ERJ Open Res. 2024 Aug 5;10(4):00227-2024. doi: 10.1183/23120541.00227-2024. eCollection 2024 Jul.

ABSTRACT

STUDY QUESTION: In large multinational patient surveys, spirometry (which requires repeated, reproducible maximal efforts) can be associated with cough, breathlessness and tiredness, particularly in those with idiopathic pulmonary fibrosis (IPF). Oscillometry is an effort-independent test of airways resistance and reactance. We hypothesised that oscillometry would take less time to perform and would be associated with reduced symptom burden than spirometry.

PATIENTS AND METHODS: Spirometry and oscillometry were performed in 66 participants with IPF and repeated 2 weeks later. We compared time taken to perform tests, symptom burden and test-retest reliability with Bland-Altman plots and intraclass correlation coefficients (ICCs).

RESULTS: Oscillometry took significantly less time to perform than spirometry (mean -4.5 (99% CI -6.0 to -3.0) min) and was associated with lower symptom burden scores for cough (-1.3, 99% CI -1.7 to -0.8), breathlessness (-1.0, 99% CI -1.4 to -0.5), and tiredness (-0.5, 99% CI -0.9 to -0.2). On Bland-Altman analysis, all measures showed good agreement, with narrow limits of agreement and the mean bias lying close to 0 in all cases. The ICCs for forced expiratory volume in 1 s and forced vital capacity were 0.94 and 0.89, respectively, and ranged between 0.70 and 0.90 for oscillometry measures.

CONCLUSION: Oscillometry is quicker to perform and provokes less symptoms than spirometry in patients with IPF.

PMID:39104963 | PMC:PMC11299002 | DOI:10.1183/23120541.00227-2024

ERJ Open Res. 2024 Aug 5;10(4):00061-2024. doi: 10.1183/23120541.00061-2024. eCollection 2024 Jul.

ABSTRACT

Genes involved in cell death, inflammation and viral infection are common to both COPD and IPF. A link to rheumatic disease is unique to COPD, and IPF-specific analyses showed increases in gene expression of keratins, collagens, mucins and MMPs. https://bit.ly/3JoW73H.

PMID:39104962 | PMC:PMC11299008 | DOI:10.1183/23120541.00061-2024

Am J Physiol Lung Cell Mol Physiol. 2024 Aug 6. doi: 10.1152/ajplung.00037.2024. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible respiratory disease with limited therapeutic options. A hallmark of IPF is excessive fibroblast activation and extracellular matrix (ECM) deposition. The resulting increase in tissue stiffness amplifies fibroblast activation and drives disease progression. Dampening stiffness-dependent activation of fibroblasts could slow disease progression. We performed an unbiased, next generation sequencing (NGS) screen to identify signaling pathways involved in stiffness-dependent lung fibroblast activation. Adipocytokine signaling was downregulated in primary lung fibroblasts (PFs) cultured on stiff matrices. Re-activating adipocytokine signaling with adiponectin suppressed stiffness-dependent activation of human PFs. Adiponectin signaling depended on CDH13 expression and p38 mitogen-activated protein kinase gamma (p38MAPKγ) activation. CDH13 expression and p38MAPKγ activation were strongly reduced in lungs from IPF donors. Our data suggest that adiponectin-signaling via CDH13 and p38MAPKγ activation suppresses pro-fibrotic activation of fibroblasts in the lung. Targeting of the adiponectin signaling cascade may provide therapeutic benefits in IPF.

PMID:39104319 | DOI:10.1152/ajplung.00037.2024

Clin Exp Pharmacol Physiol. 2024 Sep;51(9):e13913. doi: 10.1111/1440-1681.13913.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by chronic inflammation, lung tissue fibrotic changes and impaired lung function. Pulmonary fibrosis 's pathological process is thought to be influenced by macrophage-associated phenotypes. IPF treatment requires specific targets that target macrophage polarization. Cytokine-like 1(CYTL1) is a secreted protein with multiple biological functions first discovered in CD34+ haematopoietic cells. However, its possible effects on IPF progression remain unclear. This study investigated the role of CYTL1 in IPF progression in a bleomycin-induced lung injury and fibrosis model. In bleomycin-induced mice, CYTL1 is highly expressed. Moreover, CYTL1 ablation alleviates lung injury and fibrosis in vivo. Further, downregulating CYTL1 reduces macrophage M2 polarization. Mechanically, CYTL1 regulates transforming growth factor β (TGF-β)/connective tissue growth factor (CCN2) axis and inhibition of TGF-β pathway alleviates bleomycin-induced lung injury and fibrosis. In conclusion, highly expressed CYTL1 inhibits macrophage M2 polarization by regulating TGF-β/CCN2 expression, alleviating bleomycin-induced lung injury and fibrosis. CYTL1 could, therefore, serve as a promising IPF target.

