BMJ Case Rep. 2022 Jul 5;15(7):e251483. doi: 10.1136/bcr-2022-251483.

NO ABSTRACT

PMID:35790325 | DOI:10.1136/bcr-2022-251483

J Allergy Clin Immunol Pract. 2022 Jul 1:S2213-2198(22)00654-7. doi: 10.1016/j.jaip.2022.06.031. Online ahead of print.

ABSTRACT

BACKGROUND: YKL-40 (chitinase 3-like-1) and Krebs von den Lungen-6 (KL-6) are two promising biomarkers that may have an important role in the management of interstitial lung diseases (ILD).

OBJECTIVES: The aim of this study was to investigate the values of KL-6 and YKL-40 as biomarkers in the diagnosis and prognosis of patients with hypersensitivity pneumonitis (HP).

METHODS: Cross-sectional study conducted in 49 patients diagnosed with HP due to exposure to birds (n = 32) or fungi (n = 17), 48 patients with other ILD and 67 healthy volunteers. HP patients were divided into fibrotic and non-fibrotic. Serum and sputum YKL-40 and KL-6 levels were determined using commercial ELISA kits. ROC curves were used to determine the sensitivity and specificity of both biomarkers for the diagnosis of HP. Pulmonary function tests were performed in patients during follow-up.

RESULTS: KL-6 and YKL-40 levels were significantly higher in serum of HP patients exposed to birds with a fibrotic pattern than in controls (p < 0.0001 and 0.0055 respectively). Serum KL-6 levels were also significantly higher in fibrotic HP patients exposed to fungi compared with the control group (p = 0.0001). In HP patients exposed to fungi, sputum KL-6 and YKL-40 levels were higher in those with a fibrotic pattern (p = 0.0289 and 0.016 respectively). ROC analysis showed that the range between 55-121 ng/ml for serum YKL-40 levels and 346-1441 U/ml for serum KL-6 levels had the best sensitivity and specificity for discriminating between HP patients, healthy controls and patients with idiopathic pulmonary fibrosis (IPF). In HP patients, serum KL-6 levels correlated negatively with total lung capacity (TLC, r = -0.485; p = 0.0103) and diffusing capacity of the lungs for carbon monoxide (DLCO, r = -0.534; p = 0.0002) at 12 months.

CONCLUSIONS: Both KL-6 and YKL-40 proteins seem to be capable of distinguishing HP patients from healthy individuals and from patients with IPF. Their sensitivity and specificity confirm their potential role as biomarkers. KL-6 may also be a predictor of disease progression.

PMID:35788062 | DOI:10.1016/j.jaip.2022.06.031

Am J Physiol Lung Cell Mol Physiol. 2022 Jul 5. doi: 10.1152/ajplung.00565.2020. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fatal lung disorder characterized by aberrant extracellular matrix deposition in the interstitium. Pirfenidone is an anti-fibrotic agent used to treat patients with IPF. Pirfenidone shows a pleiotropic mode of action, but its underlying anti-fibrotic mechanism is unclear. Transient receptor potential vanilloid 4 (TRPV4), which is a mechanosensitive calcium channel, was recently shown to be related to pulmonary fibrosis. To clarify the anti-fibrotic mechanisms of pirfenidone, we investigated whether TRPV4 blockade has a pharmacological effect in a murine model of pulmonary fibrosis and whether pirfenidone contributes to suppression of TRPV4. Our synthetic TRPV4 antagonist and pirfenidone treatment attenuated lung injury in the bleomycin mouse model. TRPV4-mediated increases in intracellular calcium were inhibited by pirfenidone. Additionally, TRPV4-stimulated interleukin-8 release from cells was reduced and a delay in cell migration was abolished by pirfenidone. Furthermore, pirfenidone decreased TRPV4 endogenous ligands in bleomycin-administered mouse lungs and their production by microsomes of human lungs. We found TRPV4 expression in the bronchiolar and alveolar epithelium and activated fibroblasts of the lungs in patients with IPF. Finally, we showed that changes in forced vital capacity of patients with IPF treated with pirfenidone were significantly correlated with metabolite levels of TRPV4 endogenous ligands in bronchoalveolar lavage fluid. These results suggest that the anti-fibrotic action of pirfenidone is partly mediated by TRPV4 and that TRPV4 endogenous ligands in bronchoalveolar lavage fluid may be biomarkers for distinguishing responders to pirfenidone.

