Respir Med Res. 2022 Aug 4;83:100948. doi: 10.1016/j.resmer.2022.100948. Online ahead of print.

ABSTRACT

BACKGROUND: Since the latest 2017 French guidelines, knowledge about idiopathic pulmonary fibrosis has evolved considerably.

METHODS: Practical guidelines were drafted on the initiative of the Coordinating Reference Center for Rare Pulmonary Diseases, led by the French Language Pulmonology Society (SPLF), by a coordinating group, a writing group, and a review group, with the involvement of the entire OrphaLung network, pulmonologists practicing in various settings, radiologists, pathologists, a general practitioner, a health manager, and a patient association. The method followed the "Clinical Practice Guidelines" process of the French National Authority for Health (HAS), including an online vote using a Likert scale.

RESULTS: After a literature review, 54 guidelines were formulated, improved, and then validated by the working groups. These guidelines addressed multiple aspects of the disease: epidemiology, diagnostic procedures, quality criteria and interpretation of chest CT scans, lung biopsy indication and procedures, etiological workup, methods and indications for family screening and genetic testing, assessment of the functional impairment and prognosis, indication and use of antifibrotic agents, lung transplantation, management of symptoms, comorbidities and complications, treatment of chronic respiratory failure, diagnosis and management of acute exacerbations of fibrosis.

CONCLUSION: These evidence-based guidelines are intended to guide the diagnosis and practical management of idiopathic pulmonary fibrosis.

PMID:36630775 | DOI:10.1016/j.resmer.2022.100948

Anal Chim Acta. 2023 Jan 25;1239:340731. doi: 10.1016/j.aca.2022.340731. Epub 2022 Dec 19.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory disease destroying lungs irreversibly with high mortality rates. There are challenges in diagnosing IPF and treating it at an early stage. Mounting evidence suggests that hypochlorous acid (HClO) can help in diagnosing inflammation and relevant conditions. Pulmonary fibrosis is linked to the mitochondrial oxidative stress where excessive HClO production is a key molecular mechanism. Measuring mitochondrial HClO levels assists in the investigations of how the mitochondrial oxidative stress affects IPF. Herein, NIR-PTZ-HClO was developed and optimized as a probe for detecting fluctuations in HClO concentrations of cells and mice models through near-infrared (NIR) fluorescence. The probe featured large Stokes shift of 150 nm, NIR turn-on signal at 650 nm, high sensitivity (45-fold) and quick HClO detection (2 s). The probe is selective for HClO in the presence of range of other analytes. NIR-PTZ-HClO visualized both endogenous and exogenous HClO in living cells (RAW264.7, H460 and A549). The probe monitored HClO in mice models with IPF and moreover the HClO profile could be tracked during the IPF process. The probe also detected precipitous decrease in HClO levels in IPF mice treated with OFEV. NIR-PTZ-HClO probe has thus the potential for earlier diagnosis of lung fibrosis, thereby improving the treatment efficacy.

PMID:36628728 | DOI:10.1016/j.aca.2022.340731

BMC Pulm Med. 2023 Jan 10;23(1):11. doi: 10.1186/s12890-023-02307-9.

ABSTRACT

BACKGROUND: Prolonged mechanical ventilation (PMV), mostly defined as mechanical ventilation > 72 h after lung transplantation with or without tracheostomy, is associated with increased mortality. Nevertheless, the predictive factors of PMV after lung transplant remain unclear. The present study aimed to develop a novel scoring system to identify PMV after lung transplantation.

METHODS: A total of 141 patients who underwent lung transplantation were investigated in this study. The patients were divided into PMV and non-prolonged ventilation (NPMV) groups. Univariate and multivariate logistic regression analyses were performed to assess factors associated with PMV. A risk nomogram was then established based on the multivariate analysis, and model performance was further examined regarding its calibration, discrimination, and clinical usefulness.

RESULTS: Eight factors were finally identified to be significantly associated with PMV by the multivariate analysis and therefore were included as risk factors in the nomogram as follows: the body mass index (BMI, P = 0.036); primary diagnosis as idiopathic pulmonary fibrosis (IPF, P = 0.038); pulmonary hypertension (PAH, P = 0.034); primary graft dysfunction grading (PGD, P = 0.011) at T0; cold ischemia time (CIT P = 0.012); and three ventilation parameters (peak inspiratory pressure [PIP, P < 0.001], dynamic compliance [Cdyn, P = 0.001], and P/F ratio [P = 0.015]) at T0. The nomogram exhibited superior discrimination ability with an area under the curve of 0.895. Furthermore, both calibration curve and decision-curve analysis indicated satisfactory performance.

