to review the evidence about chest physiotherapy in IPF, specifically meta-analyzing quality of life, exercise capacity and pulmonary function.

METHODS: A wide search was conducted in PubMed, Embase, Cochrane and Web of Science for articles included until October 2023. PROSPERO Identifier: CRD42022333496. The Downs and Black scale and the Cochrane tool were employed to evaluate quality assessments and to assess the risk of bias. Data were pooled, and a meta-analysis was conducted.

RESULTS: We selected 10 studies in which a chest physiotherapy program was performed with a total of 340 patients; of these, three articles were meta-analyzed. Significant effects in favor of chest physiotherapy were found for quality of life (MD = -8.60, 95% CI = -11.30, -5.90; p < 0.00001; I2 = 24%), exercise capacity (MD = 37.62, 95% CI = 15.10, 60.13; p = 0.001; I2 = 65%) and pulmonary function (MD = 7.86, 95% CI = 2.54, 13.17; p = 0.004; I2 = 80%).

CONCLUSIONS: The systematic review showed significant results for the application of chest physiotherapy regarding pulmonary capacity, diffusion of gases and quality of life in IPF patients. The meta-analysis showed a significant improvement associated with applying chest physiotherapy in pulmonary function, exercise capacity and quality of life.

PMID:37998418 | DOI:10.3390/healthcare11222925

Funct Integr Genomics. 2023 Nov 24;23(4):346. doi: 10.1007/s10142-023-01274-y.

ABSTRACT

Patients with idiopathic pulmonary fibrosis (IPF) have a significantly higher prevalence of lung adenocarcinoma (LUAD) than normal subjects, although the underlying association is unclear. The raw data involved were obtained from the Gene Expression Omnibus (GEO) database. Differential expression analysis and weighted gene co-expression network analysis were used to screen for differentially expressed genes (DEGs) and modular signature genes (MSGs). Genes intersecting DEGs and MSGs were considered hub genes for IPF and LUAD. Machine learning algorithms were applied to capture epithelial cell-derived signature genes (EDSGs) shared. External cohort data were exploited to validate the robustness of EDSGs. Immunohistochemical staining and K-M plots were used to denote the prognostic value of EDSGs in LUAD. Based on EDSGs, we constructed a TF-gene-miRNA regulatory network. Molecular docking can validate the strength of action between candidate drugs and EDSGs. Epithelial cells, 650 DEGs, and 1773 MSGs were shared by IPF and LUAD. As for 379 hub genes, we performed pathway and functional enrichment analysis. By analyzing sc-RNA seq data, we identified 1234 marker genes of IPF epithelial cell-derived and 1481 of LUAD. And these genes shared 8 items with 379 hub genes. Through the machine learning algorithms, we further fished TRIM2, S100A14, CYP4B1, LMO7, and SFN. The ROC curves emphasized the significance of EDSGs in predicting the onset of LUAD and IPF. The TF-gene-miRNA network revealed regulatory relationships behind EDSGs. Finally, we predicted appropriate therapeutic agents. Our study preliminarily identified potential mechanisms between IPF and LUAD, which will inform subsequent studies.

PMID:37996625 | DOI:10.1007/s10142-023-01274-y

Tuberc Respir Dis (Seoul). 2023 Nov 23. doi: 10.4046/trd.2023.0131. Online ahead of print.

ABSTRACT

Chronic respiratory diseases such as idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and respiratory infections injure the alveoli; the damage evoked is mostly irreversible and occasionally leads to death. Achieving a detailed understanding of the pathogenesis of these fatal respiratory diseases has been hampered by limited access to human alveolar tissue and the differences between mice and humans. Thus, the development of human alveolar organoid (AO) models that mimic in vivo physiology and pathophysiology has gained tremendous attention over the last decade. In recent years, human pluripotent stem cells (hPSCs) have been successfully employed to generate several types of organoids representing different respiratory compartments, including alveolar regions. However, despite continued advances in three-dimensional (3D) culture techniques and single-cell genomics, there is still a profound need to improve the cellular heterogeneity and maturity of AOs to recapitulate the key histological and functional features of in vivo alveolar tissue. In particular, the incorporation of immune cells such as macrophages into hPSC-AO systems is crucial for disease modeling and subsequent drug screening. In this review, we summarize current methods for differentiating alveolar epithelial cells from hPSCs followed by AO generation and their applications in disease modeling, drug testing, and toxicity evaluation. In addition, we review how current hPSC-AOs closely resemble in vivo alveoli in terms of phenotype, cellular heterogeneity, and maturity.

