Thorax. 2023 Feb 20:thorax-2022-219731. doi: 10.1136/thorax-2022-219731. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a debilitating, progressive disease with a median survival time of 3-5 years. Diagnosis remains challenging and disease progression varies greatly, suggesting the possibility of distinct subphenotypes.

METHODS AND RESULTS: We analysed publicly available peripheral blood mononuclear cell expression datasets for 219 IPF, 411 asthma, 362 tuberculosis, 151 healthy, 92 HIV and 83 other disease samples, totalling 1318 patients. We integrated the datasets and split them into train (n=871) and test (n=477) cohorts to investigate the utility of a machine learning model (support vector machine) for predicting IPF. A panel of 44 genes predicted IPF in a background of healthy, tuberculosis, HIV and asthma with an area under the curve of 0.9464, corresponding to a sensitivity of 0.865 and a specificity of 0.89. We then applied topological data analysis to investigate the possibility of subphenotypes within IPF. We identified five molecular subphenotypes of IPF, one of which corresponded to a phenotype enriched for death/transplant. The subphenotypes were molecularly characterised using bioinformatic and pathway analysis tools identifying distinct subphenotype features including one which suggests an extrapulmonary or systemic fibrotic disease.

CONCLUSIONS: Integration of multiple datasets, from the same tissue, enabled the development of a model to accurately predict IPF using a panel of 44 genes. Furthermore, topological data analysis identified distinct subphenotypes of patients with IPF which were defined by differences in molecular pathobiology and clinical characteristics.

PMID:36808085 | DOI:10.1136/thorax-2022-219731

Eur J Pharmacol. 2023 Feb 17:175594. doi: 10.1016/j.ejphar.2023.175594. Online ahead of print.

ABSTRACT

PURPOSE: Astragalus polysaccharide (APS) is a naturally-occurring compound derived from Astragalus membranaceus with anti-inflammatory and antioxidant properties. However, its beneficial effects and mechanisms on pulmonary fibrosis are unknown. Gut microbiota impact lung diseases via the gut-lung axis. Herein, we investigated APS progression to intervene in pulmonary fibrosis via the toll-like receptor 4(TLR4)/nuclear factor-kappa B(NF-κB) signaling pathway and gut microbiota homeostasis regulation.

METHODS: We used bleomycin (BLM) to construct an idiopathic pulmonary fibrosis (IPF) mouse model and assessed the pathology with Masson, hematoxylin-eosin (HE), and Sirius red staining. Enzyme-linked immunosorbent assay (ELISA) kits were employed to evaluate the inflammatory cytokine levels. Western blot evaluated TLR4/NF-κB signaling pathway expression. TUNEL staining to detect apoptosis. Mice feces samples were gathered for 16S rRNA gene sequencing.

RESULTS: Our findings revealed that APS ameliorated the extent of damage and collagen deposition in lung tissues, reduced inflammatory cytokines TNF-α, IL-6, and IL-1β levels, and decreased apoptosis. APS might attenuate the inflammatory response through TLR4/NF-κB signaling pathway inhibition. Meanwhile, the IPF mice model exhibited dysregulation of gut microbiota, and these changes were restored after APS intervention. APS may increase the proportion of probiotics, decrease that of harmful bacteria, and balance the gut microbiota via regulating metabolic pathways.

CONCLUSION: APS ameliorated lung tissue injury in the IPF mice model, inhibited TLR4/NF-κB signaling pathway, suppressed inflammatory cytokines activation, and reduced apoptosis. Moreover, APS regulated the metabolism of gut microbiota besides beneficial bacteria content elevation.