CONCLUSION: A novel nomogram to predict individual risk of receiving PMV for patients after lung transplantation was established, which may guide preventative measures for tackling this adverse event.

PMID:36627599 | DOI:10.1186/s12890-023-02307-9

JCI Insight. 2023 Jan 10:e158100. doi: 10.1172/jci.insight.158100. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease. Recent findings have shown a marked metabolic reprogramming associated with changes in mitochondrial homeostasis and autophagy during pulmonary fibrosis. The microRNA-33 (miR-33) family of microRNAs (miRNAs) encoded within the introns of SREBP (sterol regulatory element binding protein) genes are master regulators of sterol and fatty acid (FA) metabolism. miR-33 controls macrophage immuno-metabolic response and enhances mitochondrial biogenesis, FA oxidation, and cholesterol efflux. Here, we show that miR-33 levels are increased in Broncho Alveolar Lavage (BAL) cells isolated from IPF patients compared to healthy controls. We demonstrate that specific genetic ablation of miR-33 in macrophages protects against bleomycin-induced pulmonary fibrosis. The absence of miR-33 in macrophages improves mitochondrial homeostasis and increases autophagy while decreasing inflammatory response after bleomycin injury. Notably, pharmacological inhibition of miR-33 in macrophages via administration of anti-miR-33 Peptide Nucleic Acids (PNA-33) attenuates fibrosis in different in vivo and ex vivo mice and human models of pulmonary fibrosis. Together, these studies elucidate a major role of miR-33 in macrophages in the regulation of pulmonary fibrosis and uncover a novel therapeutic approach to treat this disease.

PMID:36626225 | DOI:10.1172/jci.insight.158100

Am J Physiol Lung Cell Mol Physiol. 2023 Jan 10. doi: 10.1152/ajplung.00253.2021. Online ahead of print.

ABSTRACT

The most common preclinical, in vivo model to study lung fibrosis is the bleomycin-induced lung fibrosis model in 2-3-month-old mice. Although this model resembles key aspects of idiopathic pulmonary fibrosis (IPF), there are limitations in its predictability for the human disease. One of the main differences is the juvenile age of animals that are commonly used in experiments, resembling humans of around 20 years. Because IPF patients are usually older than 60 years, aging appears to play an important role in the pathogenesis of lung fibrosis. Therefore, we compared young (3 months) and old mice (21 months) 21 days after intratracheal bleomycin instillation. Analyzing lung transcriptomics (mRNAs & miRNAs) and proteomics, we found most pathways to be similarly regulated in young and old mice. However, old mice show an imbalanced protein homeostasis as well as an increased inflammatory state in the fibrotic phase compared to young mice. Comparisons with published human transcriptomic data sets (GSE47460, GSE32537 and GSE24206) revealed that the gene signature of old animals correlates significantly better with IPF patients and it also turned human healthy individuals better into "IPF patients" using an approach based on predictive disease modelling. Both young and old animals show similar molecular hallmarks of IPF in the bleomycin-induced lung fibrosis model. Although, old mice more closely resemble several features associated with IPF in comparison to young animals.

PMID:36625483 | DOI:10.1152/ajplung.00253.2021

Am J Physiol Lung Cell Mol Physiol. 2023 Jan 10. doi: 10.1152/ajplung.00180.2022. Online ahead of print.

