Lancet Respir Med. 2023 Nov;11(11):953-955. doi: 10.1016/S2213-2600(23)00325-9.

NO ABSTRACT

PMID:37914467 | DOI:10.1016/S2213-2600(23)00325-9

Sci Rep. 2023 Oct 30;13(1):18637. doi: 10.1038/s41598-023-45305-x.

ABSTRACT

Lung fibrosis (LF) is a chronic progressive, incurable, and debilitating condition of the lung, which is associated with different lung disease. Treatment options are still sparse. Nintedanib, an oral tyrosine kinase inhibitor, significantly slows the LF progression. However, there is a strong need of further research and the development of novel therapies. In this study, we used a correlative set-up that combines X-ray based lung function (XLF) with microCT and whole body plethysmography (WBP) for a comprehensive functional and structural evaluation of lung fibrosis (LF) as well as for monitoring response to orally administered Nintedanib in the mouse model of bleomycin induced LF. The decline in lung function as early as one week after intratracheal bleomycin instillation was reliably detected by XLF, revealing the lowest decay rate in the LF mice compared to healthy ones. Simultaneously performed microCT and WBP measurements corroborated XLF findings by exhibiting reduced lung volume [Formula: see text] and tidal volume [Formula: see text]. In LF mice XLF also revealed profound improvement in lung function one week after Nintedanib treatment. This positive response to Nintedanib therapy was further substantiated by microCT and WBP measurements which also showed significantly improved [Formula: see text] and [Formula: see text] in the Nintedanib treated mice. By comparing the XLF data to structural features assessing the extent of fibrosis obtained by ex-vivo high-resolution synchrotron radiation-based imaging and classical histology we demonstrate that: (1) a simple low dose x-ray measurement like XLF is sensitive enough to pick up treatment response, (2) Nintedanib treatment successfully improved lung function in a bleomycin induced LF mouse model and (3) differences between the fully restored lung function and the partially reduced fibrotic burden compared to healthy and untreated mice. The presented analysis pipeline underlines the importance of a combined functional and anatomical readout to reliably measure treatment response and could easily be adapted to other preclinical lung disease models.

PMID:37903864 | PMC:PMC10616088 | DOI:10.1038/s41598-023-45305-x

IET Syst Biol. 2023 Oct 31. doi: 10.1049/syb2.12081. Online ahead of print.

ABSTRACT

With increasing research on idiopathic pulmonary fibrosis (IPF) and gastroesophageal reflux disease (GERD), more and more studies have indicated that GERD is associated with IPF, but the underlying pathological mechanisms remain unclear. The aim of the present study is to identify and analyse the differentially expressed genes (DEGs) between IPF and GERD and explore the relevant molecular mechanisms via bioinformatics analysis. Four GEO datasets (GSE24206, GSE53845, GSE26886, and GSE39491) were downloaded from the GEO database, and DEGs between IPF and GERD were identified with the online tool GEO2R. Subsequently, a series of bioinformatics analyses are conducted, including Kyoto Encyclopaedia of Genes and Genomes (KEGG) and gene ontology (GO) enrichment analyses, the PPI network, biological characteristics, TF-gene interactions, TF-miRNA coregulatory networks, and the prediction of drug molecules. Totally, 71 genes were identified as DEGs in IPF and GERD. Five KEGG pathways, including Amoebiasis, Protein digestion and absorption, Relaxin signalling pathway, AGE-RAGE signalling pathway in diabetic complications, and Drug metabolism - cytochrome P450, were significantly enriched. In addition, eight hub genes, including POSTN, MMP1, COL3A1, COL1A2, CXCL12, TIMP3, VCAM1, and COL1A1 were selected from the PPI network by Cytoscape software. Then, five hub genes (MMP1, POSTN, COL3A1, COL1A2, and COL1A1) with high diagnostic values for IPF and GERD were validated by GEO datasets. Finally, TF-gene and miRNA interaction was identified with hub genes and predicted drug molecules for the IPF and GERD. And the results suggest that cetirizine, luteolin, and pempidine may have great potential therapeutic value in IPF and GERD. This study will provide novel strategies for the identification of potential biomarkers and valuable therapeutic targets for IPF and GERD.