PMID:39103233 | DOI:10.1111/1440-1681.13913

Hum Genet. 2024 Aug 6. doi: 10.1007/s00439-024-02696-9. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease accompanied by both local and systemic comorbidities. Genetic factors play a role in the development of IPF and certain associated comorbidities. Nevertheless, it is uncertain whether there are shared genetic factors underlying IPF and these comorbidities. To bridge this knowledge gap, we conducted a systematic investigation into the shared genetic architecture between IPF and ten prevalent heritable comorbidities (i.e., body mass index [BMI], coronary artery disease [CAD], chronic obstructive pulmonary disease [COPD], gastroesophageal reflux disease, lung cancer, major depressive disorder [MDD], obstructive sleep apnoea, pulmonary hypertension [PH], stroke, and type 2 diabetes), by utilizing large-scale summary data from their respective genome-wide association studies and multi-omics studies. We revealed significant (false discovery rate [FDR] < 0.05) and moderate genetic correlations between IPF and seven comorbidities, excluding lung cancer, MDD and PH. Evidence suggested a partially putative causal effect of IPF on CAD. Notably, we observed FDR-significant genetic enrichments in lung for the cross-trait between IPF and CAD and in liver for the cross-trait between IPF and COPD. Additionally, we identified 65 FDR-significant genes over-represented in 20 biological pathways related to the etiology of IPF, BMI, and COPD, including inflammation-related mucin gene clusters. Several of these genes were associated with clinically relevant drugs for the treatment of IPF, CAD, and/or COPD. Our results underscore the pervasive shared genetic basis between IPF and its common comorbidities and hold future implications for early diagnosis of IPF-related comorbidities, drug repurposing, and the development of novel therapies for IPF.

PMID:39103522 | DOI:10.1007/s00439-024-02696-9

Front Immunol. 2024 Jul 19;15:1425466. doi: 10.3389/fimmu.2024.1425466. eCollection 2024.

ABSTRACT

INTRODUCTION: Genetic mutations in critical nodes of pulmonary epithelial function are linked to the pathogenesis of pulmonary fibrosis (PF) and other interstitial lung diseases. The slow progression of these pathologies is often intermitted and accelerated by acute exacerbations, complex non-resolving cycles of inflammation and parenchymal damage, resulting in lung function decline and death. Excess monocyte mobilization during the initial phase of an acute exacerbation, and their long-term persistence in the lung, is linked to poor disease outcome.

METHODS: The present work leverages a clinical idiopathic PF dataset and a murine model of acute inflammatory exacerbations triggered by mutation in the alveolar type-2 cell-restricted Surfactant Protein-C [SP-C] gene to spatially and phenotypically define monocyte/macrophage changes in the fibrosing lung.

RESULTS: SP-C mutation triggered heterogeneous CD68+ macrophage activation, with highly active peri-injured cells relative to those sampled from fully remodeled and healthy regions. Ingenuity pathway analysis of sorted CD11b-SigF+CD11c+ alveolar macrophages defined asynchronous activation of extracellular matrix re-organization, cellular mobilization, and Apolipoprotein E (Apoe) signaling in the fibrosing lung. Cell-cell communication analysis of single cell sequencing datasets predicted pro-fibrogenic signaling (fibronectin/Fn1, osteopontin/Spp1, and Tgfb1) emanating from Trem2/TREM2 + interstitial macrophages. These cells also produced a distinct lipid signature from alveolar macrophages and monocytes, characterized by Apoe expression. Mono- and di-allelic genetic deletion of ApoE in SP-C mutant mice had limited impact on inflammation and mortality up to 42 day after injury.

DISCUSSION: Together, these results provide a detailed spatio-temporal picture of resident, interstitial, and monocyte-derived macrophages during SP-C induced inflammatory exacerbations and end-stage clinical PF, and propose ApoE as a biomarker to identify activated macrophages involved in tissue remodeling.