PMID:35787697 | DOI:10.1152/ajplung.00565.2020

BMJ Open Respir Res. 2022 Jul;9(1):e001310. doi: 10.1136/bmjresp-2022-001310.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) greatly impacts quality of life and eventually leads to premature death from respiratory failure. Inhaled treprostinil was associated with improvements in forced vital capacity (FVC) and reduced exacerbations of underlying lung disease in post hoc analyses from a phase 3 study in patients with precapillary pulmonary hypertension due to interstitial lung disease. These results, combined with preclinical evidence of treprostinil's antifibrotic activity, support its investigation in the treatment of IPF.

METHODS AND ANALYSIS: The TETON programme consists of two replicate, 52-week, randomised, double-blind placebo-controlled, phase 3 studies, each enrolling 396 subjects (NCT04708782, NCT05255991). Eligible subjects must have a diagnosis of IPF confirmed by central imaging review, along with an FVC ≥45%. Stable background use of pirfenidone or nintedanib is allowed. The primary endpoint is change in absolute FVC at week 52. Secondary endpoints include time to clinical worsening (first event of death, respiratory hospitalisation or ≥10% decline in % predicted FVC), time to first acute exacerbation of IPF, overall survival, change in % predicted FVC and change in the King's Brief Interstitial Lung Disease Questionnaire at week 52. Safety parameters include adverse events, hospitalisations, oxygenation and laboratory parameters. Patients who complete week 52 will be eligible to enter an open-label extension study.

ETHICS AND DISSEMINATION: Studies will be conducted in accordance with the International Conference on Harmonisation Guideline for Good Clinical Practice, Declaration of Helsinki principles, and local regulatory, ethical and legal requirements. Results will be published in a peer-reviewed publication.

PMID:35787522 | DOI:10.1136/bmjresp-2022-001310

Tuberk Toraks. 2022 Jun;70(2):113-121. doi: 10.5578/tt.20229801.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive disease of unknown etiology with an unpredictable course. We aimed to investigate the effects of the presence of hiatal hernia (HH) and its consequences on the clinical manifestation of IPF.

MATERIALS AND METHODS: Patients diagnosed with IPF with or without hiatal hernia were retrospectively compared in terms of clinical findings, total fibrosis scores (TFS), and lung function in the interstitial lung diseases (ILD) outpatient clinic.

RESULT: A total of 142 IPF patients were included in the study. HH was detected in 62.7% (n= 89) of the patients. There was no statistically significant difference between IPF patients with or without HH in terms of age, gender, smoking history, and anti-reflux drug use (p> 0.05). There was no statistically significant difference between IPF patients with or without HH in terms of symptoms such as dyspnea, cough, regurgitation, heartburn, nausea, dysphagia, chest pain, and hoarseness (p> 0.05). In addition, no statistically significant difference was found between IPF patients with or without HH in terms of mortality rate, survival time after diagnosis, and exacerbations (p> 0.05). Six-minute walking distance and SpO2 change, percentage of predicted forced vital capacity (FVC) value, and percentage of predicted diffusing capacity for carbon monoxide (DLCO) value did not differ significantly between the groups (p> 0.05). There was no statistically significant difference between the groups in terms of total fibrosis score (p= 0.668).

CONCLUSIONS: According to the results of this study, 62.7% (n= 89) of IPF patients had HH, and there was no difference in clinical outcomes, TFS, and pulmonary functions between IPF patients with or without HH.