PMID:37993994 | DOI:10.4046/trd.2023.0131

Ther Adv Respir Dis. 2023 Jan-Dec;17:17534666231212301. doi: 10.1177/17534666231212301.

ABSTRACT

BACKGROUND: Progressive fibrosis can occur in connective tissue disease (CTD)-related interstitial lung disease (ILD) and make the prognosis worse.

OBJECTIVES: This study aimed to investigate factors related to progressive pulmonary fibrosis (PPF) phenotype in CTD-ILDs.

DESIGN: Medical records of patients diagnosed as CTD and ILD at a single, tertiary hospital in South Korea were retrospectively reviewed.

METHODS: Patients whose lung functions were followed up for more than a year were included in analysis. PPF was defined as forced vital capacity (FVC) declined ⩾10% or diffusion capacity of carbon monoxide (DLco) ⩾15%.

RESULTS: Of 110 patients with CTD-ILD, 24.5% progressed into PPF. Rheumatoid arthritis (RA) and Sjogren's disease accounted for more than 63% of PPF. Compositions of CTD type were similar between PPF and non-PPF. Clinical characteristics and proportion of usual interstitial pneumonia (UIP) pattern on chest images were also similar between PPF and non-PPF. Approximately 10% of patients in both groups were treated with anti-fibrotic agents. Use of systemic steroids and/or other immunomodulating agents lowered the risk of developing PPF in CTD-ILD patients after adjusting for gender-age-physiology score and smoking status (adjusted odds ratio: 0.25, 95% confidence interval: 0.07-0.85).

CONCLUSION: About a quarter of CTD-ILD progressed into PPF. The use of immunomodulating agents lowered the risk of developing PPF. To improve outcomes of patients, future studies need to detect patients at higher risk for PPF earlier and set up clinical guidelines for treatment strategies in the process of PPF.

PMID:37991015 | PMC:PMC10666675 | DOI:10.1177/17534666231212301

Semin Diagn Pathol. 2023 Nov 15:S0740-2570(23)00099-0. doi: 10.1053/j.semdp.2023.11.006. Online ahead of print.

ABSTRACT

The recognition of immunoglobulin G4-related disease (IgG4-RD) as an entity in the pancreaticobiliary tract was followed by a slew of papers describing inflammation and fibrosis containing IgG4-positive plasma cells in a variety of sites including the respiratory tract, leading to the hypothesis that these abnormalities were attributable to IgG4-RD. Predictably, pathologists began to see requests from clinicians to perform IgG4 immunohistochemistry in lung biopsies "to rule out IgG4-RD". Several years later, the notion that IgG4-RD would prove to be the underlying cause of a wide array of fibroinflammatory lesions in the lung has not panned out as promised. To the contrary, it has become clear that IgG4-positive plasma cells are not specific for IgG4-RD, and that large numbers of IgG4-positive plasma cells can be encountered in other well-defined entities, including inflammatory myofibroblastic tumor and nodular lymphoid hyperplasia, as well as in lymphoplasmacytic infiltrates in other entities, including connective tissue disease and idiopathic forms of interstitial lung disease. It has also become clear that raised serum IgG4 levels can occur in settings other than IgG4-RD. These observations suggest that true IgG4-RD of the lung is far less common than previously surmised. Pathologists must familiarize themselves with mimics of IgG4-RD in the lung and exercise caution before attributing lymphoplasmacytic infiltrates in the lung to IgG4-RD.