PMID:36804541 | DOI:10.1016/j.ejphar.2023.175594

Biomed Pharmacother. 2023 Feb 15;160:114405. doi: 10.1016/j.biopha.2023.114405. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease. The disease involves excessive accumulation of fibroblasts and myofibroblasts, and myofibroblasts differentiated by pro-fibrotic factors promote the deposition of extracellular matrix proteins such as collagen and fibronectin. Transforming growth factor-β1 is a pro-fibrotic factor that promotes fibroblast-to-myofibroblast differentiation (FMD). Therefore, inhibition of FMD may be an effective strategy for IPF treatment. In this study, we screened the anti-FMD effects of various iminosugars and showed that some compounds, including N-butyldeoxynojirimycin (NB-DNJ, miglustat, an inhibitor of glucosylceramide synthase (GCS)), a clinically approved drug for treating Niemann-Pick disease type C and Gaucher disease type 1, inhibited TGF-β1-induced FMD by inhibiting the nuclear translocation of Smad2/3. N-butyldeoxygalactonojirimycin having GCS inhibitory effect did not attenuate the TGF-β1-induced FMD, suggesting that NB-DNJ exerts the anti-FMD effects by GCS inhibitory effect independent manner. N-butyldeoxynojirimycin did not inhibit TGF-β1-induced Smad2/3 phosphorylation. In a mouse model of bleomycin (BLM)-induced pulmonary fibrosis, intratracheal or oral administration of NB-DNJ at an early fibrotic stage markedly ameliorated lung injury and deterioration of respiratory functions, such as specific airway resistance, tidal volume, and peak expiratory flow. Furthermore, the anti-fibrotic effects of NB-DNJ in the BLM-induced lung injury model were similar to those of pirfenidone and nintedanib, which are clinically approved drugs for the treatment of IPF. These results suggest that NB-DNJ may be effective for IPF treatment.

PMID:36804125 | DOI:10.1016/j.biopha.2023.114405

Chest. 2023 Feb 18:S0012-3692(23)00273-8. doi: 10.1016/j.chest.2023.02.027. Online ahead of print.

ABSTRACT

BACKGROUND: Two antifibrotic medications, pirfenidone and nintedanib, are approved for treatment of idiopathic pulmonary fibrosis (IPF). Little is known about their real-world adoption.

RESEARCH QUESTION: What are the real-world antifibrotic utilization rates and factors associated with uptake among a national cohort of Veterans with IPF?

STUDY DESIGN AND METHODS: We identified Veterans with IPF who received care either provided by the Veterans Affairs (VA) Healthcare System or non-VA care paid for by the VA. We identified those who had filled at least one antifibrotic prescription through VA pharmacy or Medicare Part D between 10/15/2014 and 12/31/2019. Hierarchical logistic regression models were used to examine factors associated with antifibrotic uptake, accounting for comorbidities, facility clustering, and follow-up time. Fine-Gray models were used to evaluate antifibrotic use by demographic factors, accounting for the competing risk of death.

RESULTS: Among 14,792 Veterans with IPF, 17% received antifibrotics. There were significant disparities in adoption, with lower uptake associated with female sex (adjusted OR 0.41, 95% CI 0.27 - 0.63, p<0.001), Black race (adjusted OR 0.60, 95% CI 0.50 - 0.74, p<0.001), and rural residence (adjusted OR 0.88, 95% CI 0.80 - 0.97, p=0.01). Veterans who received their index diagnosis of IPF outside the VA were less likely to receive antifibrotic therapy (adjusted OR 0.15, 95% CI 0.10 - 0.22, p<0.001).

INTERPRETATION: This is the first study to evaluate the real-world adoption of antifibrotic medications among Veterans with IPF. Overall uptake was low and there were significant disparities in use. Interventions to address them deserve further investigation.

PMID:36801465 | DOI:10.1016/j.chest.2023.02.027

BMC Pulm Med. 2023 Feb 19;23(1):68. doi: 10.1186/s12890-023-02360-4.

ABSTRACT

BACKGROUND: Although reticulocalbin 3 (Rcn3) has a critical role in alveolar epithelial function as well as in pathogenesis of pulmonary fibrosis, no study has yet examined its diagnostic and prognostic values for interstitial lung disease (ILD). This study aimed to evaluate Rcn3 as a potential marker in differential diagnosis of idiopathic pulmonary fibrosis (IPF) and connective tissue disease-associated interstitial lung disease (CTD-ILD) and in reflecting the severity of disease.