PMID:37907428 | DOI:10.1049/syb2.12081

Respirology. 2023 Oct 31. doi: 10.1111/resp.14614. Online ahead of print.

NO ABSTRACT

PMID:37905590 | DOI:10.1111/resp.14614

Cardiol Young. 2023 Oct 31:1-3. doi: 10.1017/S1047951123003359. Online ahead of print.

ABSTRACT

In utero idiopathic constriction of the arterial duct is a rare condition with only a handful reported cases. Ductal aneurysms with thrombus formations on the other hand are significantly more common. We report a case of a term infant who presented with right heart failure due to premature ductal closure and postnatal severe respiratory distress. Subsequent diagnostics revealed paresis of left laryngeal nerve and obstruction of the left pulmonary artery secondary to a ductal aneurysm. Consequently, surgical intervention was considered necessary. Post-operatively, right ventricular function and hoarseness resolved slowly.

PMID:37905342 | DOI:10.1017/S1047951123003359

Front Med (Lausanne). 2023 Oct 12;10:1246767. doi: 10.3389/fmed.2023.1246767. eCollection 2023.

ABSTRACT

BACKGROUND: Usual interstitial pneumonia (UIP) is a pattern of interstitial pneumonia that is caused by different etiologies. This study aimed to investigate the transplant-free survival (TFS) and the decline in forced vital capacity (FVC) of the patients with UIP and probable UIP patterns on CT caused by various underlying conditions.

METHODS: A retrospective cohort study was conducted, enrolling patients with interstitial lung disease exhibiting a CT pattern consistent with UIP or probable UIP. Clinical and prognostic data of patients categorized by the etiology were compared.

RESULTS: A total of 591 patients were included and classified into the following groups: idiopathic pulmonary fibrosis (IPF) (n = 320), connective tissue disease (CTD)-UIP (n = 229), asbestosis-UIP (n = 28), and hypersensitivity pneumonitis (HP)-UIP (n = 14). Advanced age, elevated levels of serum cytokeratin fraction 21-1 and percentage of neutrophils in bronchoalveolar lavage were observed in all groups. IPF patients showed a more rapid decline in FVC (133.9 mL/year) compared to CTD-UIP (24.5 mL/year, p = 0.001) and asbestosis-UIP (61.0 mL/year, p = 0.008) respectively. Sub-analysis of CTD-UIP revealed that patients with rheumatoid arthritis (RA)-UIP (88.1 mL/year) or antineutrophil cytoplasmic antibody-associated vasculitis (AAV)-UIP (72.9 mL/year) experienced a faster deterioration in FVC compared to those with primary Sjögren's syndrome (pSS)-UIP (25.9 mL/year, p < 0.05). Kaplan-Meier curves showed that IPF had the poorest TFS (median 55.9 months), followed by HP-UIP (57.5 months), CTD-UIP (66.7 months), and asbestosis-UIP (TFS not reached). RA-UIP or AAV-UIP did not exhibit any prognostic advantages compared to IPF, while asbestosis-UIP and pSS-UIP showed better survival rates.

CONCLUSION: Patients with UIP caused by different underlying conditions share certain common features, but the trajectories of disease progression and survival outcomes differ.

PMID:37901393 | PMC:PMC10601466 | DOI:10.3389/fmed.2023.1246767

Respir Res. 2023 Oct 28;24(1):259. doi: 10.1186/s12931-023-02577-1.

ABSTRACT

INTRODUCTION: The diaphragm function assessed by ultrasound has been well-studied in COPD, asthma, and intensive care. However, there are only a few studies on diffuse interstitial lung disease, while dyspnea and quality of life are major issues in the management that may depend on the diaphragm.

METHODS: We retrospectively included idiopathic pulmonary fibrosis (IPF) patients followed in our center (Marseille, France) between January 2020 and February 2023 who underwent diaphragmatic ultrasound. Our objectives were to describe the diaphragmatic function of IPFs compared to healthy controls and to correlate with clinical, functional, and lung density on CT-scan.