PMID:35785875 | DOI:10.5578/tt.20229801

Environ Toxicol. 2022 Jul 4. doi: 10.1002/tox.23603. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an interstitial pulmonary disease with slow onset and high mortality. Epithelial-mesenchymal transition (EMT) is a significant condition for tissue fibrosis, and lncRNA-Snhg6 (small nucleolar RNA host gene 6) is related to EMT in some cancer cells, but its role in pulmonary fibrosis remains obscure. Here, we found that TGF-β1 and Snhg6 were up-regulated in lung tissues of BLM-induced lung fibrosis mouse, and Snhg6 expression was significantly increased in primary lung fibroblasts after BLM treatment. Snhg6 knockdown notably alleviated the pulmonary dysfunction, and the increase of fibrosis area and collagen deposition induced by BLM. MiR-26a-5p was downregulated in BLM-induced fibrotic lung tissues, and it was negatively regulated by Snhg6. Silencing Snhg6 markedly alleviated the TGF-β1-induced increase in fibrotic marker expression, cell proliferation, migration and differentiation, as well as the nuclear transport of p-Smad2/3 by modulating miR-26a-5p expression in mouse lung fibroblasts. Moreover, overexpressing Snhg6-induced collagen accumulation and fibroblast activation in fibroblasts, which was reversed by treatment with miR-26a-5p mimic or oxymatrine (an inhibitor of TGF-β1-Smads pathway). Interestingly, silencing Snhg6 in vivo mitigated BLM-driven pulmonary fibrosis by regulating the miR-26a-5p/TGF-β1-Smads axis. Our data revealed that Snhg6 contributed to the process of BLM-driven lung fibrosis in mouse by modulating the miR-26a-5p/TGF-β1-Smads axis, suggesting that Snhg6 might be a therapeutic target for lung fibrosis.

PMID:35785413 | DOI:10.1002/tox.23603

Front Pharmacol. 2022 Jun 15;13:919388. doi: 10.3389/fphar.2022.919388. eCollection 2022.

ABSTRACT

Overview: Idiopathic pulmonary fibrosis (IPF) is a disease caused by many factors, eventually resulting in lung function failure. Jinbei oral liquid (JBOL) is a traditional Chinese clinical medicine used to treat pulmonary diseases. However, the pharmacological effects and mechanism of the action of JBOL on IPF remain unclear. This study investigated the protective effects and mechanism of the action of JBOL on IPF using network pharmacology analysis, followed by in vivo and in vitro experimental validation. Methods: The components of JBOL and their targets were screened using the TCMSP database. IPF-associated genes were obtained using DisGeNET and Drugbank. The common targets of JBOL and IPF were identified with the STRING database, and a protein-protein interaction (PPI) network was constructed. GO and KEGG analyses were performed. Sprague-Dawley rats were injected with bleomycin (BLM) to establish an IPF model and treated orally with JBOL at doses of 5.4, 10.8, and 21.6 ml/kg. A dose of 54 mg/kg of pirfenidone was used as a control. All rats were treated for 28 successive days. Dynamic pulmonary compliance (Cdyn), minute ventilation volume (MVV), vital capacity (VC), and lung resistance (LR) were used to evaluate the efficacy of JBOL. TGF-β-treated A549 cells were exposed to JBOL, and epithelial-to-mesenchymal transition (EMT) changes were assessed. Western blots were performed. Results: Two hundred seventy-eight compounds and 374 targets were screened, and 103 targets related to IPF were identified. Core targets, including MAPK1 (ERK2), MAPK14 (p38), JUN, IL-6, AKT, and others, were identified by constructing a PPI network. Several pathways were involved, including the MAPK pathway. Experimentally, JBOL increased the levels of the pulmonary function indices (Cdyn, MVV, and VC) in a dose-dependent manner and reduced the RL level in the BLM-treated rats. JBOL increased the epithelial marker E-cadherin and suppressed the mesenchymal marker vimentin expression in the TGF-β-treated A549 cells. The suppression of ERK1/2, JNK, and p38 phosphorylation by JBOL was validated. Conclusion: JBOL had therapeutic effects against IPF by regulating pulmonary function and EMT through a systemic network mechanism, thus supporting the need for future clinical trials of JBOL.

PMID:35784749 | PMC:PMC9240387 | DOI:10.3389/fphar.2022.919388

Front Immunol. 2022 Jun 15;13:891448. doi: 10.3389/fimmu.2022.891448. eCollection 2022.

ABSTRACT

BACKGROUNDS: Growth differentiation factor 15 (GDF-15) is a highly divergent member of the TGF-β superfamily and has been implicated in various biological functions. However, the expression of GDF-15 in patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is unclear.

METHOD: The study included 47 AE-IPF patients, 61 stable IPF (S-IPF) subjects, and 31 healthy controls (HCs). Serum GDF-15 levels and their expression in the lung were measured. The correlation between serum GDF-15 and other clinical parameters and the risk factors for AE occurrence and the survival of IPF patients were analyzed.