PMID:39100672 | PMC:PMC11294112 | DOI:10.3389/fimmu.2024.1425466

Drug Dev Ind Pharm. 2024 Aug 5:1-23. doi: 10.1080/03639045.2024.2387166. Online ahead of print.

ABSTRACT

OBJECTIVE: The present study was aimed to develop a cationic lipoplex formulation loaded with Nintedanib and miR-29b (LP-NIN-miR) as an alternative approach in the combination therapy of Idiopathic Pulmonary Fibrosis (IPF) by proving its additive anti-fibrotic therapeutic effects through in vitro lung fibrosis model.Significance: This is the first research article reported that the LP-NIN-MIR formulations in the treatment of IPF.

METHODS: To optimize cationic liposomes, Quality by Design (QbD) approach was carried out. Optimized blank liposomes (LP) formulation was prepared with DOTAP, CHOL, DOPE and DSPE-mPEG 2000 at the molar ratio of 10:10:1:1. Nintedanib loaded liposomes (LP-NIN) were produced by microfluidization method and were incubated with miR-29b at room temperature for 30 minutes to obtain LP-NIN-miR. To evaluate the cellular uptake of LP-NIN-miR, NIH/3T3 cells were treated with 20 ng/ml Transforming Growth Factor β1 (TGF-β1) for 96h to establish the in vitro IPF model and incubated with LP-NIN-miR for 48h.

RESULTS: The hydrodynamic diameter, polydispersity index and zeta potential of the LP-NIN-miR were 87.3 ± 0.9 nm, 0.184 ± 0.003 and +24 ± 1 mV, respectively. The encapsulation efficiencies of Nintedanib and miR-29b were 99.8% ± 0.08% and 99.7% ± 1.2%, respectively. The results of the cytotoxicity study conducted with NIH/3T3 cells indicated that LP-NIN-miR is a safe delivery system.

CONCLUSIONS: The outcome of the transfection study proved the additive anti-fibrotic therapeutic effect of LP-NIN-miR and suggested that lipoplexes are effective delivery systems for drug and nucleic acid to the NIH/3T3 cells in the treatment of IPF.

PMID:39099436 | DOI:10.1080/03639045.2024.2387166

Zhongguo Zhong Yao Za Zhi. 2024 Jul;49(14):3878-3886. doi: 10.19540/j.cnki.cjcmm.20240321.701.

ABSTRACT

To investigate the mechanism by which Peitu Yifei Granules inhibit idiopathic pulmonary fibrosis(IPF) in rats, fifty specific-pathogen-free(SPF) grade male Wistar rats were randomly divided into blank group and modeling group. IPF was induced in the modeling group rats by tracheal infusion of 5 mg·kg~(-1) bleomycin(BLM) and then randomly divided into model group, pirfenidone group, and high-dose, medium-dose, and low-dose groups treated with Peitu Yifei Granules. After 24 hours of modeling, the treatment groups received intragastric administration of either Peitu Yifei Granules or pirfenidone as a positive control drug; meanwhile, the model group received an equal volume of normal saline. After 21 days of treatment administration, lung tissue samples were collected for analysis. Pathological changes in lung tissues were assessed using hematoxylin-eosin(HE) staining and Masson's trichrome staining. The expression levels of protein kinase B(Akt), mammalian target of rapamycin(mTOR), their phosphorylated forms, and sequestosome 1(p62) were determined through Western blot(WB). Fluorescent quantitative real-time polymerase chain reaction(RT-qPCR) was used to measure messenger ribonucleic acid(mRNA) expression levels of Beclin-1, microtubule-associated proteins 1A/1B light chain 3B(LC3B), and p62. Immunohistochemistry was performed to assess protein expression levels of Beclin-1 and LC3B in lung tissue samples. RESULTS:: demonstrated that lung tissue structure appeared normal without significant collagen deposition in the blank group rats. In contrast, rats from the model group exhibited thickened alveolar septa along with evident inflammatory changes and collagen deposition. Compared to the model group rats, those treated with Peitu Yifei Granules or pirfenidone showed significantly improved lung tissue structure with reduced inflammation and collagen deposition observed histologically. Furthermore, compared with those of the blank group, the expressions of p62 and its mRNA, p-Akt and p-mTOR protein in lung tissues of the model group were significantly increased, while Beclin-1, LC3B and their mRNA levels were significantly decreased. Compared with those of the model group, the expressions of p62 and its mRNA, p-Akt and p-mTOR in lung tissues of the pirfenidone group and Peitu Yifei Granules high-dose and medium-dose groups were significantly decreased, while Beclin-1, LC3B and their mRNA expressions were significantly increased. The above results indicate that Peitu Yifei Granules can improve autophagy levels in lung tissues by inhibiting the phosphoinositide 3-kinase(PI3K)/Akt/mTOR signaling pathway and delay the development of IPF disease.