RESULTS: 24 IPF patients and 157 controls were included. The diaphragmatic amplitude in IPF was increased at rest (median of 2.20 cm vs 1.88 cm on the right, p < 0.007, and 2.30 cm vs 1.91 cm on the left, p < 0.03, in IPF and controls respectively) and decreased in deep breathing (median of 4.85 cm vs 5.45 cm on the right, p < 0.009, and 5.10 cm vs 5.65 cm on the left, p < 0.046, in IPF and controls respectively). Diaphragmatic thickness was significantly reduced at rest on the right side (median of 1.75 mm vs 2.00 mm, p < 0.02, in IPF and controls respectively) and in deep breathing on both sides compared to controls (mean of 3.82 mm vs 4.15 mm on the right, p < 0.02, and 3.53 mm vs 3.94 mm, on the left, p < 0.009, in IPF and controls respectively). Diaphragmatic amplitude in deep breathing was moderate to strongly correlated with FVC, DLCO, and 6MWT and negatively correlated with the dyspnea and lung density on CT scan.

CONCLUSION: The diaphragmatic amplitude and thickness were impaired in IPF compared to controls. Diaphragmatic amplitude is the parameter best correlated with clinical, functional, and lung density criteria. Further studies are needed to determine if diaphragmatic amplitude can be a prognostic factor in IPF.

PMID:37898765 | DOI:10.1186/s12931-023-02577-1

Pharmaceuticals (Basel). 2023 Oct 9;16(10):1434. doi: 10.3390/ph16101434.

ABSTRACT

AIM: Idiopathic pulmonary fibrosis (IPF) is associated with a poor prognosis, presenting the most aggressive form of interstitial lung diseases (ILDs). Activated fibroblasts are crucial for pathological processes. Fibroblast activation protein (FAP) inhibitor (FAPI) tracers would be promising imaging agents for these diseases. The purpose of this study was to evaluate a 99mTc-labeled FAPI tracer, 99mTc-HFAPI imaging in IPF patients.

METHODS: Eleven IPF patients (nine males and two females; age range 55-75 year) were included in this pilot study. 99mTc-HFAPI serial whole-body scintigraphy at 5 min, 20 min, 40 min, 1 h, 2 h, 3 h, 4 h, and 6 h was acquired for dynamic biodistribution and dosimetry estimation in seven representative patients. SPECT/CT tomography fusion imaging of the chest region was performed in all patients at 4 h post-injection, which was considered as the optimal acquisition time. Dosimetry was calculated using OLINDA/EXM software (version 2.0; HERMES Medical Solutions). The quantified or semi-quantified standardized uptake values (SUVs) and lesion-to-background ratios (LBRs) of affected lung parenchyma were also calculated. The high-resolution CT (HRCT) stage was determined with visual evaluation, and the total HRCT score of each patient was measured using a weighting factor formula. Pulmonary function tests (PFTs) were recorded as well. Then, the relationships between the 99mTc-HFAPI results, disease extent on HRCT, and PFT results were investigated.

RESULTS: Normal physiological uptake of 99mTc-HFAPI was observed mainly in the liver, intestinal tract, pancreas, gallbladder, and to a lesser extent in the spleen, kidneys, and thyroid, with no apparent retention in the blood circulation at the late time point. The mean injected activity of 99mTc-HFAPI was 813.4 MBq (range 695.6-888.0 MBq). No subjective side effects were noticed. The average whole-body effective dose was 0.0041 mSv/MBq per patient. IPF patients exhibited elevated pulmonary 99mTc-HFAPI uptake in abnormal lung regions, which was correlated with fibrotic regions on HRCT. Among different HRCT stage groups, both SUVmax and LBR showed significant differences (p < 0.001). The higher HRCT stage demonstrated significantly higher SUVmax and LBR. A linear correlation between 99mTc-HFAPI uptake and total HRCT score was observed for SUVmax (r = 0.7839, F = 54.41, p = 0.0094) and LBR (r = 0.7402, F = 56.33, p = 0.0092). 99mTc-HFAPI uptake also had moderate correlations with PFT results.

CONCLUSIONS: Our preliminary data show that the 99mTc-HFAPI SPECT imaging is a promising new imaging modality in IPF patients. Investigations of its clinical value in monitoring disease progression and treatment response are needed in the future.