PMID:37993385 | DOI:10.1053/j.semdp.2023.11.006

J Integr Med. 2023 Nov 8:S2095-4964(23)00084-5. doi: 10.1016/j.joim.2023.11.003. Online ahead of print.

ABSTRACT

BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is an important occurrence in the natural history of idiopathic pulmonary fibrosis (IPF), associated with high hospitalization rates, high mortality and poor prognosis. At present, there is no effective treatment for AE-IPF. Chinese herbal medicine has some advantages in treating IPF, but its utility in AE-IPF is unclear.

OBJECTIVE: The treatment of AE-IPF with Kangxian Huanji Granule (KXHJ), a compound Chinese herbal medicine, lacks an evidence-based justification. This study explores the efficacy and safety of KXHJ in patients with AE-IPF.

DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: We designed a randomized, double-blind, placebo-controlled, exploratory clinical trial. A total of 80 participants diagnosed with AE-IPF were randomly assigned to receive KXHJ or a matching placebo; the treatment included a 10 g dose, administered twice daily for 4 weeks, in addition to conventional treatment. Participants were followed up for 12 weeks after the treatment.

MAIN OUTCOME MEASURES: The primary endpoints were treatment failure rate and all-cause mortality. Secondary endpoints included the length of hospitalization, overall survival, acute exacerbation rate, intubation rate, the modified British Medical Research Council (mMRC) score, and the St George's Respiratory Questionnaire for IPF (SGRQ-I) score.

RESULTS: The rate of treatment failure at 4 weeks was lower in the intervention group compared to the control group (risk ratio [RR]: 0.22; 95% confidence interval [CI]: 0.051 to 0.965, P = 0.023). There was no significant difference in all-cause mortality at 16 weeks (RR: 0.75; 95% CI: 0.179 to 3.138; P > 0.999) or in the acute exacerbation rate during the 12-week follow-up period (RR: 0.69; 95% CI: 0.334 to 1.434; P = 0.317). The intervention group had a shorter length of hospitalization than the control group (mean difference [MD]: -3.30 days; 95% CI, -6.300 to -0.300; P = 0.032). Significant differences in the mean change from baseline in the mMRC (between-group difference: -0.67; 95% CI: -0.89 to -0.44; P < 0.001) and SGRQ-I score (between-group difference: -10.36; 95% CI: -16.483 to -4.228; P = 0.001) were observed after 4 weeks, and also in the mMRC (between-group difference: -0.67; 95% CI: -0.91 to -0.43; P < 0.001) and SGRQ-I (between-group difference: -10.28; 95% CI, -15.838 to -4.718; P < 0.001) at 16 weeks. The difference in the adverse events was not significant.

CONCLUSION: KXHJ appears to be effective and safe for AE-IPF and can be considered a complementary treatment in patients with AE-IPF. As a preliminary exploratory study, our results provide a basis for further clinical research.

TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR1900026289). Please cite this article as: Li JS, Zhang HL, Guo W, Wang L, Zhang D, Zhao LM, Zhou M. Efficacy and safety of Kangxian Huanji Granule as adjunctive treatment in acute exacerbation of idiopathic pulmonary fibrosis: an exploratory randomized controlled trial. J Integr Med. 2023; Epub ahead of print.