PMID:39099361 | DOI:10.19540/j.cnki.cjcmm.20240321.701

EBioMedicine. 2024 Aug 3;106:105267. doi: 10.1016/j.ebiom.2024.105267. Online ahead of print.

ABSTRACT

BACKGROUND: Checkpoint inhibitor pneumonitis (CIP) is a potentially fatal adverse event characterized by new pulmonary infiltrates in cancer patients receiving immune checkpoint inhibitor therapy. This study aims to explore the interplay between lung microbiota, dysregulated metabolites, and host immunity in CIP.

METHODS: We recruited thirteen hospitalized CIP patients, eleven idiopathic pulmonary fibrosis (IPF) patients, and ten new-onset non-small cell lung cancer patients. Bronchoalveolar lavage fluid samples were collected for 16S rRNA gene sequencing. The percentages of immune cells were determined using manual counting and flow cytometry. Interactions among microbiota, metabolites, and lymphocytes were analyzed using cultured mouse splenocytes and human T cells.

FINDINGS: Proteobacteria emerged as the dominant phylum, notably abundant in both the CIP and IPF groups. Vibrio, Halomonas, Mangrovibacter, and Salinivibrio were the predominant microbiota because of their discriminative abundance patterns. Vibrio (r = 0.72, P-adj = 0.007) and Halomonas (r = 0.65, P-adj = 0.023) demonstrated strong correlations with lymphocytes. Vibrio metschnikovii and Mangrovibacter plantisponsors were more abundant in the CIP group than in the IPF group. Lauroylcarnitine, a key intermediary metabolite co-occurring with the predominant microbiota, exhibited a potent effect on cytokine secretion by mouse and human T cells, notably enhancing IFN-γ and TNF-α production from CD4 and CD8 cells in vitro.

INTERPRETATION: Lauroylcarnitine, co-occurring with the predominant lung microbiota in CIP, could activate T cells in vitro. These findings suggest potential involvement of lung microbiota and acylcarnitine metabolism dysregulation in the pathogenesis of CIP.

FUNDING: This work was supported by Peking University People's Hospital Scientific Research Development Funds (RDJ2022-15) and Provincial Key Clinical Specialty Capacity Building Project 2020 (Department of the Respiratory Medicine).

PMID:39098109 | DOI:10.1016/j.ebiom.2024.105267

Thorax. 2024 Aug 3:thorax-2024-221939. doi: 10.1136/thorax-2024-221939. Online ahead of print.

NO ABSTRACT

PMID:39097411 | DOI:10.1136/thorax-2024-221939

Cell Stem Cell. 2024 Jul 27:S1934-5909(24)00254-6. doi: 10.1016/j.stem.2024.07.004. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic disease. Recent studies have highlighted the persistence of an intermediate state of alveolar stem cells in IPF lungs. In this study, we discovered a close correlation between the distribution pattern of intermediate alveolar stem cells and the progression of fibrotic changes. We showed that amphiregulin (AREG) expression is significantly elevated in intermediate alveolar stem cells of mouse fibrotic lungs and IPF patients. High levels of serum AREG correlate significantly with profound deteriorations in lung function in IPF patients. We demonstrated that AREG in alveolar stem cells is both required and sufficient for activating EGFR in fibroblasts, thereby driving lung fibrosis. Moreover, pharmacological inhibition of AREG using a neutralizing antibody effectively blocked the initiation and progression of lung fibrosis in mice. Our study underscores the therapeutic potential of anti-AREG antibodies in attenuating IPF progression, offering a promising strategy for treating fibrotic diseases.