PMID:37895905 | DOI:10.3390/ph16101434

Int J Mol Sci. 2023 Oct 12;24(20):15104. doi: 10.3390/ijms242015104.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is the most common and lethal form of the interstitial pneumonias. The cause of the disease is unknown, and new therapies that stop or reverse disease progression are desperately needed. Recent advances in next-generation sequencing have led to an abundance of freely available, clinically relevant, organ-and-disease-specific, single-cell transcriptomic data, including studies from patients with IPF. We mined data from published IPF data sets and identified gene signatures delineating pro-fibrotic or antifibrotic macrophages and then used the Enrichr platform to identify compounds with the potential to drive the macrophages toward the antifibrotic transcriptotype. We then began testing these compounds in a novel in vitro phenotypic drug screening assay utilising human lung macrophages recovered from whole-lung lavage of patients with silicosis. As predicted by the Enrichr tool, glitazones potently modulated macrophage gene expression towards the antifibrotic phenotype. Next, we assayed a subset of the NatureBank pure compound library and identified the cyclobutane lignan, endiandrin A, which was isolated from the roots of the endemic Australian rainforest plant, Endiandra anthropophagorum, with a similar antifibrotic potential to the glitazones. These methods open new avenues of exploration to find treatments for lung fibrosis.

PMID:37894784 | DOI:10.3390/ijms242015104

Biomedicines. 2023 Oct 16;11(10):2796. doi: 10.3390/biomedicines11102796.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) represents a chronic progressive fibrotic interstitial lung disease of unknown cause with an ominous prognosis. It remains an unprecedent clinical challenge due to its delayed diagnosis and unpredictable clinical course. The need for accurate diagnostic, prognostic and predisposition biomarkers in everyday clinical practice becomes more necessary than ever to ensure prompt diagnoses and early treatment. The identification of such blood biomarkers may also unravel novel drug targets against IPF development and progression. So far, the role of diverse blood biomarkers, implicated in various pathogenetic pathways, such as in fibrogenesis (S100A4), extracellular matrix remodelling (YKL-40, MMP-7, ICAM-1, LOXL2, periostin), chemotaxis (CCL-18, IL-8), epithelial cell injury (KL-6, SP-A, SP-D), autophagy and unfolded protein response has been investigated in IPF with various results. Moreover, the recent progress in genetics in IPF allows for a better understanding of the underlying disease mechanisms. So far, the causative mutations in pulmonary fibrosis include mutations in telomere-related genes and in surfactant-related genes, markers that could act as predisposition biomarkers in IPF. The aim of this review is to provide a comprehensive overview from the bench to bedside of current knowledge and recent insights on biomarkers in IPF, and to suggest future directions for research. Large-scale studies are still needed to confirm the exact role of these biomarkers.

PMID:37893169 | DOI:10.3390/biomedicines11102796

Nutrients. 2023 Oct 22;15(20):4473. doi: 10.3390/nu15204473.

ABSTRACT

BACKGROUND: The value of the phase angle (PhA), measured via bioelectrical impedance analysis (BIA), could be considered a good marker of the cell mass and the cell damage of a patient; however, there are new techniques, such as muscle ultrasonography, that allow the quantity and quality of muscle to be assessed in a minimally invasive way. The aim of this study is to determine the prognostic value of morphofunctional techniques in the prognosis of mortality in patients with idiopathic pulmonary fibrosis (IPF).

METHODS: This multicenter, cross-sectional study included 86 patients with idiopathic pulmonary fibrosis with a mean age of 71 years, 82.7% of whom were male. The nutritional risk of the patients was assessed by means of questionnaires, such as the Subjective Global Assessment (SGA), and non-invasive functional techniques, including BIA, nutritional ultrasound, and hand grip strength (HGS). Statistical analysis of the sample was performed using JAMOVI version 2.3.22.