ABSTRACT

The development of new drugs for Idiopathic Pulmonary Fibrosis strongly relies on preclinical experimentation, which requires the continuous improvement of animal models and integration with in-vivo imaging data. Here, we investigated the lung distribution of bleomycin (BLM) associated with the Indocyanine Green (ICG) dye by fluorescence imaging. A long-lasting lung retention (up to 21 days) was observed upon oropharyngeal aspiration (OA) of either ICG or BLM+ICG, with a significantly more severe pulmonary fibrosis, accompanied by the progressive appearance of emphysema-like features, uniquely associated to the latter combination. A more severe and persistent lung fibrosis, together with a progressive air space enlargement uniquely associated to the BLM+ICG group, was confirmed by longitudinal micro-CT and histological analyses. Multiple inflammation and fibrosis biomarkers were found to be increased in the bronchoalveolar lavage fluid of BLM- and BLM+ICG-treated animals, but with a clear trend toward a much stronger increase in the latter group. Similarly, in-vitro assays performed on macrophage and epithelial cell lines, revealed a significantly more marked cytotoxicity in the case of BLM+ICG-treated mice. Also unique to this group was the synergistic upregulation of apoptotic markers both in lung sections and cell lines. Although the exact mechanism underlying the more intense lung fibrosis phenotype with emphysema-like features induced by BLM+ICG remains to be elucidated, we believe that this combination treatment, whose overall effects more closely resemble the human disease, represents a valuable alternative model for studying fibrosis development and for the identification of new antifibrotic compounds.

PMID:36625471 | DOI:10.1152/ajplung.00180.2022

Respir Res. 2023 Jan 9;24(1):7. doi: 10.1186/s12931-022-02309-x.

ABSTRACT

BACKGROUND: Several observational studies have found that idiopathic pulmonary fibrosis (IPF) is often accompanied by elevated circulating C-reactive protein (CRP) levels. However, the causal relationship between them remains to be determined. Therefore, our study aimed to explore the causal effect of circulating CRP levels on IPF risk by the two-sample Mendelian randomization (MR) analysis.

METHODS: We analyzed the data from two genome-wide association studies (GWAS) of European ancestry, including circulating CRP levels (204,402 individuals) and IPF (1028 cases and 196,986 controls). We primarily used inverse variance weighted (IVW) to assess the causal effect of circulating CRP levels on IPF risk. MR-Egger regression and MR-PRESSO global test were used to determine pleiotropy. Heterogeneity was examined with Cochran's Q test. The leave-one-out analysis tested the robustness of the results.

RESULTS: We obtained 54 SNPs as instrumental variables (IVs) for circulating CRP levels, and these IVs had no significant horizontal pleiotropy, heterogeneity, or bias. MR analysis revealed a causal effect between elevated circulating CRP levels and increased risk of IPF (ORIVW = 1.446, 95% CI 1.128-1.854, P = 0.004).

CONCLUSIONS: The present study indicated that elevated circulating CRP levels could increase the risk of developing IPF in people of European ancestry.

PMID:36624433 | DOI:10.1186/s12931-022-02309-x

Exp Gerontol. 2023 Jan 6:112085. doi: 10.1016/j.exger.2023.112085. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible lung disease with limited therapeutic options. Aspirin can alleviate liver, kidney, and cardiac fibrosis. However, its role in lung fibrosis is unclear. This study aims to investigate the effects of aspirin on lung fibroblast differentiation and pulmonary fibrosis. TGF-β1-induced human embryonic lung fibroblasts, IPF lung fibroblasts, and bleomycin-induced lung fibrosis mouse model were used in this study. The results showed that aspirin significantly decreased the expression of Collagen 1A1, Fibronectin, Alpha-smooth muscle actin, and equestosome1, and increased the ratio of light chain 3 beta II/I and the number of autophagosome in vivo and in vitro; reduced bleomycin-induced lung fibrosis. Aspirin also decreased the ratios of phosphorylated phosphatidylinositol 3 kinase (p-PI3K)/PI3K, protein kinase B (p-AKT)/AKT, and mechanistic target of rapamycin (p-mTOR)/mTOR in vitro. Autophagy inhibitor 3-methyladenine, bafilomycin-A1, and AKT activator SC-79 abrogated the effects of aspirin. These findings indicate that aspirin ameliorates pulmonary fibrosis through a PI3K/AKT/mTOR-dependent autophagy pathway.

PMID:36623738 | DOI:10.1016/j.exger.2023.112085

Am J Respir Crit Care Med. 2023 Jan 9. doi: 10.1164/rccm.202204-0781OC. Online ahead of print.

ABSTRACT

RATIONALE AND OBJECTIVES: Up to 20% of idiopathic interstitial lung disease is familial, referred to as Familial Pulmonary Fibrosis (FPF). We performed an integrated analysis of FPF genetic risk by comprehensively evaluating for genetic rare variants (RVs) in a large cohort of FPF kindreds.