PMID:39096904 | DOI:10.1016/j.stem.2024.07.004

Redox Biol. 2024 Jul 29;75:103294. doi: 10.1016/j.redox.2024.103294. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a serious interstitial lung disease. However, the definitive diagnosis of IPF is impeded by the limited capabilities of current diagnostic methods, which may fail to capture the optimal timing for treatment. The main goal of this study is to determine the feasibility of a nitroreductase (NTR) responsive probe, 18F-NCRP, for early detection and deterioration monitoring of IPF. 18F-NCRP was obtained with high radiochemical purity (>95 %). BLM-injured mice were established by intratracheal instillation with bleomycin (BLM) and characterized through histological analysis. Longitudinal PET/CT imaging, biodistribution study and in vitro autoradiography were performed. The correlations between the uptake of 18F-NCRP and mean lung density (tested by CT), as well as histopathological characteristics were analyzed. In PET imaging study, 18F-NCRP exhibited promising efficacy in monitoring the progression of IPF, which was earlier than CT. The ratio of uptake in BLM-injured lung to control lung increased from 1.4-fold on D15 to 2.2-fold on D22. Biodistribution data showed a significant lung uptake of 18F-NCRP in BLM-injured mice. There was a strong positive correlation between the 18F-NCRP uptake in the BLM-injured lungs and the histopathological characteristics. Given that, 18F-NCRP PET imaging of NTR, a promising biomarker for investigating the underlying pathogenic mechanism of IPF, is attainable as well as desirable, which might lay the foundation for establishing an NTR-targeted imaging evaluation system of IPF.

PMID:39096854 | DOI:10.1016/j.redox.2024.103294

Biomed Pharmacother. 2024 Aug 2;178:117246. doi: 10.1016/j.biopha.2024.117246. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis is a progressive lung disease characterized by excessive extracellular matrix accumulation and myofibroblast proliferation with limited treatment options available. M2 macrophages are pivotal in pulmonary fibrosis, where they induce the epithelial-to-mesenchymal and fibroblast-to-myofibroblast transitions. In this study, we evaluated whether MEL-dKLA, a hybrid peptide that can eliminate M2 macrophages, could attenuate pulmonary fibrosis in a cell co-culture system and in a bleomycin-induced mouse model. Our findings demonstrated that the removal of M2 macrophages using MEL-dKLA stimulated reprogramming to an antifibrotic environment, which effectively suppressed epithelial-to-mesenchymal and fibroblast-to-myofibroblast transition responses in lung epithelial and fibroblast cells and reduced extracellular matrix accumulation both in vivo and in vitro. Moreover, MEL-dKLA exhibited antifibrotic efficacy without damaging tissue-resident macrophages in the bleomycin-induced mouse model. Collectively, our findings suggest that MEL-dKLA may be a new therapeutic option for the treatment of idiopathic pulmonary fibrosis.

PMID:39096617 | DOI:10.1016/j.biopha.2024.117246

Phytomedicine. 2024 Jul 27;133:155882. doi: 10.1016/j.phymed.2024.155882. Online ahead of print.

ABSTRACT

BACKGROUND: Treating Idiopathic pulmonary fibrosis (IPF) remains challenging owing to its relentless progression, grim prognosis, and the scarcity of effective treatment options. Emerging evidence strongly supports the critical role of accelerated senescence in alveolar epithelial cells (AECs) in driving the progression of IPF. Consequently, targeting senescent AECs emerges as a promising therapeutic strategy for IPF.

PURPOSE: Curcumin analogue EF24 is a derivative of curcumin and shows heightened bioactivity encompassing anti-inflammatory, anti-tumor and anti-aging properties. The objective of this study was to elucidate the therapeutic potential and underlying molecular mechanisms of EF24 in the treatment of IPF.

METHODS: A549 and ATII cells were induced to become senescent using bleomycin. Senescence markers were examined using different methods including senescence-associated β-galactosidase (SA-β-gal) staining, western blotting, and q-PCR. Mice were intratracheally administrated with bleomycin to induce pulmonary fibrosis. This was validated by micro-computed tomography (CT), masson trichrome staining, and transmission electron microscope (TEM). The role and underlying mechanisms of EF24 in IPF were determined in vitro and in vivo by evaluating the expressions of PTEN, AKT/mTOR/NF-κB signaling pathway, and mitophagy using western blotting or flow cytometry.