RESULTS: Correlations were made between the RF-CSA techniques with PhA (r = 0.48, p < 0.001), BCM (r = 0.70, p < 0.001), SMI (r = 0.64, p < 0.001), and HGS (r = 0.54, p < 0.001). The cut-off points for 12-month mortality were PhA = 4.5° (AUC = 0.722, sensitivity of 72.7% and specificity of 66.6%), BCM = 28.8 kg (AUC = 0.609, sensitivity of 32.4% and specificity of 100.0%), RF-CSA = 3.00 cm2 (AUC = 0.857, sensitivity of 64.4% and specificity of 100.0%), 6MMW = 420 m (AUC = 0.830, sensitivity of 63.27% and specificity of 100.0%), and TUG = 7.2 s (AUC = 0.771, sensitivity of 100.0% and specificity of 56.67%). In addition, a multivariate analysis was performed with RF-CSA, HR = 8.11 (1.39-47.16, p = 0.020), and PhA of 6.35 (1.29-31.15, p = 0.023), taking into account age, sex, and BMI to determine mortality. Finally, a Kaplan-Meier survival analysis was conducted with low or normal values for classical parameters (GAP and T6MM) and new parameters (PhA, BCM, RF-CSA, and TUG).

CONCLUSION: RF-CSA and PhA were shown to be good prognostic markers of 12-month mortality and could, therefore, be useful screening tools to complement the nutritional assessment of IPF patients.

PMID:37892547 | DOI:10.3390/nu15204473

Metabolites. 2023 Oct 10;13(10):1069. doi: 10.3390/metabo13101069.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive condition characterized by the impairment of alveolar epithelial cells. Despite continued research efforts, the effective therapeutic medication is still absent due to an incomplete understanding of the underlying etiology. It has been shown that rhythmic alterations are of significant importance in the pathophysiology of IPF. However, a comprehensive understanding of how metabolite level changes with circadian rhythms in individuals with IPF is lacking. Here, we constructed an extensive metabolite database by utilizing an unbiased reference system culturing with 13C or 15N labeled nutrients. Using LC-MS analysis via ESI and APCI ion sources, 1300 potential water-soluble metabolites were characterized and applied to evaluate the metabolic changes with rhythm in the lung from both wild-type mice and mice with IPF. The metabolites, such as glycerophospholipids and amino acids, in WT mice exhibited notable rhythmic oscillations. The concentrations of phospholipids reached the highest during the fast state, while those of amino acids reached their peak during fed state. Similar diurnal variations in the metabolite rhythm of amino acids and phospholipids were also observed in IPF mice. Although the rhythmic oscillation of metabolites in the urea cycle remained unchanged, there was a significant up-regulation in their levels in the lungs of IPF mice. 15N-ammonia in vivo isotope tracing further showed an increase in urea cycle activity in the lungs of mice with IPF, which may compensate for the reduced efficiency of the hepatic urea cycle. In sum, our metabolomics database and method provide evidence of the periodic changes in lung metabolites, thereby offering valuable insights to advance our understanding of metabolic reprogramming in the context of IPF.

PMID:37887394 | DOI:10.3390/metabo13101069

Cells. 2023 Oct 21;12(20):2501. doi: 10.3390/cells12202501.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a pathological condition wherein lung injury precipitates the deposition of scar tissue, ultimately leading to a decline in pulmonary function. Existing research indicates a notable exacerbation in the clinical prognosis of IPF patients following infection with COVID-19. This investigation employed bulk RNA-sequencing methodologies to describe the transcriptomic profiles of small airway cell cultures derived from IPF and post-COVID fibrosis patients. Differential gene expression analysis unveiled heightened activation of pathways associated with microtubule assembly and interferon signaling in IPF cell cultures. Conversely, post-COVID fibrosis cell cultures exhibited distinctive characteristics, including the upregulation of pathways linked to extracellular matrix remodeling, immune system response, and TGF-β1 signaling. Notably, BMP signaling levels were elevated in cell cultures derived from IPF patients compared to non-IPF control and post-COVID fibrosis samples. These findings underscore the molecular distinctions between IPF and post-COVID fibrosis, particularly in the context of signaling pathways associated with each condition. A better understanding of the underlying molecular mechanisms holds the promise of identifying potential therapeutic targets for future interventions in these diseases.

PMID:37887346 | DOI:10.3390/cells12202501

Adv Respir Med. 2023 Oct 12;91(5):407-431. doi: 10.3390/arm91050032.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible disease with a high mortality rate worldwide. However, the etiology and pathogenesis of IPF have not yet been fully described. Moreover, lung cancer is a significant complication of IPF and is associated with increased mortality. Nevertheless, identifying common genes involved in developing IPF and its progression to lung cancer remains an unmet need. The present study aimed to identify hub genes related to the development of IPF by meta-analysis. In addition, we analyzed their expression and their relationship with patients' progression in lung cancer.