PMID:37993378 | DOI:10.1016/j.joim.2023.11.003

Biomaterials. 2023 Nov 17;303:122404. doi: 10.1016/j.biomaterials.2023.122404. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) stands as a highly heterogeneous and deadly lung disease, yet the available treatment options remain limited. Combining myofibroblast inhibition with ROS modulation in damaged AECs offers a comprehensive strategy to halt IPF progression, but delivering drugs separately to these cell types is challenging. Inspired by the successful application of pulmonary surfactant (PS) replacement therapy in lung disease treatment, we have developed PS nano-biomimetic liposomes (PSBs) to utilize its natural transport pathway for targeting AECs while reducing lung tissue clearance. In this collaborative pulmonary drug delivery system, PSBs composed of DPPC/POPG/DPPG/CHO (20:9:5:4) were formulated for inhalation. These PSBs loaded with ROS-scavenger astaxanthin (AST) and anti-fibrosis drug pirfenidone (PFD) were aerosolized for precise quantification and mimicking patient inhalation. Through aerosol inhalation, the lipid membrane of PSBs gradually fused with natural PS, enabling AST delivery to AECs by hitchhiking with PS circulation. Simultaneously, PFD was released within the PS barrier, effectively penetrating lung tissue to exert therapeutic effects. In vivo results have shown that PSBs offer numerous therapeutic advantages in mice with IPF, particularly in terms of lung function recovery. This approach addresses the challenges of drug delivery to specific lung cells and offers potential benefits for IPF patients.

PMID:37992600 | DOI:10.1016/j.biomaterials.2023.122404

Zhonghua Jie He He Hu Xi Za Zhi. 2023 Nov 14;46:1176-1188. doi: 10.3760/cma.j.cn112147-20230726-00030. Online ahead of print.

ABSTRACT

Interstitial lung disease (ILD) is a group of heterogeneous diseases characterized by interstitial lung inflammation and fibrosis. Its causes are diverse, symptoms can be non-specific, and the associated imaging and pathologic patterns can vary widely. The diagnosis and management of these conditions often require input from multiple medical disciplines. Over the past few decades, the importance of multidisciplinary discussion (MDD) in the management of ILD has grown internationally, and MDD has gradually become a part of the gold standard for ILD diagnosis and an essential reference for disease management. Recognizing this, the Chinese Medical Association-Chinese Thoracic Society and the Chinese Association of Chest Physicians have collaborated with experts to standardize the ILD-MDD process in China.Key recommendations:1. Formation of teams: ILD centers should establish multidisciplinary teams (MDT) and integrate MDD into the ILD patient care process. (strong recommendation)2. Patient preparation: Prior to ILD-MDD, patients should undergo as thorough an ILD assessment as possible, including medical history, diagnostic tests, and functional evaluations. (strong recommendation)3. MDD frequency & logistics:(1) The frequency, duration and number of cases to be discussed in ILD-MDD should be based on the clinical needs of each center, but should be held at least monthly. (2) Consistent timing and location of ILD-MDD is recommended to improve attendance. (medium recommendation)4. Team composition: The MDT should include experts from a range of disciplines with experience of ILD. These should include specialists in Pulmonary and Critical Care Medicine, Radiology, and Pathology. Where appropriate, experts in Rheumatology, Hematology, Thoracic Surgery, and Respiratory Care and Rehabilitation should also be involved. (strong recommendation)5. Case presentation & goals:(1) The physician in charge should present clinical information, preferably using standardized slides. Real-time imaging and pathology data are encouraged. (2) The primary goals of ILD-MDD discussions should be disease diagnosis and management. (strong recommendation)6. Operational leadership: Assign a dedicated professional to manage the ILD-MDD operations and maintain the information discussed. (strong recommendation)7. Specific conditions:(1) Suspected idiopathic pulmonary fibrosis should be diagnosed by a standardized MDD process. (2) Suspected idiopathic interstitial pneumonia (IIP) should be classified by MDD. If IIP is indicated by imaging or pathology, prioritize identifying potential underlying causes such as connective tissue diseases (CTDs), certain medications, or aspiration.(3) Suspected hypersensitivity pneumonitis should also be diagnosed by MDD. (4) If an ILD patient shows signs suggestive of CTDs, the diagnosis should be made by ILD-MDD with the involvement of rheumatologists. (strong recommendation)8. Unclassifiable ILD: For ILD patients who cannot be clearly classified, create a tailored management plan based on the patient's specific disease features. (strong recommendation)9. Progressive pulmonary fibrosis: Use ILD-MDD to determine whether an ILD patient meets the criteria for progressive pulmonary fibrosis and to discuss a personalized care plan. (strong recommendation).