METHODS: This was a retrospective observational pilot study included 71 ILD patients and 39 healthy controls. These patients were stratified into IPF group (39) and CTD-ILD group (32). The severity of ILD was evaluated through pulmonary function test.

RESULTS: Serum Rcn3 level was statistically higher in CTD-ILD patients than that in IPF patients (p = 0.017) and healthy controls (p = 0.010). Serum Rcn3 further showed statistically negative correlation with pulmonary function indexes (TLC% pred and DLCO% pred) and positive correlation with inflammatory indexes (CRP and ESR) (r = - 0.367, p = 0.039; r = - 0.370, p = 0.037; r = 0.355, p = 0.046; r = 0.392, p = 0.026, respectively) in CTD-ILD patients rather than IPF patients. ROC analysis demonstrated that serum Rcn3 had superior diagnostic value for CTD-ILD and a cutoff value of 2.73 ng/mL had a sensitivity of 69%, a specificity of 69% and an accuracy of 45% for diagnose of CTD-ILD.

CONCLUSIONS: Serum Rcn3 levels might be a clinically useful biomarker in screening and evaluating CTD-ILD.

PMID:36800954 | DOI:10.1186/s12890-023-02360-4

Sci Rep. 2023 Feb 16;13(1):2804. doi: 10.1038/s41598-023-28638-5.

ABSTRACT

Higher blood monocyte counts are related to worse survival in idiopathic pulmonary fibrosis. However, studies evaluating the association between blood monocyte counts and clinical outcomes of idiopathic nonspecific interstitial pneumonia (iNSIP) are lacking. We evaluated the impact of monocyte counts on iNSIP prognosis. iNSIP patients (n = 126; median age, 60 years; female, n = 64 [50.8%]) diagnosed by surgical lung biopsy were enrolled and categorized into low (monocyte < 600/µL) and high (monocyte ≥ 600/µL) monocyte groups. The median follow-up duration was 53.0 months. After adjusting for age, sex, and smoking history, the annual decline in forced vital capacity (FVC) showed differences between the monocyte groups (Pinteraction = 0.006) (low vs. high; - 28.49 mL/year vs. - 65.76 mL/year). The high-monocyte group showed a worse survival rate (P = 0.01) compared to low monocyte group. The 5-year survival rates were 83% and 72% in the low- and high-monocyte groups, respectively. In the Cox-proportional hazard analysis, older age, male sex, low baseline FVC, and diffusing capacity of the lung for carbon monoxide were independent risk factors for mortality. However, monocyte count (Hazard ratio 1.61, P = 0.126) was not an independent prognostic factor. Although high monocyte count might be associated with faster lung function decline, it could not independently predict survival in iNSIP.

PMID:36797265 | DOI:10.1038/s41598-023-28638-5

Am J Respir Crit Care Med. 2023 Feb 16. doi: 10.1164/rccm.202209-1812OC. Online ahead of print.

ABSTRACT

Transbronchial cryobiopsies (TBCB) for the diagnosis of interstitial lung disease (ILD) have shown promising results but prospective studies with matched surgical lung biopsy (SLB) yielded conflicting results. We aimed to assess within- and between-center diagnostic agreement between TBCB and SLB at both the histopathologic and multidisciplinary discussion (MDD) levels in patients with diffuse ILD. In a multicenter prospective study, we obtained matched TBCB and SLB in patients referred for SLB. After blinded review by three pulmonary pathologists, all cases were reviewed by three independent ILD teams in a MDD. MDD was performed first with TBC, than with SLB in a second session. Within center and between center diagnostic agreement was evaluated by percentage and correlation coefficient. Twenty patients were recruited and underwent contemporaneous TBCB and SLB. Diagnostic agreement within center between TBCB-MDD and SLB-MDD was reached in 37 of the 60 (61.7%) paired observations, resulting in a k of 0.46 (95%CI 0.29-0.63). Diagnostic agreement increased amongst high-confidence/definitive diagnosis at TBCB-MDD (21 of 29 (72.4%)), but not significantly, and was more likely amongst cases with a SLB-MDD diagnosis of idiopathic pulmonary fibrosis (IPF) than fibrotic hypersensitivity pneumonitis (fHP) (13 of 16 (81.2%) vs 16 of 31 (51.6%), p=0.047). Between center agreement for cases was markedly higher for SLB-MDD (k = 0.71; 95%CI 0.52-0.89) than TBCB-MDD (k = 0.29; 95%IC 0.09-0.49).This study demonstrated moderate TBCB-MDD/SLB-MDD diagnostic agreement which was insufficient to reliably distinguish fHP from IPF. The between centre agreement for TBCB-MDD was only fair, while it was substantial for SLB-MDD. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT02235779.