RESULTS: We identified that the curcumin analogue EF24 was the most promising candidate among 12 compounds against IPF. EF24 treatment significantly reduced senescence biomarkers in bleomycin-induced senescent AECs, including SA-β-Gal, PAI-1, P21, and the senescence-associated secretory phenotype (SASP). EF24 also effectively inhibited fibroblast activation which was induced by senescent AECs or TGF-β. We revealed that PTEN activation was integral for EF24 to inhibit AECs senescence by suppressing the AKT/mTOR/NF-κB signaling pathway. Additionally, EF24 improved mitochondrial dysfunction through induction of mitophagy. Furthermore, EF24 administration significantly reduced the senescent phenotype induced by bleomycin in the lung tissues of mice. Notably, EF24 mitigates fibrosis and promotes overall health benefits in both the acute and chronic phases of IPF, suggesting its therapeutic potential in IPF treatment.

CONCLUSION: These findings collectively highlight EF24 as a new and effective therapeutic agent against IPF by inhibiting senescence in AECs.

PMID:39096545 | DOI:10.1016/j.phymed.2024.155882

Lipids Health Dis. 2024 Aug 1;23(1):237. doi: 10.1186/s12944-024-02218-6.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a respiratory disorder of obscure etiology and limited treatment options, possibly linked to dysregulation in lipid metabolism. While several observational studies suggest that lipid-lowering agents may decrease the risk of IPF, the evidence is inconsistent. The present Mendelian randomization (MR) study aims to determine the association between circulating lipid traits and IPF and to assess the potential influence of lipid-modifying medications for IPF.

METHODS: Summary statistics of 5 lipid traits (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, apolipoprotein A, and apolipoprotein B) and IPF were sourced from the UK Biobank and FinnGen Project Round 10. The study's focus on lipid-regulatory genes encompassed PCSK9, NPC1L1, ABCG5, ABCG8, HMGCR, APOB, LDLR, CETP, ANGPTL3, APOC3, LPL, and PPARA. The primary effect estimates were determined using the inverse-variance-weighted method, with additional analyses employing the contamination mixture method, robust adjusted profile score, the weighted median, weighted mode methods, and MR-Egger. Summary-data-based Mendelian randomization (SMR) was used to confirm significant lipid-modifying drug targets, leveraging data on expressed quantitative trait loci in relevant tissues. Sensitivity analyses included assessments of heterogeneity, horizontal pleiotropy, and leave-one-out methods.

RESULTS: There was no significant effect of blood lipid traits on IPF risk (all P＞0.05). Drug-target MR analysis indicated that genetic mimicry for inhibitor of NPC1L1, PCSK9, ABCG5, ABCG8, and APOC3 were associated with increased IPF risks, with odds ratios (ORs) and 95% confidence intervals (CIs) as follows: 2.74 (1.05-7.12, P = 0.039), 1.36 (1.02-1.82, P = 0.037), 1.66 (1.12-2.45, P = 0.011), 1.68 (1.14-2.48, P = 0.009), and 1.42 (1.20-1.67, P = 3.17×10-5), respectively. The SMR method identified a significant association between PCSK9 gene expression in whole blood and reduced IPF risk (OR = 0.71, 95% CI: 0.50-0.99, P = 0.043). Sensitivity analyses showed no evidence of bias.

CONCLUSIONS: Serum lipid traits did not significantly affect the risk of idiopathic pulmonary fibrosis. Drug targets MR studies examining 12 lipid-modifying drugs indicated that PCSK9 inhibitors could dramatically increase IPF risk, a mechanism that may differ from their lipid-lowering actions and thus warrants further investigation.

PMID:39090671 | DOI:10.1186/s12944-024-02218-6

Heart Lung. 2024 Jul 31;68:242-253. doi: 10.1016/j.hrtlng.2024.07.010. Online ahead of print.

ABSTRACT

BACKGROUND: Anti-fibrotics can reduce restrictive impairment in idiopathic pulmonary fibrosis (IPF). However, its effectiveness in non-IPF progressive fibrosing interstitial lung disease (non-IPF PF-ILD) remains uncertain.

OBJECTIVE: We assess the efficacy and safety of anti-fibrotics pirfenidone and nintedanib versus placebo among non-IPF PF-ILD adult patients.

METHODS: Meta-analysis was performed using PubMed, SCOPUS, and Cochrane databases to identify randomized controlled trials (RCTs). At respective centers, non-IPF PF-ILD was defined as clinical and radiological findings inconsistent with IPF and greater than 5 % forced vital capacity (FVC) decline, worsening radiological fibrosis or respiratory symptoms.