METHOD: Microarray datasets GSE24206, GSE21369, GSE110147, GSE72073, and GSE32539 were downloaded from Gene Expression Omnibus (GEO). Next, we conducted a series of bioinformatics analysis to explore possible hub genes in IPF and evaluated the expression of hub genes in lung cancer and their relationship with the progression of different stages of cancer.

RESULTS: A total of 1888 differentially expressed genes (DEGs) were identified, including 1105 upregulated and 783 downregulated genes. The 10 hub genes that exhibited a high degree of connectivity from the PPI network were identified. Analysis of the KEGG pathways showed that hub genes correlate with pathways such as the ECM-receptor interaction. Finally, we found that these hub genes are expressed in lung cancer and are associated with the progression of different stages of lung cancer.

CONCLUSIONS: Based on the integration of GEO microarray datasets, the present study identified DEGs and hub genes that could play an essential role in the pathogenesis of IPF and its association with the development of lung cancer in these patients, which could be considered potential diagnostic biomarkers or therapeutic targets for the disease.

PMID:37887075 | DOI:10.3390/arm91050032

Res Sq. 2023 Oct 3:rs.3.rs-3384541. doi: 10.21203/rs.3.rs-3384541/v1. Preprint.

ABSTRACT

Background : Single cell RNA sequencing technology (scRNA-seq) has been proven useful in understanding cell-specific disease mechanisms. However, identifying genes of interest remains a key challenge. Pseudo-bulk methods that pool scRNA-seq counts in the same biological replicates have been commonly used to identify differentially expressed genes. However, such methods may lack power due to the limited sample size of scRNA-seq datasets, which can be prohibitively expensive. Results : Motivated by this, we proposed to use the Bayesian-frequentist hybrid (BFH) framework to increase the power. Conclusion : In our idiopathic pulmonary fibrosis (IPF) case study, we demonstrated that with a proper informative prior, the BFH approach identified more genes of interest. Furthermore, these genes were reasonable based on the current knowledge of IPF. Thus, the BFH offers a unique and flexible framework for future scRNA-seq analyses.

PMID:37886581 | PMC:PMC10602069 | DOI:10.21203/rs.3.rs-3384541/v1

BMC Pulm Med. 2023 Oct 26;23(1):407. doi: 10.1186/s12890-023-02714-y.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disorder with unknown etiology. To date, the identification of new diagnostic, prognostic and progression biomarkers of IPF turns out to be necessary. MicroRNA (miRNA) are small non-coding RNAs which negatively regulate gene expression at the post-transcriptional level in several biological and pathological processes. An aberrant regulation of gene expression by miRNA is often associated with various diseases, including IPF. As result, miRNAs have emerged as potential biomarkers with relevance to pulmonary fibrosis. Several reports suggested that miRNAs are secreted as microvesicles or exosome, and hance they are stable and can be readily detected in the circulation. In the contest of miRNAs as circulating biomarkers, different studies show their role in various types of interstitial lung diseases and suggest that these small molecules could be used as prognostic markers of the disease. Exosomes are small, lipid-bound vesicles able to carry various elements of the naïve cells such as proteins, lipids, mRNAs and miRNA to facilitate cell communication under normal and diseases condition. Exosomal miRNAs (exo-miRNA) have been studied in relation to many diseases. However, there is little or no knowledge regarding exo-miRNA in bronchoalveolar lavage (BAL) in IPF. Our study's aim is to evaluate the changes in the expression of two exo-miRNAs in BAL, respectively miR-21 and miR-92a, through highlighting the differences between IPF, progressive pulmonary fibrosis (PPF) and not-progressive pulmonary fibrosis (nPPF).

METHODS: Exosomes were characterized by Western Blot and Multiplex Surface Marker Analysis. Exosomal miRNA expression was performed by qRT-PCR. ANOVA or Kruskal-Wallis test, based on data normality, was used to compare the differential expression between groups.

RESULTS: MiR-21 expression was significantly higher in the nPPF group than in both IPF and PPF. A result that could point above a possible role of miR-21, as a biomarker in the differential diagnosis between PPF and nPPF. MiR-92a, indeed, was down regulated in PPF compared to IPF and down regulated in PPF compared to nPPF.