PMID:36796092 | DOI:10.1164/rccm.202209-1812OC

Front Pharmacol. 2023 Jan 30;14:1064307. doi: 10.3389/fphar.2023.1064307. eCollection 2023.

ABSTRACT

Background: Interstitial lung disease (ILD) is a significant complication associated with microscopic polyangiitis (MPA) that has a poor prognosis. However, the long-term clinical course, outcomes, and prognostic factors of MPA-ILD are not well defined. Hence, this study aimed to investigate the long-term clinical course, outcomes, and prognostic factors in patients with MPA-ILD. Methods: Clinical data of 39 patients with MPA-ILD (biopsy proven cases, n = 6) were retrospectively analyzed. High resolution computed tomography (HRCT) patterns were assessed based on the 2018 idiopathic pulmonary fibrosis diagnostic criteria. Acute exacerbation (AE) was defined as the worsening of dyspnea within 30 days, with new bilateral lung infiltration that is not fully explained by heart failure or fluid overload and that does not have identified extra-parenchymal causes (pneumothorax, pleural effusion, or pulmonary embolism). Results: The median follow-up period was 72.0 months (interquartile range: 44-117 months). The mean age of the patients was 62.7 years and 59.0% were male. Usual interstitial pneumonia (UIP) and probable usual interstitial pneumonia patterns on high resolution computed tomography were identified in 61.5 and 17.9% of the patients, respectively. During the follow-up, 51.3% of patients died, and the 5- and 10-year overall survival rates were 73.5% and 42.0%, respectively. Acute exacerbation occurred in 17.9% of the patients. The non-survivors had higher neutrophil counts in bronchoalveolar lavage (BAL) fluid and more frequent acute exacerbation than the survivors. In the multivariable Cox analysis, older age (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.01-1.14; p = 0.028) and higher BAL counts (HR, 1.09; 95% CI, 1.01-1.17; p = 0.015) were found to be the independent prognostic factors associated with mortality in patients with MPA-ILD. Conclusion: During the 6 years-follow-up, about half of patients with MPA-ILD died and approximately one-fifth experienced acute exacerbation. Our results suggest that older age and higher BAL neutrophil counts mean poor prognosis in patients with MPA-ILD.

PMID:36794274 | PMC:PMC9922778 | DOI:10.3389/fphar.2023.1064307

J Thorac Dis. 2023 Jan 31;15(1):186-203. doi: 10.21037/jtd-22-886. Epub 2022 Dec 27.

ABSTRACT

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial pneumonia of unknown etiology. An increasing number of studies have reported that the incidence of IPF increases with age. Simultaneously, the number of senescent cells increased in IPF. Epithelial cell senescence, an important component of epithelial cell dysfunction, plays a key role in IPF pathogenesis. This article summarizes the molecular mechanisms associated with alveolar epithelial cell senescence and recent advances in the applications of drugs targeting pulmonary epithelial cell senescence to explore novel therapeutic approaches for the treatment of pulmonary fibrosis.

METHODS: All literature published in English on PubMed, Web of Science, and Google Scholar were electronically searched online using the following keyword combinations: aging, alveolar epithelial cell, cell senescence, idiopathic pulmonary fibrosis, WNT/β-catenin, phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), mammalian target of rapamycin (mTOR), and nuclear factor kappa B (NF-κB).