RESULTS: Among seven RCTs involving 1,816 non-IPF PF-ILD patients, anti-fibrotics significantly reduced decline in FVC from baseline in milliliters (MD -66.80milliliters; P < 0.01) and percent predicted (MD -1.80 %; P < 0.01) compared to placebo. However, severity of FVC decline was less than 10 % (P = 0.33) in both groups. No significant difference in the decline of 6MWD from baseline in meters (P = 0.19) while on anti-fibrotics, although those on pirfenidone had less decline in 6MWD (MD -25.12 m; P < 0.01) versus placebo. The rates of all-cause mortality (P = 0.34), all-cause hospitalization (P = 0.44), and hospitalization for respiratory etiology (P = 0.06) were comparable in both groups. Adverse events of nausea/vomiting (54.2 % vs. 20.3 %; P < 0.01), diarrhea (65.2 % vs. 27.6 %; P = 0.02), anorexia/weight loss (23.0 % vs. 7.7 %; P < 0.01), neurological disorders (20.8 % vs. 12.6 %; P < 0.01), and events requiring therapy discontinuation were higher (18.4 % vs. 9.9 %; P < 0.01) in the anti-fibrotic group. Other adverse events of skin (P = 0.18) and respiratory disorders (P = 0.20) were equal.

CONCLUSION: The advent of anti-fibrotics offers alternative treatment to reduce lung function decline.

PMID:39089077 | DOI:10.1016/j.hrtlng.2024.07.010

Mol Immunol. 2024 Jul 31;173:99. doi: 10.1016/j.molimm.2024.07.013. Online ahead of print.

NO ABSTRACT

PMID:39088936 | DOI:10.1016/j.molimm.2024.07.013

Respir Res. 2024 Jul 31;25(1):293. doi: 10.1186/s12931-024-02922-y.

ABSTRACT

BACKGROUND AND OBJECTIVE: Pooled analyses of previous randomized controlled trials reported that antifibrotics improved survival in patients with idiopathic pulmonary fibrosis (IPF), but the results were only based on short-term outcome data from selected patients who met strict criteria. Observational studies/meta-analyses also suggested that antifibrotics improve survival, but these studies failed to control for immortal time bias that considerably exaggerates drug effects. Therefore, whether antifibrotics truly improve long-term survival in patients with IPF in the real world remains undetermined and requires external validity.

METHODS: We used data from the Japanese National Claims Database to estimate the intention-to-treat effect of antifibrotics on mortality. To address immortal time bias, we employed models treating antifibrotic initiation as a time-dependent covariate and target trial emulation (TTE), both incorporating new-user designs for antifibrotics and treating lung transplantation as a competing event.

RESULTS: Of 30,154 patients with IPF, 14,525 received antifibrotics. Multivariate Fine-Gray models with antifibrotic initiation as a time-dependent covariate revealed that compared with no treatment, nintedanib (adjusted hazard ratio [aHR], 0.85; 95% confidence interval [CI], 0.81-0.89) and pirfenidone (aHR, 0.89; 95% CI, 0.86-0.93) were associated with reduced mortality. The TTE model also replicated the associations of nintedanib (aHR, 0.69; 95% CI, 0.65-0.74) and pirfenidone (aHR, 0.81; 95% CI, 0.78-0.85) with reduced mortality. Subgroup analyses confirmed this association regardless of age, sex, and comorbidities, excluding certain subpopulations.

CONCLUSIONS: The results of this large-scale real-world analysis support the generalizability of the association between antifibrotics and improved survival in various IPF populations.

PMID:39085869 | DOI:10.1186/s12931-024-02922-y

BMC Pulm Med. 2024 Jul 31;24(1):373. doi: 10.1186/s12890-024-03188-2.

ABSTRACT

BACKGROUND: The six-minute walk test (6MWT) is widely used to assess functional capacity and prognosis in patients with idiopathic pulmonary fibrosis (IPF). However, studies on oxygen saturation recovery after the 6MWT in patients with IPF are rare. In our study, we investigated the relationship between oxygen saturation recovery time and dyspnea, fatigue, quality of life, prognostic markers and pulmonary hypertension (PH).