METHODS: We performed whole-exome sequencing and/or candidate gene sequencing from affected individuals in 569 FPF kindreds, followed by co-segregation analysis in large kindreds, gene burden analysis, gene-based risk scoring, cell type enrichment analysis, and co-expression network construction.

MEASUREMENTS AND MAIN RESULTS: We found that 14.9% - 23.4% of genetic risk in kindreds could be explained by RVs in genes previously linked to FPF, predominantly telomere related genes. We identified new candidate genes in a small number of families, including SYDE1, SERPINB8, GPR87, and NETO1, and developed tools for evaluation and prioritization of RV-containing genes across kindreds. Several pathways were enriched for RV-containing genes in FPF, including focal adhesion and mitochondrial complex I assembly. By combining single cell transcriptomics with prioritized candidate genes, we discovered that expression of RV-containing genes was enriched in smooth muscle cells, type II alveolar epithelial cells, and endothelial cells.

CONCLUSIONS: In the most comprehensive FPF genetic study to date, we defined the prevalence of RVs in known FPF-related genes and identified new candidate genes and pathways relevant to FPF. However, we did not identify new RV-containing genes shared across multiple kindreds, thereby suggesting that heterogeneous genetic variants involving a variety of genes and pathways mediate genetic risk in most FPF kindreds.

PMID:36622818 | DOI:10.1164/rccm.202204-0781OC

Physiother Theory Pract. 2023 Jan 9:1-10. doi: 10.1080/09593985.2022.2160679. Online ahead of print.

ABSTRACT

BACKGROUND: Despite the high prevalence of sleep disturbances in idiopathic pulmonary fibrosis (IPF), the relationship between physical activity in daily life (PADL) and sleep in this population remains unclear.

OBJECTIVES: Investigate the impact of sleep on different domains of PADL in IPF and characterize their PADL profile.

METHODS: Sixty-seven participants (thirty-three with IPF and thirty-four healthy subjects [control group]) were included. The subjects underwent assessments of pulmonary function, exercise capacity, respiratory and peripheral muscle strength, PADL, sleep, dyspnea, and health-related quality of life. PADL and sleep measures were assessed using an activity monitor (Actigraph®, wGT3x-BT). Associations between sleep and PADL were done using correlation and regression models.

RESULTS: In the IPF, sleep duration at night associated significantly with step counts, sedentary, light, and moderate-to-vigorous physical activity (MVPA) (-0.82 ≤ R ≤ 0.43; p < .05 for all). Lung function and sleep partially explained PADL variables (0.19 ≤ R2 ≤ 0.65, p < .05 for all). Compared to controls, the IPF subjects presented lower step counts, less time spent in MVPA, standing position, and more time spent in lying position (p < .05, for all).

CONCLUSIONS: Sleep duration is associated with PADL in IPF. The PADL profile of patients is worse than in control subjects.

PMID:36622293 | DOI:10.1080/09593985.2022.2160679

Elife. 2023 Jan 9;12:e81801. doi: 10.7554/eLife.81801. Online ahead of print.

ABSTRACT

Background: WHO has called for research into predictive factors for selecting persons who could be successfully treated with shorter durations of direct acting antiviral (DAA) therapy for Hepatitis C. We evaluated early virological response as a means of shortening treatment and explored host, viral and pharmacokinetic contributors to treatment outcome.

Methods: Duration of sofosbuvir and daclatasvir (SOF/DCV) was determined according to day 2 (D2) virologic response for HCV genotype (gt) 1- or 6-infected adults in Vietnam with mild liver disease. Participants received 4- or 8-weeks treatment according to whether D2 HCV RNA was above or below 500 IU/ml (standard duration is 12 weeks). Primary endpoint was sustained virological response (SVR12). Those failing therapy were retreated with 12 weeks SOF/DCV. Host IFNL4 genotype and viral sequencing was performed at baseline, with repeat viral sequencing if virological rebound was observed. Levels of SOF, its inactive metabolite GS-331007 and DCV were measured on day 0 and 28.