RESULTS: Serum GDF-15 levels were significantly elevated in AE-IPF patients (1279.22 ± 540.02 pg/ml) as compared with HCs (891.30 ± 479.90 pg/ml) or S-IPF subjects (107.82 ± 14.21 pg/ml) (both p < 0.001). The protein and mRNA expressions of GDF-15 in the lung of AE-IPF patients were significantly increased as compared with S-IPF cases (p = 0.007 and p = 0.026, respectively). The serum GDF-15 level was correlated with the clinical variables of inflammation, metabolism, and disease severity in IPF subjects (all p < 0.05). The GDF-15 serum concentration was significantly higher in decedents than in survivors (p = 0.005). A serum GDF-15 level above 989.3 pg/ml was a risk factor for AE occurrence (p = 0.04), and the level above 1,075.76 pg/ml was an independent predictor for survival in IPF cases (p = 0.007).

CONCLUSIONS: The GDF-15 level was significantly elevated in subjects with AE-IPF. GDF-15 could be a promising biomarker for AE occurrence and survival in IPF patients.

PMID:35784345 | PMC:PMC9241490 | DOI:10.3389/fimmu.2022.891448

Front Mol Med. 2022;2:842558. doi: 10.3389/fmmed.2022.842558. Epub 2022 Mar 15.

ABSTRACT

Idiopathic pulmonary fibrosis is a lethal disease driven by myofibroblast expansion. Currently no therapies exist that target the epigenetic mechanisms controlling myofibroblast transdifferentiation, which is responsible for unregulated extracellular matrix (ECM) production. We have recently shown that bromodomain-containing protein 4 (BRD4), an epigenetic regulator that forms a scaffold for nuclear activators and transcription factors, is essential for TGFβ-induced myofibroblast transdifferentiation. However, its role in the development and progression of pulmonary fibrosis in vivo has not been established. Here, we evaluate the hypothesis that BRD4 bromodomain interactions mediate myofibroblast expansion and fibrosing disease in vivo. C57BL/6J mice challenged with intratracheal bleomycin were systemically treated with a selective allosteric inhibitor of the BRD4 bromodomain 1 (BD1), ZL0591 (10 mg/kg), during the established fibrotic phase (14 days post-bleomycin) in a rigorous therapeutic paradigm. Eleven days after initiation of ZL0591 treatment (25 days post-bleomycin), we detected a significant improvement in blood O2 saturation compared to bleomycin/vehicle control. Twenty-eight days post-bleomycin, we observed a reduction in the volumetric Hounsfield Unit (HU) density by micro computed tomography (μCT) in the ZL0591-treated group, as well as a reduction in collagen deposition (hydroxyproline content) and severity of injury (Ashcroft scoring). Myofibroblast transdifferentiation was measured by smooth muscle α-actin (αSMA) staining, indicating a loss of this cell population in the ZL0591-treated group, and corresponded to reduced transcript levels of myofibroblast-associated extracellular matrix genes, tenascin-C and collagen 1α1. We conclude that BRD4 BD1 interactions are critical for myofibroblast transdifferentiation and fibrotic progression in a mouse model of pulmonary fibrosis.

PMID:35782526 | PMC:PMC9245900 | DOI:10.3389/fmmed.2022.842558

Asian J Pharm Sci. 2022 May;17(3):447-461. doi: 10.1016/j.ajps.2022.04.004. Epub 2022 Apr 30.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a serious and fatal pulmonary inflammatory disease with an increasing incidence worldwide. The drugs nintedanib and pirfenidone, are listed as conditionally recommended drugs in the "Evidence-Based Guidelines for the Diagnosis and Treatment of Idiopathic Pulmonary Fibrosis". However, these two drugs have many adverse reactions in clinical application. Salvianolic acid B (Sal B), a water-soluble component of Salvia miltiorrhiza, could alleviate bleomycin-induced peroxidative stress damage, and prevent or delay the onset of IPF by regulating inflammatory factors and fibrotic cytokines during the disease's progression. However, Sal B is poorly absorbed orally, and patient compliance is poor when administered intravenously. Therefore, there is an urgent need to find a new non-injection route of drug delivery. In this study, Sal B was used as model drug and l-leucine (LL) as excipient to prepare Sal B dry powder inhaler (Sal B-DPI) by spray drying method. Modern preparation evaluation methods were used to assess the quality of Sal B-DPI. Sal B-DPI is promising for the treatment of IPF, according to studies on pulmonary irritation evaluation, in vivo and in vitro pharmacodynamics, metabolomics, pharmacokinetics, and lung tissue distribution.