METHODS: In this cross-sectional study, IPF patients diagnosed according to current guidelines and followed up in our Interstitial Lung Disease Outpatient Clinic between 2021 and 2022 were included. Demographics, data from spirometry, diffusion capacity measurement, arterial blood gas analysis, transthoracic echocardiography and the 6MWT were recorded. The oxygen saturation recovery time, distance saturation product (DSP), gender-age-physiology (GAP) index and composite physiological index (CPI) scores were calculated. Dyspnea severity was assessed by the modified Medical Research Council (mMRC) and Dyspnoea-12 (D-12) scales, fatigue severity by the Multidimensional Fatigue Inventory (MFI-20) and quality of life by the St George's Respiratory Questionnaire (SGRQ).

RESULTS: Fifty IPF patients (34 men, 16 women, age: 66.8 ± 7.3 years) were included in the study. The mean FVC was 77.8 ± 19.3%, the DLCO was 52.9 ± 17.1%, the 6-minute walk distance (6MWD) was 385.7 ± 90.6 m, the GAP index was 3.5 ± 1.5, and the CPI was 43.7 ± 14.1. Oxygen saturation after the 6MWT reached pretest values at an average of 135.6 ± 73.5 s. The oxygen saturation recovery time was longer in patients with higher GAP index scores (Rs = 0.870, p < 0.001), CPI scores (Rs = 0.906, p < 0.001), desaturation (Rs = 0.801, p < 0.001), FVC%/DLCO% (Rs = 0.432, p = 0.002), sPAP (Rs = 0.492, p = 0.001), TRV (Rs = 0.504, p = 0.001), mMRC (Rs = 0.913, p < 0.001), MFI-20 (Rs = 0.944, p < 0.001), D-12 scale (Rs = 0.915, p < 0.001) and SGRQ scores (Rs = 0.927, p < 0.001); lower FVC (%) (Rs=-0.627, p < 0.001), DLCO (%) (Rs=-0.892, p < 0.001), PaO2 (Rs=-0.779, p < 0.001), DSP (Rs=-0.835, p < 0.001), and 6MWD (Rs=-0.763, p < 0.001). A total of twenty patients (40%) exhibited an increased risk of PH. According to our multiple regression analysis, oxygen saturation recovery time was independently associated with the GAP index (p = 0.036), the lowest oxygen saturation occurring during the 6MWT (p = 0.011) and the SGRQ score (p < 0.001).

CONCLUSIONS: Our results showed that oxygen saturation recovery time is associated with dyspnea, fatigue, quality of life, increased risk of PH and prognostic markers in IPF. Therefore, we recommend continuous measurement of oxygen saturation after 6MWT until pretest values are reached.

PMID:39085811 | DOI:10.1186/s12890-024-03188-2

BMC Pulm Med. 2024 Jul 30;24(1):367. doi: 10.1186/s12890-024-03092-9.

ABSTRACT

PURPOSE: The extent of honeycombing and reticulation predict the clinical prognosis of IPF. Emphysema, consolidation, and ground glass opacity are visible in HRCT scans. To date, there have been few comprehensive studies that have used these parameters. We conducted automated quantitative analysis to identify predictive parameters for clinical outcomes and then grouped the subjects accordingly.

METHODS: CT images were obtained while patients held their breath at full inspiration. Parameters were analyzed using an automated lung texture quantification system. Cluster analysis was conducted on 159 IPF patients and clinical profiles were compared between clusters in terms of survival.

RESULTS: Kaplan-Meier analysis revealed that survival rates declined as fibrosis, reticulation, honeycombing, consolidation, and emphysema scores increased. Cox regression analysis revealed that reticulation had the most significant impact on survival rate, followed by honeycombing, consolidation, and emphysema scores. Hierarchical and K-means cluster analyses revealed 3 clusters. Cluster 1 (n = 126) with the lowest values for all parameters had the longest survival duration, and relatively-well preserved FVC and DLCO. Cluster 2 (n = 15) with high reticulation and consolidation scores had the lowest FVC and DLCO values with a predominance of female, while cluster 3 (n = 18) with high honeycombing and emphysema scores predominantly consisted of male smokers. Kaplan-Meier analysis revealed that cluster 2 had the lowest survival rate, followed by cluster 3 and cluster 1.

CONCLUSION: Automated quantitative CT analysis provides valuable information for predicting clinical outcomes, and clustering based on these parameters may help identify the high-risk group for management.

PMID:39080584 | DOI:10.1186/s12890-024-03092-9