KEY CONTENT AND FINDINGS: We focused on signaling pathways associated with alveolar epithelial cell senescence in IPF, including WNT/β-catenin, PI3K/Akt, NF-κB, and mTOR signaling pathways. Some of these signaling pathways are involved in alveolar epithelial cell senescence by affecting cell cycle arrest and secretion of senescence-associated secretory phenotype-associated markers. We also found that changes in lipid metabolism in alveolar epithelial cells can be induced by mitochondrial dysfunction, both of which contribute to cellular senescence and development of IPF.

CONCLUSIONS: Decreasing senescent alveolar epithelial cells may be a promising strategy for the treatment of IPF. Therefore, further investigations into new treatments of IPF by applying inhibitors of relevant signaling pathways, as well as senolytic drugs, are warranted.

PMID:36794134 | PMC:PMC9922607 | DOI:10.21037/jtd-22-886

Pneumologie. 2023 Feb;77(2):94-119. doi: 10.1055/a-1983-6796. Epub 2023 Feb 15.

NO ABSTRACT

PMID:36791790 | DOI:10.1055/a-1983-6796

Am J Physiol Lung Cell Mol Physiol. 2023 Feb 15. doi: 10.1152/ajplung.00263.2022. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is characterized by increased collagen accumulation that is progressive and non-resolving. Although fibrosis progression may be regulated by fibroblasts and alveolar macrophage (AM) interactions, this cellular interplay has not been fully elucidated. To study AM-fibroblast interactions, cells were isolated from IPF and normal human lung tissue and cultured independently or together in direct 2D co-culture, direct 3D co-culture, indirect transwell, and in 3D hydrogels. AM influence on fibroblast function was assessed by gene expression, cytokine/chemokine secretion, and gel/matrix contractility. Normal AMs cultured in direct contact with fibroblasts down-regulated ECM gene expression while IPF AMs showed little to no effect. Fibroblast contractility was assessed by encapsulating co-cultures in 3D collagen hydrogels and monitoring gel diameter over time. Both normal and IPF AMs reduced baseline contractility of normal fibroblasts but had little to no effect on IPF fibroblasts. When stimulated with Toll-like receptor (TLR) agonists, IPF AMs increased production of pro-inflammatory cytokines TNFα and IL-1β, compared to normal AMs. TLR ligand stimulation did not alter fibroblast contraction, but stimulation with exogenous TNFα and TGF-β did alter contraction. To determine if the observed changes required cell-to-cell contact, AM-conditioned media and transwell systems were utilized. Transwell culture showed decreased ECM gene expression changes compared to direct co-culture and conditioned media from AMs did not alter fibroblast contraction regardless of disease state. Taken together, these data indicate that normal fibroblasts are more responsive to AM crosstalk, and that AM influence on fibroblast behavior depends on cell proximity.

PMID:36791050 | DOI:10.1152/ajplung.00263.2022

Pulm Ther. 2023 Feb 15. doi: 10.1007/s41030-023-00215-1. Online ahead of print.

ABSTRACT

INTRODUCTION: Obstructive sleep apnea (OSA) is often observed in subjects with interstitial lung disease (ILD). It may have a negative impact on the course of ILD, but its prognostic significance in relation to other known indicators of poor outcome is unclear.

METHODS: After a detailed work-up, including overnight unattended type III polygraphy, all subjects newly diagnosed with ILDs referred to our clinics were followed-up for at least 1.5 years or until death or progression of disease [> 10% decline in forced vital capacity (FVC) below baseline]. We analyzed relationships between some prespecified variables of interest, including sleeping results, to establish parameters predictive of progressive course.

RESULTS: Our population consisted of 46 subjects (mean age 59.6 years; males 61%); 23.9% and 41% had idiopathic pulmonary fibrosis and ILD associated with systemic diseases, respectively. Mean baseline forced vital capacity and diffusion capacity of carbon monoxide were 83% and 57% of predicted, respectively. Mean (± SE) Apnea-Hypopnea Index (AHI) was 17 (± 3) events/h. AHI in the ranges 5-14.9, 15-29.9, and ≥ 30 was recorded in 14 (31%), 6 (13%), and 9 (20%) subjects, respectively. Mean distance covered in the 6-MWG walk test (6MWT) was 302 (± 19) m and 26 subjects (57%) showed exertional oxyhemoglobin desaturation. The median follow-up was about 18 months. Multivariate logistic regression analysis showed that exertional desaturation (HR 8.2; 1.8-36.5 95% CI; p = 0.006) and AHI ≥ 30, namely the threshold of severe OSA (HR 7.5; 1.8-30.6; p = 0.005), were the only independent variables related to progressive disease course.