PMID:35782322 | PMC:PMC9237582 | DOI:10.1016/j.ajps.2022.04.004

Quant Imaging Med Surg. 2022 Jul;12(7):3655-3665. doi: 10.21037/qims-21-1232.

ABSTRACT

BACKGROUND: The quantitative analysis of high-resolution computed tomography (HRCT) is increasingly being used to quantify the severity and evaluate the prognosis of disease. Our aim was to quantify the HRCT features of idiopathic pulmonary fibrosis (IPF) and identify their association with pulmonary function tests.

METHODS: This was a retrospective, single-center, clinical research study. Patients with IPF were retrospectively included. Pulmonary segmentation was performed using the deep learning-based method. Radiologists manually segmented 4 findings of IPF, including honeycombing (HC), reticular pattern (RE), traction bronchiectasis (TRBR), and ground glass opacity (GGO). Pulmonary vessels were segmented with the automatic integration segmentation method. All segmentation results were quantified by the corresponding segmentation software. Correlations between the volume of the 4 findings on HRCT, volume of the lesions at different sites, pulmonary vascular-related parameters, and pulmonary function tests were analyzed.

RESULTS: A total of 101 IPF patients (93 males) with a median age of 63 years [interquartile range (IQR), 58 to 68 years] were included in this study. Total lesion extent demonstrated a stronger negative correlation with diffusion capacity for carbon monoxide (DLco) compared to HC, RE, and TRBR [total lesion ratio, correlation coefficient (r) =-0.67, P<0.001; HC, r=-0.45, P<0.001; RE, r=-0.41, P<0.001; TRBR, r=-0.25, P<0.05, respectively]. Correlations with lung function were similar among various lesion sites with r from -0.38 to -0.61 (P<0.001). Pulmonary artery volume (PAV) displayed a slightly increased positive association with the DLco compared to total pulmonary vascular volume (PVV); for PAV, r=0.41 and P<0.001 and for total PVV, r=0.36 and P<0.001. Additionally, total lesion extent, HC, and RE indicated a negative relationship with vascular-related parameters, and the strength of the correlations was independent of lesion site.

CONCLUSIONS: Quantitative analysis of HRCT features of IPF indicated a decline in function and an aggravation of vascular destruction with increasing lesion extent. Furthermore, a positive correlation between vascular-related parameters and pulmonary function was confirmed. This co-linearity indicated the potential of vascular-related parameters as new objective markers for evaluating the severity of IPF.

PMID:35782232 | PMC:PMC9246749 | DOI:10.21037/qims-21-1232

Adv Ther. 2022 Jul 3. doi: 10.1007/s12325-022-02229-8. Online ahead of print.

ABSTRACT

Interstitial lung diseases (ILD) encompasses a heterogeneous group of parenchymal lung diseases characterized by variable amounts of inflammation and fibrosis. The targeting of fibroblasts and myofibroblasts with antifibrotic treatments is a potential therapeutic target for these potentially fatal diseases. Treprostinil is unique among the prostacyclin mimetics in that it has distinct actions at additional prostaglandin receptors. Preclinical and clinical evidence suggests that treprostinil has antifibrotic effects through the activation of the prostaglandin E receptor 2 (EP2), the prostaglandin D receptor 1 (DP1), and peroxisome proliferator-activated receptors (PPAR). In vivo studies of EP2 and the DP1 have found that administration of treprostinil resulted in a reduction in cell proliferation, reduced collagen secretion and synthesis, and reduced lung inflammation and fibrosis. In vitro and in vivo studies of PPARβ and PPARγ demonstrated that treprostinil inhibited fibroblast proliferation in a dose-dependent manner. Clinical data from a post hoc analysis of the INCREASE trial found that inhaled treprostinil improved forced vital capacity in the overall population as well as in idiopathic interstitial pneumonia and idiopathic pulmonary fibrosis subgroups. These preclinical and clinical findings suggest a dual benefit of treprostinil through the amelioration of both lung fibrosis and pulmonary hypertension.