PMID:37989522 | DOI:10.3760/cma.j.cn112147-20230726-00030

bioRxiv. 2023 Nov 7:2023.11.06.565810. doi: 10.1101/2023.11.06.565810. Preprint.

ABSTRACT

Aging and cellular senescence are increasingly recognized as key contributors to pulmonary fibrosis. However, our understanding in the context of scleroderma associated interstitial lung disease (SSc-ILD) is limited. To investigate, we leveraged previously established lung aging and cell-specific senescence signatures to determine their presence and potential relevance to SSc-ILD. We performed a gene expression meta-analysis of lung tissue from 38 SSc-ILD and 18 healthy controls and found markers (GDF15, COMP, CDKN2A) and pathways (p53) of senescence were significantly increased in SSc-ILD. When probing the established aging and cellular senescence signatures, we found epithelial and fibroblast senescence signatures had a 3.6-fold and 3.7-fold enrichment respectively in the lung tissue of SSc-ILD and that lung aging genes ( CDKN2A, FRZB, PDE1A, NAPI12) were increased in SSc-ILD. These signatures were also enriched in SSc skin and associated with degree of skin involvement (limited vs. diffuse cutaneous). To further support these findings, we examined telomere length (TL), a surrogate for aging, in lung tissue and found independent of age, SSc-ILD had significantly shorter telomeres than controls in type II alveolar cells in the lung. TL in SSc-ILD was comparable to idiopathic pulmonary fibrosis, a disease of known aberrant aging. Taken together, this study provides novel insight into the possible mechanistic effects of accelerated aging and aberrant cellular senescence in SSc-ILD pathogenesis.

PMID:37986995 | PMC:PMC10659335 | DOI:10.1101/2023.11.06.565810

bioRxiv. 2023 Nov 7:2023.11.07.566074. doi: 10.1101/2023.11.07.566074. Preprint.

ABSTRACT

A hallmark of Idiopathic Pulmonary Fibrosis is the TGF-β-dependent activation of lung fibroblasts, leading to excessive deposition of collagen proteins and progressive scarring. We have previously shown that synthesis of collagen by lung fibroblasts requires de novo synthesis of glycine, the most abundant amino acid in collagen protein. TGF-β upregulates the expression of the enzymes of the de novo serine/glycine synthesis pathway in lung fibroblasts through mTORC1 and ATF4- dependent transcriptional programs. SHMT2, the final enzyme of the de novo serine/glycine synthesis pathway, transfers a one-carbon unit from serine to tetrahydrofolate (THF), producing glycine and 5,10-methylene-THF (meTHF). meTHF is converted back to THF in the mitochondrial one-carbon (1C) pathway through the sequential actions of MTHFD2 (which converts meTHF to 10-formyl-THF), and either MTHFD1L, which produces formate, or ALDH1L2, which produces CO 2 . It is unknown how the mitochondrial 1C pathway contributes to glycine biosynthesis or collagen protein production in fibroblasts, or fibrosis in vivo . Here, we demonstrate that TGF-β induces the expression of MTHFD2 , MTHFD1L , and ALDH1L2 in human lung fibroblasts. MTHFD2 expression was required for TGF-β-induced cellular glycine accumulation and collagen protein production. Combined knockdown of both MTHFD1L and ALDH1L2 also inhibited glycine accumulation and collagen protein production downstream of TGF-β; however knockdown of either protein alone had no inhibitory effect, suggesting that lung fibroblasts can utilize either enzyme to regenerate THF. Pharmacologic inhibition of MTHFD2 recapitulated the effects of MTHFD2 knockdown in lung fibroblasts and ameliorated fibrotic responses after intratracheal bleomycin instillation in vivo . Our results provide insight into the metabolic requirements of lung fibroblasts and provide support for continued development of MTHFD2 inhibitors for the treatment of IPF and other fibrotic diseases.