CONCLUSION: We conclude that exertional desaturation and elevated AHI had independent negative prognostic significance in our ILD population.

PMID:36790678 | DOI:10.1007/s41030-023-00215-1

Biomark Med. 2023 Feb 15. doi: 10.2217/bmm-2022-0395. Online ahead of print.

ABSTRACT

Background: This study analyzed the utility of soluble ST2 (sST2) and GDF-15 as biomarkers of right ventricular (RV) function in patients with pulmonary hypertension (PH). Methods: GDF-15 and sST2 serum concentrations were measured in patients with PH (n = 628), dilated cardiomyopathy (n = 31) and left ventricular hypertrophy (n = 47), and in healthy controls (n = 61). Results: Median sST2 and GDF-15 levels in patients with left ventricular hypertrophy were higher than in patients with PH and dilated cardiomyopathy. In tertile analysis GDF-15 >1363 pg/ml and sST2 >38 ng/ml were associated with higher N-terminal pro-brain natriuretic peptide, RV systolic dysfunction, RV-pulmonary arterial uncoupling and hemodynamic impairment. Conclusion: GDF-15 and sST2 are potential biomarkers of RV dysfunction in patients with PH.

PMID:36790217 | DOI:10.2217/bmm-2022-0395

Respir Res. 2023 Feb 14;24(1):51. doi: 10.1186/s12931-023-02333-5.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that affects 3 million people worldwide. Senescence and small extracellular vesicles (sEVs) have been implicated in the pathogenesis of IPF, although how sEVs promote disease remains unclear. Here, we profile sEVs from bronchial epithelial cells and determine small RNA (smRNA) content.

METHODS: Conditioned media was collected and sEVs were isolated from normal human bronchial epithelial cells (NHBEs) and IPF-diseased human bronchial epithelial cells (DHBEs).

RESULTS: Increased sEV release from DHBEs compared to NHBEs (n = 4; p < 0.05) was detected by nanoparticle tracking analysis. NHBEs co-cultured with DHBE-derived sEVs for 72 h expressed higher levels of SA-β-Gal and γH2AX protein, p16 and p21 RNA and increased secretion of IL6 and IL8 proteins (all n = 6-8; p < 0.05). sEVs were also co-cultured with healthy air-liquid interface (ALI) cultures and similar results were observed, with increases in p21 and p16 gene expression and IL6 and IL8 (basal and apical) secretion (n = 6; p < 0.05). Transepithelial electrical resistance (TEER) measurements, a reflection of epithelial barrier integrity, were decreased upon the addition of DHBE-derived sEVs (n = 6; p < 0.05). smRNA-sequencing identified nineteen significantly differentially expressed miRNA in DHBE-derived sEVs compared to NHBE-derived sEVs, with candidate miRNAs validated by qPCR (all n = 5; p < 0.05). Four of these miRNAs were upregulated in NHBEs co-cultured with DHBE-derived sEVs and three in healthy ALI cultures co-cultured with DHBE-derived sEVs (n = 3-4; p < 0.05).

CONCLUSIONS: This data demonstrates that DHBE-derived sEVs transfer senescence to neighbouring healthy cells, promoting the disease state in IPF.

PMID:36788603 | DOI:10.1186/s12931-023-02333-5

Cell Death Discov. 2023 Feb 14;9(1):62. doi: 10.1038/s41420-023-01344-x.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) has been extensively studied in recent decades due to its rising incidence and high mortality. Despite an abundance of research, the mechanisms, immune-associated mechanisms, of IPF are poorly understood. While defining immunopathogenic mechanisms as the primary pathogenesis is controversial, recent studies have verified the contribution of the immune system to the fibrotic progression of IPF. Extensive evidence has shown the potential role of T cells in fibrotic progression. In this review, we emphasize the features of T cells in IPF and highlight the controversial roles of different subtypes of T cells or even two distinct effects of one type of T-cell in diverse settings, and multiple chemokines and cell products are discussed. Furthermore, we discuss the potential development of treatments targeting the immune molecules of T cells and the feasibility of immune therapies for IPF in clinical practice.