PMID:35781186 | DOI:10.1007/s12325-022-02229-8

Sci Rep. 2022 Jul 1;12(1):11122. doi: 10.1038/s41598-022-15321-4.

ABSTRACT

Antibodies to Ro52/tripartite motif-containing 21 (TRIM21), referred to as anti-Ro52, are found in patients diagnosed with diverse systemic autoimmune rheumatic disease and associated with interstitial lung diseases. However, little is known about the clinical characteristics of anti-Ro52 in patients with idiopathic interstitial pneumonias (IIPs). We aimed to analyze the prevalence, co-existent autoantibodies, and clinical characteristics of anti-Ro52 in patients with IIP. The study enrolled 288 patients diagnosed with IIP. Clinical, laboratory and radiographic findings of IIP patients were compared between anti-Ro52 positives and negatives. Anti-Ro52 (20/288; 6.9%), anti-ARS (18/288; 6.3%), and anti-Ro60/SS-A (16/288; 5.6%) were the most common autoantibodies detected in IIP patients. Among 20 IIP patients who had anti-Ro52, anti-ARS was present in 8 (40%) patients. The criteria for interstitial pneumonia with autoimmune features (IPAF) were significantly better fulfilled by patients with anti-Ro52 than those without (P = 0.001). Meeting serological domain (P < 0.001) and Raynaud's phenomenon (P = 0.009) were significantly more common in the anti-Ro52-positive patients. Anti-Ro52-positive IIP patients have clinical features consistent with IPAF. Anti-Ro52 may have an important role in detecting the autoimmune phenotype in IIP patients.

PMID:35778430 | PMC:PMC9249750 | DOI:10.1038/s41598-022-15321-4

Pathology. 2022 Jun 29:S0031-3025(22)00173-8. doi: 10.1016/j.pathol.2022.05.002. Online ahead of print.

ABSTRACT

The pathogenesis of idiopathic pulmonary fibrosis (IPF) and its histological counterpart, usual interstitial pneumonia (UIP) remains debated. IPF/UIP is a disease characterised by respiratory restriction, and while there have been recent advances in treatment, mortality remains high. Genetic and environmental factors predispose to its development and aberrant alveolar repair is thought to be central. Following alveolar injury, the type II pneumocyte (AEC2) replaces the damaged thin type I pneumocytes. Despite the interstitial fibroblast being considered instrumental in formation of the fibrosis, there has been little consideration for a role for AEC2 in the repair of the septal interstitium. Elastin is a complex protein that conveys flexibility and recoil to the lung. The fibroblast is presumed to produce elastin but there is evidence that the AEC2 may have a role in production or deposition. While the lung is an elastic organ, the role of elastin in repair of lung injury and its possible role in UIP has not been explored in depth. In this paper, pathogenetic mechanisms of UIP involving AEC2 and elastin are reviewed and the possible role of AEC2 in elastin generation is proposed.

PMID:35778287 | DOI:10.1016/j.pathol.2022.05.002

Thorax. 2022 Jul 1:thoraxjnl-2021-218315. doi: 10.1136/thoraxjnl-2021-218315. Online ahead of print.

ABSTRACT

BACKGROUND: Interstitial lung abnormalities (ILAs) are associated with increased mortality. It is unclear whether multimorbidity accounts for the mortality association or how strongly ILA is associated with mortality relative to other common age-associated diseases. We determined the association of ILA with all-cause mortality adjusted for multimorbidity, compared mortality associated with ILA and prevalent cardiovascular disease (CVD), diabetes mellitus, chronic kidney disease, chronic obstructive pulmonary disease and cancer and also determined the association between ILA and these diseases.

METHODS: We measured ILA (none, indeterminant, definite) using blinded reads of CT images, prevalent chronic diseases and potential confounders in two observational cohorts, the Framingham Heart Study (FHS) (n=2449) and Age, Gene/Environment Susceptibility - Reykjavik Study (AGES-Reykjavik) (n=5180). We determined associations with mortality using Cox proportional hazards models and between ILA and diseases with multinomial logistic regression.