CONCLUSIONS: This study demonstrated the putative role of both miR-21 and miR-92a as possible biomarkers of pulmonary fibrosis progression. Moreover, the role of exo-miRNAs is examined as a possible future direction that could lead to new therapeutic strategies for the treatment of progressive and non-progressive pulmonary fibrosis.

PMID:37884953 | DOI:10.1186/s12890-023-02714-y

Drugs Real World Outcomes. 2023 Oct 26. doi: 10.1007/s40801-023-00396-w. Online ahead of print.

ABSTRACT

BACKGROUND: The antifibrotic drugs, nintedanib and pirfenidone, inhibit the decline in forced vital capacity in patients with idiopathic pulmonary fibrosis (IPF). Nintedanib also inhibits the onset of acute exacerbation and reduces the risk of all-cause mortality. However, their effectiveness in real-world practice remains unclear. Our study aimed to investigate the changes in forced vital capacity, survival period, causes of death, and risk factors for mortality in patients with IPF receiving antifibrotic drugs.

METHODS: This retrospective study enrolled Japanese patients who visited Toho University Sakura Medical Center who were diagnosed with IPF and received antifibrotic drugs.

RESULTS: We included 102 patients [mean age ± standard deviation (SD): 71.8 ± 7.5 years], of whom 76 were males. The decline in forced vital capacity (mean ± SD) during the antifibrotic therapy period was - 154 ± 259 mL/year, which was significantly lower than before the antifibrotic therapy period (- 484 ± 589 mL/year; n = 80, p = 0.003). Altogether, 52 deaths were confirmed, and the median survival time from antifibrotic therapy initiation was 38.0 months (95% confidence interval: 25.9-50.1 months). Acute exacerbation accounted for 9.6% of all deaths (95% confidence interval: 1.6-17.6). The decline in forced vital capacity during antifibrotic therapy was a risk factor for mortality.

CONCLUSIONS: In actual clinical practice in Japan, antifibrotic drugs suppressed the gradual decline in forced vital capacity, which is a risk factor for mortality. However, the median survival period remained poor at 38 months.

PMID:37883007 | DOI:10.1007/s40801-023-00396-w

Drugs. 2023 Oct 26. doi: 10.1007/s40265-023-01950-0. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) remains a disease with poor survival. The pathogenesis is complex and encompasses multiple molecular pathways. The first-generation antifibrotics pirfenidone and nintedanib, approved more than 10 years ago, have been shown to reduce the rate of progression, increase the length of life for patients with IPF, and work for other fibrotic lung diseases. In the last two decades, most clinical trials on IPF have failed to meet the primary endpoint and an urgent unmet need remains to identify agents or treatment strategies that can stop disease progression. The pharmacotherapeutic landscape for IPF is moving forward with a number of new drugs currently in clinical development, mostly in phase I and II trials, while only a few phase III trials are running. Since our understanding of IPF pathogenesis is still limited, we should keep focusing our efforts to deeper understand the mechanisms underlying this complex disease and their reflection on clinical phenotypes. This review discusses the key pathogenetic concepts for the development of new antifibrotic agents, presents the newest data on approved therapies, and summarizes new compounds currently in clinical development. Finally, future directions in antifibrotics development are discussed.

PMID:37882943 | DOI:10.1007/s40265-023-01950-0

Chest. 2023 Oct 23:S0012-3692(23)05666-0. doi: 10.1016/j.chest.2023.10.021. Online ahead of print.

ABSTRACT

BACKGROUND: Different patterns of fibrosis on high resolution computer tomography scans (HRCT) have been associated with reduced survival in some interstitial lung diseases. Nothing is known about HRCT patterns and survival in sarcoidosis.

RESEARCH QUESTION: Will a detailed description of the extent and pattern of HRCT fibrosis in patients with Stage IV pulmonary sarcoidosis impact pulmonary function and survival ?