PMID:36788232 | DOI:10.1038/s41420-023-01344-x

Cell Rep Med. 2023 Feb 9:100945. doi: 10.1016/j.xcrm.2023.100945. Online ahead of print.

ABSTRACT

Accumulation of senescent cells contributes to age-related diseases including idiopathic pulmonary fibrosis (IPF). Insulin-like growth factor binding proteins (IGFBPs) regulate many biological processes; however, the functional contributions of IGFBP2 in lung fibrosis remain largely unclear. Here, we report that intranasal delivery of recombinant IGFBP2 protects aged mice from weight loss and demonstrated antifibrotic effects after bleomycin lung injury. Notably, aged human-Igfbp2 transgenic mice reveal reduced senescence and senescent-associated secretory phenotype factors in alveolar epithelial type 2 (AEC2) cells and they ameliorated bleomycin-induced lung fibrosis. Finally, we demonstrate that IGFBP2 expression is significantly suppressed in AEC2 cells isolated from fibrotic lung regions of patients with IPF and/or pulmonary hypertension compared with patients with hypersensitivity pneumonitis and/or chronic obstructive pulmonary disease. Altogether, our study provides insights into how IGFBP2 regulates AEC2-cell-specific senescence and that restoring IGFBP2 levels in fibrotic lungs can prove effective for patients with IPF.

PMID:36787736 | DOI:10.1016/j.xcrm.2023.100945

Inn Med (Heidelb). 2023 Feb 14. doi: 10.1007/s00108-023-01476-3. Online ahead of print.

ABSTRACT

Interstitial lung diseases (ILD) comprise a heterogeneous group of chronic lung disorders of different etiologies that can not only affect the interstitium but also the alveolar space and the bronchial system. According to the "Global Burden of Disease Study" there has been an increase in incidence over the last decades and it is expected that the number of ILD-associated deaths will double over the next 20 years. ILD are grouped into those of unknown cause, e.g. idiopathic pulmonary fibrosis (IPF), and ILD of known cause, which include drug-induced and connective tissue disease-associated ILD as well as granulomatous ILD such as sarcoidosis and hypersensitivity pneumonitis. In addition, some ILD present a progressive fibrosing phenotype, which influences therapeutic decisions. Predominantly inflammatory entities are treated with immunosuppressives, whereas predominantly fibrosing ILD are treated with antifibrotic drugs; in some cases, a combination of both is necessary. The spectrum of differential diagnoses in ILD is broad, but definite diagnosis is essential for treatment selection; therefore, the multidisciplinary ILD board plays a pivotal role.

PMID:36786822 | DOI:10.1007/s00108-023-01476-3

Respir Res. 2023 Feb 14;24(1):49. doi: 10.1186/s12931-023-02359-9.

ABSTRACT

BACKGROUND: Interstitial lung abnormalities (ILA) are CT findings suggestive of interstitial lung disease in individuals without a prior diagnosis or suspicion of ILD. Previous studies have demonstrated that ILA are associated with clinically significant outcomes including mortality. The aim of this study was to determine the prevalence of ILA in a large CT lung cancer screening program and the association with clinically significant outcomes including mortality, hospitalizations, cancer and ILD diagnosis.

METHODS: This was a retrospective study of individuals enrolled in a CT lung cancer screening program from 2012 to 2014. Baseline and longitudinal CT scans were scored for ILA per Fleischner Society guidelines. The primary analyses examined the association between baseline ILA and mortality, all-cause hospitalization, and incidence of lung cancer. Kaplan-Meier plots were generated to visualize the associations between ILA and lung cancer and all-cause mortality. Cox regression proportional hazards models were used to test for this association in both univariate and multivariable models.