RESULTS: Over a median (IQR) follow-up of 8.8 (1.4) years in FHS and 12.0 (7.7) years in AGES-Reykjavik, in adjusted models, ILAs were significantly associated with increased mortality (HR, 95% CI 1.95, 1.23 to 3.08, p=0.0042, in FHS; HR 1.60, 1.41 to 1.82, p<0.0001, in AGES-Reykjavik) adjusted for multimorbidity. In both cohorts, the association of ILA with mortality was of similar magnitude to the association of most other diseases. In adjusted models, ILAs were associated only with prevalent kidney disease (OR, 95% CI 1.90, 1.01 to 3.57, p=0.0452) in FHS and with prevalent CVD (OR 1.42, 1.12 to 1.81, p=0.0040) in AGES-Reykjavik.

CONCLUSIONS: ILAs were associated with mortality adjusted for multimorbidity and were similarly associated with increased mortality compared with several common chronic diseases. ILAs were not consistently associated with the prevalence of these diseases themselves.

PMID:35777957 | DOI:10.1136/thoraxjnl-2021-218315

Eur Respir J. 2022 Jul 1:2102307. doi: 10.1183/13993003.02307-2021. Online ahead of print.

ABSTRACT

Accumulation of myofibroblasts is critical to fibrogenesis in idiopathic pulmonary fibrosis (IPF). Senescence and insufficient mitophagy in fibroblasts contribute to their differentiation into myofibroblasts, thereby promoting the development of lung fibrosis. Bone morphogenetic protein 4 (BMP4), a multifunctional growth factor, is essential for the early stage of lung development, however, the role of BMP4 in modulating lung fibrosis remains unknown.This study was to evaluate the role of BMP4 in lung fibrosis using BMP4-haplodeleted mice, BMP4-overexpressed mice, primary lung fibroblasts, and lung samples from patients with IPF.BMP4 expression was down-regulated in IPF lungs and fibroblasts compared to control individuals, negatively correlated with fibrotic genes, and BMP4 decreased with TGF-β1 stimulation in lung fibroblasts in a time- and dose-dependent manner. In mice challenged with bleomycin, BMP4 haploinsufficiency perpetuated activation of lung myofibroblasts and caused accelerated lung function decline, severe fibrosis and mortality. While BMP4 overexpression using AAV9 vectors showed preventative and therapeutic efficacy against lung fibrosis. In vitro, BMP4 attenuated TGF-β1-induced fibroblast-to-myofibroblast differentiation and extracellular matrix (ECM) production by reducing impaired mitophagy and cellular senescence in lung fibroblasts. Whereas Pink1 silencing by shRNA transfection abolished the ability of BMP4 to reverse the TGF-β1-induced myofibroblast differentiation and ECM production, indicating dependence on Pink1-mediated mitophagy. Moreover, the inhibitory effect of BMP4 on fibroblast activation and differentiation was accompanied with an activation of Smad1/5/9 signaling and suppression of TGF-β1-meidtaed Smad2/3 signaling in vivo and in vitroIn conclusion, strategies for enhancing BMP4 signaling may represent an effective treatment for pulmonary fibrosis.

PMID:35777761 | DOI:10.1183/13993003.02307-2021

Ann Am Thorac Soc. 2022 Jul;19(7):1095-1097. doi: 10.1513/AnnalsATS.202203-276ED.

NO ABSTRACT

PMID:35772099 | DOI:10.1513/AnnalsATS.202203-276ED

Sci Rep. 2022 Jun 30;12(1):11086. doi: 10.1038/s41598-022-14832-4.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is the most common and fatal form of interstitial lung disease. IPF is characterized by irreversible scarring of the lungs leading to lung function decline. Although the etiology remains poorly understood, dysregulated autophagy in alveolar-epithelial cells (AECs) together with interplay between apoptotic-AECs and proliferative-myofibroblasts have been strongly implicated in IPF pathogenesis. Recent studies have revealed that a caveolin-1-derived 7-mer peptide, CSP7, mitigates established PF at least in part by improving AEC viability. In the present study, we aimed to determine whether and how CSP7 regulates autophagy in fibrotic-lung AECs. We found that p53 and autophagic proteins were markedly upregulated in AECs from mice with single/multi-doses of bleomycin-or silica-induced PF. This was abolished following treatment of PF-mice with CSP7. Further, CSP7 abrogated silica- or bleomycin-induced p53 and autophagy proteins in AECs. Immunoprecipitation further revealed that CSP7 abolishes the interaction of caveolin-1 with LC3BII and p62 in AECs. AEC-specific p53-knockout mice resisted silica- or bleomycin-induced changes in autophagy proteins, or CSP7 treatment. Our findings provide a novel mechanism by which CSP7 inhibits dysregulated autophagy in injured AECs and mitigates existing PF. These results affirm the potential of CSP7 for treating established PF, including IPF and silicosis.