PMID:37986788 | PMC:PMC10659399 | DOI:10.1101/2023.11.07.566074

Respir Res. 2023 Nov 20;24(1):291. doi: 10.1186/s12931-023-02610-3.

ABSTRACT

BACKGROUND: Several observational studies have found that physical inactivity and sedentary time are associated with idiopathic pulmonary fibrosis (IPF) risk. However, the causality between them still requires further investigation. Therefore, our study aimed to investigate the causal effect of physical activity (PA) and sedentary time on the risk of IPF via two-sample Mendelian randomization (MR) analysis.

METHODS: Multiple genome-wide association study (GWAS) data involving individuals of European ancestry were analyzed. The datasets encompassed published UK Biobank data (91,105-377,234 participants) and IPF data (2018 cases and 373,064 controls) from FinnGen Biobank. The inverse variance weighting (IVW) method was the primary approach for our analysis. Sensitivity analyses were implemented with Cochran's Q test, MR-Egger regression, MR-PRESSO global test, and leave-one-out analysis.

RESULTS: Genetically predicted self-reported PA was associated with lower IPF risk [OR = 0.27; 95% CI 0.09-0.82; P = 0.02]. No causal effects of accelerometry-based PA or sedentary time on the risk of IPF were observed.

CONCLUSIONS: Our findings supported a protective relationship between self-reported PA and the risk for IPF. The results suggested that enhancing PA may be an effective preventive strategy for IPF.

PMID:37986064 | DOI:10.1186/s12931-023-02610-3

Zhongguo Fei Ai Za Zhi. 2023 Sep 20;26(9):669-683. doi: 10.3779/j.issn.1009-3419.2023.101.25.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an idiopathic chronic, progressive interstitial lung disease with a diagnosed median survival of 3-5 years. IPF is associated with an increased risk of lung cancer. Therefore, exploring the shared pathogenic genes and molecular pathways between IPF and lung adenocarcinoma (LUAD) holds significant importance for the development of novel therapeutic approaches and personalized precision treatment strategies for IPF combined with lung cancer.

METHODS: Bioinformatics analysis was conducted using publicly available gene expression datasets of IPF and LUAD from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis was employed to identify common genes involved in the progression of both diseases, followed by functional enrichment analysis. Subsequently, additional datasets were used to pinpoint the core shared genes between the two diseases. The relationship between core shared genes and prognosis, as well as their expression patterns, clinical relevance, genetic characteristics, and immune-related functions in LUAD, were analyzed using The Cancer Genome Atlas (TCGA) database and single-cell RNA sequencing datasets. Finally, potential therapeutic drugs related to the identified genes were screened through drug databases.

RESULTS: A total of 529 shared genes between IPF and LUAD were identified. Among them, SULF1 emerged as a core shared gene associated with poor prognosis. It exhibited significantly elevated expression levels in LUAD tissues, concomitant with high mutation rates, genomic heterogeneity, and an immunosuppressive microenvironment. Subsequent single-cell RNA-seq analysis revealed that the high expression of SULF1 primarily originated from tumor-associated fibroblasts. This study further demonstrated an association between SULF1 expression and tumor drug sensitivity, and it identified potential small-molecule drugs targeting SULF1 highly expressed fibroblasts.

CONCLUSIONS: This study identified a set of shared molecular pathways and core genes between IPF and LUAD. Notably, SULF1 may serve as a potential immune-related biomarker and therapeutic target for both diseases.

PMID:37985153 | DOI:10.3779/j.issn.1009-3419.2023.101.25

Intern Med. 2023 Nov 20. doi: 10.2169/internalmedicine.2834-23. Online ahead of print.