RESULTS: 1699 subjects met inclusion criteria. 41 (2.4%) had ILA and 101 (5.9%) had indeterminate ILA on baseline CTs. ILD was diagnosed in 10 (24.4%) of 41 with ILA on baseline CT with a mean time from baseline CT to diagnosis of 4.47 ± 2.72 years. On multivariable modeling, the presence of ILA remained a significant predictor of death, HR 3.87 (2.07, 7.21; p < 0.001) when adjusted for age, sex, BMI, pack years and active smoking, but not of lung cancer and all-cause hospital admission. Approximately 50% with baseline ILA had progression on the longitudinal scan.

CONCLUSIONS: ILA identified on baseline lung cancer screening exams are associated with all-cause mortality. In addition, a significant proportion of patients with ILA are subsequently diagnosed with ILD and have CT progression on longitudinal scans.

TRIAL REGISTRATION NUMBER: ClinicalTrials.gov; No.: NCT04503044.

PMID:36782326 | DOI:10.1186/s12931-023-02359-9

J Occup Med Toxicol. 2023 Feb 13;18(1):2. doi: 10.1186/s12995-023-00368-4.

ABSTRACT

BACKGROUND: Patients with work-related lung disease (WRLD) are at increased risk of death caused by severe lung tissue damage and fibrosis. This study aimed to assess the clinical outcomes of lung transplantation (LTx) for WRLD and compare the results of LTx between WRLD and idiopathic pulmonary fibrosis (IPF).

METHODS: This single-center retrospective cohort study reviewed the clinical data of patients who underwent LTx for WRLD or IPF at our hospital between January 2015 and December 2021. Cumulative survival rates after LTx were estimated using the Kaplan-Meier method.

RESULTS: The final analysis included 33 cases of WRLD and 91 cases of IPF. The 33 WRLD patients consisted of 19 (57.6%) cases of silicosis, 8 (24.2%) cases of coal workers' pneumoconiosis, 3 (9.09%) cases of asbestosis, and 3 (9.09%) cases of other WRLD. Pneumothorax as an indication for LTx was significantly more common in the WRLD group than in the IPF group (51.5% vs. 2.2%, P < 0.001). There was no significant difference in the 5-year cumulative survival rate between the WRLD patients and the IPF patients (66.6% vs. 56.7%, P = 0.67). There was no significant difference in the best performance of exercise capacity and lung function between the two groups at 1 year post-transplant.

CONCLUSIONS: LTx had similar survival outcomes and lung function for WRLD and IPF patients. Pneumothorax was the primary indication for lung transplantation in WRLD.

PMID:36782253 | DOI:10.1186/s12995-023-00368-4

Am J Respir Cell Mol Biol. 2023 Feb 13. doi: 10.1165/rcmb.2022-0264OC. Online ahead of print.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is a pathological condition of unknown etiology which results from injury to the lung and an ensuing fibrotic response that leads to thickening of the alveolar walls and obliteration of the alveolar space. The pathogenesis is not clear and there are currently no effective therapies for IPF. Small airway disease and mucus accumulation are prominent features in IPF lungs, similar to Cystic Fibrosis (CF) lung disease. The ATP12A gene encodes the alpha-subunit of the non-gastric H+, K+-ATPase, which functions to acidify the airway surface fluid and impairs mucociliary transport function in cystic fibrosis patients. We hypothesize that the ATP12A protein may play a role in the pathogenesis of IPF. Our studies demonstrate that ATP12A protein is overexpressed in distal small airways from IPF patient lungs compared to normal human lungs. In addition, overexpression of the ATP12A protein in mouse lungs worsened the bleomycin (BLEO)-induced experimental pulmonary fibrosis. This was prevented by a potassium-competitive proton pump blocker, vonoprazan (VON). This data supports the concept that the ATP12A protein plays an important role in the pathogenesis of lung fibrosis. Inhibition of the ATP12A protein has the potential as a novel therapeutic strategy in IPF.

PMID:36780662 | DOI:10.1165/rcmb.2022-0264OC