STUDY DESIGN AND METHODS: 240 stage IV sarcoidosis patients at two large tertiary institutions were studied. The earliest HRCT with fibrosis was reviewed for extent of fibrosis (<10%, 10-20% and >20%) and presence of bronchiectasis, upper lobe fibrocystic changes, basal subpleural honeycombing, ground glass opacities (GGOs), large bullae and mycetomas. Presence of sarcoidosis associated pulmonary hypertension (SAPH) and PFTs performed within one year of HRCT were recorded. Patients were followed until last clinic visit, death, or lung transplant (LT).

RESULTS: The mean age was 58.4 years. 74% were African American, 63% were female, and mean follow-up was 7.4 years. Death or LT occurred in 53 patients (22%). 31% had >20% fibrosis, 25% had 10-20% fibrosis and 44% had <10% fibrosis. The most common HRCT abnormalities were bronchiectasis (76%), upper lobe fibrocystic changes (36%), and GGOs (28%). 12% had basal subpleural honeycombing and 32% had SAPH. Patients with >20% fibrosis had more severe pulmonary impairment, were more likely to have SAPH(53%) and had worse survival (44% mortality; p<0.001). Upper lobe fibrocystic changes, basal subpleural honeycombing, and large bullae were associated with worse pulmonary function and worse survival. Patients with basal subpleural honeycombing had the worst pulmonary function and survival (55% mortality, p<0.001). GGOs were associated with worse pulmonary function but not worse survival while mycetomas were associated with worse survival but not worse pulmonary function. A Cox-proportional hazards model revealed that basal subpleural honeycombing (HR 7.95), DLCO<40% (HR 5.67) and White Race (HR 2.61) were independent predictors of reduced survival.

INTERPRETATION: HRCT features of fibrotic pulmonary sarcoidosis had an impact on pulmonary function and survival. Presence of >20% fibrosis and basal subpleural honeycombing are predictive of worse pulmonary function and worse survival in patients with stage IV pulmonary sarcoidosis.

PMID:37879560 | DOI:10.1016/j.chest.2023.10.021

Respir Res. 2023 Oct 25;24(1):254. doi: 10.1186/s12931-023-02556-6.

ABSTRACT

BACKGROUND: Fibroblast activation protein-α (FAPα) is a marker of activated fibroblasts that can be selectively targeted by an inhibitor (FAPI) and visualised by PET/CT imaging. We evaluated whether the measurement of FAPα in bronchoalveolar lavage fluids (BALF) and the uptake of FAPI by PET/CT could be used as biomarkers of fibrogenesis.

METHODS: The dynamics of lung uptake of 18F-labeled FAPI ([18F]FAPI-74) was assessed in the bleomycin mouse model at various time points and using different concentrations of bleomycin by PET/CT. FAPα was measured in BALFs from these bleomycin-treated and control mice. FAPα levels were also assessed in BALFs from controls and patients with idiopathic pulmonary fibrosis (IPF).

RESULTS: Bleomycin-treated mice presented a significantly higher uptake of [18F]FAPI-74 during lung fibrinogenesis (days 10 and 16 after instillation) compared to control mice. No significant difference was observed at initial inflammatory phase (3 days) and when fibrosis was already established (28 days). [18F]FAPI-74 tracer was unable to show a dose-response to bleomycin treatment. On the other hand, BALF FAPα levels were steeply higher in bleomycin-treated mice at day 10 and a significant dose-response effect was observed. Moreover, FAPα levels were strongly correlated with lung fibrosis as measured by the modified Aschroft histological analysis, hydroxyproline and the percentage of weight loss. Importantly, higher levels of FAPα were observed in IPF patients where the disease was progressing as compared to stable patients and controls. Moreover, patients with FAPα BALF levels higher than 192.5 pg/mL presented a higher risk of progression, transplantation or death compared to patients with lower levels.

CONCLUSIONS: Our preclinical data highlight a specific increase of [18F]FAPI-74 lung uptake during the fibrotic phase of the bleomycin murine model. The measurement of FAPα in BALF appears to be a promising marker of the fibrotic activity in preclinical models of lung fibrosis and in IPF patients. Further studies are required to confirm the role of FAPα in BALF as biomarker of IPF activity and assess the relationship between FAPα levels in BALF and [18F]FAPI-74 uptake on PET/CT in patients with fibrotic lung disease.

PMID:37880678 | DOI:10.1186/s12931-023-02556-6