ABSTRACT

A 72-year-old man presented with bilateral ground-glass opacities in the lower lung fields on chest radiography. Computed chest tomography showed ground-glass opacities and micronodules in both lower lungs. A video-assisted thoracoscopic biopsy of the right lower lung showed homogeneous thickening of the alveolar septa with fibrosis and inflammatory cell infiltration consistent with fibrotic non-specific interstitial pneumonia (fNSIP). Cicatricial organizing pneumonia and intraluminal pulmonary ossification containing bone marrow that was considered to represent dendriform pulmonary ossification. Idiopathic fNSIP was diagnosed. The patient remains stable under antifibrotic treatment.

PMID:37981302 | DOI:10.2169/internalmedicine.2834-23

Thorax. 2023 Nov 18:thorax-2023-220821. doi: 10.1136/thorax-2023-220821. Online ahead of print.

ABSTRACT

OBJECTIVE: A post-hoc analysis of the INCREASE trial and its open-label extension (OLE) was performed to evaluate whether inhaled treprostinil has a long-term survival benefit in patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD).

METHODS: Two different models of survival were employed; the inverse probability of censoring weighting (IPCW) and the rank-preserving structural failure time (RPSFT) models both allow construction of a pseudo-placebo group, thereby allowing for long-term survival evaluation of patients with PH-ILD receiving inhaled treprostinil. Time-varying stabilised weights were calculated by fitting Cox proportional hazards models based on the baseline and time-varying prognostic factors to generate weighted Cox regression models with associated adjusted HRs.

RESULTS: In the INCREASE trial, there were 10 and 12 deaths in the inhaled treprostinil and placebo arms, respectively, during the 16-week randomised trial. During the OLE, all patients received inhaled treprostinil and there were 29 and 33 deaths in the prior inhaled treprostinil arm and prior placebo arm, respectively. With a conventional analysis, the HR for death was 0.71 (95% CI 0.46 to 1.10; p=0.1227). Both models demonstrated significant reductions in death associated with inhaled treprostinil treatment with HRs of 0.62 (95% CI 0.39 to 0.99; p=0.0483) and 0.26 (95% CI 0.07 to 0.98; p=0.0473) for the IPCW and RPSFT methods, respectively.

CONCLUSION: Two independent modelling techniques that have been employed in the oncology literature both suggest a long-term survival benefit associated with inhaled treprostinil treatment in patients with PH-ILD.

PMID:37979971 | DOI:10.1136/thorax-2023-220821

J Heart Lung Transplant. 2023 Nov 16:S1053-2498(23)02123-X. doi: 10.1016/j.healun.2023.11.005. Online ahead of print.

ABSTRACT

RATIONALE: The administration of inhaled prostanoids to patients with pulmonary hypertension (PH) related to idiopathic pulmonary fibrosis (IPF) and other fibrotic interstitial lung diseases improves functional outcomes. Selection of patients with IPF at high risk for concomitant PH to undergo right heart catheterization (RHC) remains challenging.

OBJECTIVE: To develop a simple clinical prediction tool based on commonly measured non-invasive parameters to facilitate the identification of PH in patients with IPF METHODS: A clinical prediction model based on non-invasive parameters was derived in patients enrolled in the ARTEMIS-IPF randomized, placebo-controlled clinical trial. Predictor variables were tested for association with the presence of PH diagnosed based on RHC. The derived multivariable logistic regression model and associated point-score index were then externally validated in a real-world cohort of patients with IPF.

RESULTS: Of the 481 patients included from the ARTEMIS-IPF study, 9.8% (N=47) were diagnosed with PH related to IPF. Four variables were associated with PH and were included in the final model: FVC%/DLCO% ratio (F), oxygen saturation nadir during 6MWT (O), race (R), and distance ambulated during 6MWT (D). A model containing continuous predictors (FORD calculator) and a simple point-score system (FORD index) performed similarly well in the derivation cohort (AUC: 0.75 and 0.75, respectively) and validation cohort (AUC: 0.69 and 0.69, respectively).

CONCLUSION: The FORD models are simple, validated tools incorporating non-invasive parameters that can be applied to identify patients at high risk of PH related to IPF who may benefit from invasive testing.

PMID:37979926 | DOI:10.1016/j.healun.2023.11.005