PMID:35773303 | DOI:10.1038/s41598-022-14832-4

Signal Transduct Target Ther. 2022 Jun 30;7(1):206. doi: 10.1038/s41392-022-01070-3.

ABSTRACT

Fibrosis is characterized by the excessive extracellular matrix deposition due to dysregulated wound and connective tissue repair response. Multiple organs can develop fibrosis, including the liver, kidney, heart, and lung. Fibrosis such as liver cirrhosis, idiopathic pulmonary fibrosis, and cystic fibrosis caused substantial disease burden. Persistent abnormal activation of myofibroblasts mediated by various signals, such as transforming growth factor, platelet-derived growth factor, and fibroblast growh factor, has been recongized as a major event in the occurrence and progression of fibrosis. Although the mechanisms driving organ-specific fibrosis have not been fully elucidated, drugs targeting these identified aberrant signals have achieved potent anti-fibrotic efficacy in clinical trials. In this review, we briefly introduce the aetiology and epidemiology of several fibrosis diseases, including liver fibrosis, kidney fibrosis, cardiac fibrosis, and pulmonary fibrosis. Then, we summarise the abnormal cells (epithelial cells, endothelial cells, immune cells, and fibroblasts) and their interactions in fibrosis. In addition, we also focus on the aberrant signaling pathways and therapeutic targets that regulate myofibroblast activation, extracellular matrix cross-linking, metabolism, and inflammation in fibrosis. Finally, we discuss the anti-fibrotic drugs based on their targets and clinical trials. This review provides reference for further research on fibrosis mechanism, drug development, and clinical trials.

PMID:35773269 | DOI:10.1038/s41392-022-01070-3

Clin Res Hepatol Gastroenterol. 2022 Jun 27:101977. doi: 10.1016/j.clinre.2022.101977. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Cystic fibrosis liver disease (CFLD) is the third leading cause of death in patients with cystic fibrosis (CF). We aim to determine the prevalence of CFLD in a cohort of adult patients with CF and to characterise liver involvement in this population highlighting the importance of histological diagnosis.

METHODS: We retrospectively studied a cohort of patients with CF. Inclusion criteria were age ≥ 18 and minimum 1 year of follow-up. We excluded lung transplant patients. CFLD was defined as having 2 out of 3 criteria: persistent elevation of transaminases and/or gamma-glutamyltransferase; abnormal ultrasound; and abnormal transient elastography. Non-invasive fibrosis biomarkers were calculated in CFLD patients. Adult-onset CFLD (Ad-CFLD) was defined as CFLD ≥18 years. Severe CFLD (s-CFLD) was defined as CFLD with cirrhosis and/or portal hypertension.

RESULTS: We included 113 patients. Median age was 29 years, 58 were male. Forty patients had CFLD. Median age at CFLD diagnosis was 10 years. Twenty-one patients had s-CFLD. Two s-CFLD patients had nodular regenerative hyperplasia, 1 had hepatocellular carcinoma and 4 underwent liver transplantation. Six patients had ad-CFLD. Both CFLD and s-CFLD groups were compared to a non-CFLD group. The CFLD group had significantly more males (p=0.034). S-CFLD group had worse pulmonary function (p=0.015).

CONCLUSION: Thirty five percent of adult patients with CF, mainly males, had CFLD. Nineteen percent had s-CFLD and had worse pulmonary function. With recent reports unravelling different pathophysiological mechanisms in CFLD, we believe it is important to better characterise liver involvement using liver biopsy.

PMID:35772685 | DOI:10.1016/j.clinre.2022.101977