Results: Of 52 adults enrolled, 34 received 4 weeks SOF/DCV, 17 got 8 weeks and one withdrew. SVR12 was achieved in 21/34 (62%) treated for 4 weeks, and 17/17 (100%) treated for 8 weeks. Overall, 38/51 (75%) were cured with first-line treatment (mean duration 37 days). Despite a high prevalence of putative NS5A-inhibitor resistance associated substitutions (RAS), all first-line treatment failures cured after retreatment (13/13). We found no evidence treatment failure was associated with host IFNL4 genotype, viral subtype, baseline RAS, SOF or DCV levels.

Conclusions: Shortened SOF/DCV therapy, with retreatment if needed, reduces DAA use in patients with mild liver disease, while maintaining high cure rates. D2 virologic response alone does not adequately predict SVR12 with 4 weeks treatment.

Funding: Funded by the Medical Research Council (grant MR/P025064/1) and The Global Challenges Research Fund (Wellcome Trust Grant 206/296/Z/17/Z).).

Clinical trial number: ISRCTN17100273.

PMID:36622106 | DOI:10.7554/eLife.81801

Chest. 2023 Jan 5:S0012-3692(23)00018-1. doi: 10.1016/j.chest.2022.12.039. Online ahead of print.

ABSTRACT

BACKGROUND: Biological sex, gender and race are important considerations in patients with interstitial lung diseases (ILD).

RESEARCH QUESTION: Do patient's sex assigned at birth and race influence ILD treatment initiation?

STUDY DESIGN AND METHODS: Patients with ILD from three longitudinal prospective registries were compared in this observational study. ILD-related medications included antifibrotics and immunomodulating medications. Race was dichotomized as "White" vs non-White". Time to treatment initiation was determined from the date of initial ILD registry visit to the date of first medication initiation. Proportions of treated patients were compared between groups using Chi2 test. Cox proportional analysis was used to determine how sex and race was associated with time to treatment initiation stratified by ILD diagnosis.

RESULTS: A total of 4572 patients were included across all cohorts. The proportion of men who received treatment was higher than for women in the Canadian cohort (47 vs 40%, p,<0.001), and the proportion of White patients who received treatment was also higher compared to non-Whites (46 vs 36%, p<0.001). In contrast, the proportion of treated men in the Chicago cohort was lower compared to women (56 vs 64%, p=0.005), and that of White patients was lower compared to non-Whites (56 vs 69%, p<0.001). No sex- or race-based differences in proportions of patients treated were found in the Australasian cohort. White race was significantly associated with earlier treatment initiation compared to non-White patients across diagnoses in the Canadian cohort, while the opposite association was found in the Australasian cohort.

INTERPRETATION: Sex- and racial-based differences exist in the initiation of ILD treatment, with variability across different cohorts in different countries. Reasons for these differences need to be further explored in future studies.

PMID:36621759 | DOI:10.1016/j.chest.2022.12.039

J Control Release. 2023 Jan 5:S0168-3659(23)00005-6. doi: 10.1016/j.jconrel.2023.01.005. Online ahead of print.

NO ABSTRACT

PMID:36621645 | DOI:10.1016/j.jconrel.2023.01.005

Respirol Case Rep. 2023 Jan 4;11(2):e01081. doi: 10.1002/rcr2.1081. eCollection 2023 Feb.

ABSTRACT

Peribronchiolar metaplasia (PBM) is a histological finding of uncertain significance commonly seen in interstitial lung disease (ILD). PBM is thought to be secondary to small airway injury from insults such as tobacco smoke and other environmental exposures. The term PBM-ILD has been proposed for patients with ILD where PBM is the major histologic finding, however a lack of radiographic changes supportive of ILD in previously reported cases has limited recognition of the diagnosis. We present a rare case of welding-associated ILD with clinical, radiographic, and histologic evidence consistent with the proposed definition of PBM-ILD. We outline an approach to its consideration as a diagnosis based on our experience through multidisciplinary discussion.

PMID:36619889 | PMC:PMC9812661 | DOI:10.1002/rcr2.1081

Int J Mol Sci. 2022 Dec 28;24(1):499. doi: 10.3390/ijms24010499.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is characterized by abnormal fibroblast accumulation in the lung leading to extracellular matrix deposition and remodeling that compromise lung function. However, the mechanisms of interstitial invasion and remodeling by lung fibroblasts remain poorly understood. The invadosomes, initially described in cancer cells, consist of actin-based adhesive structures that coordinate with numerous other proteins to form a membrane protrusion capable of degrading the extracellular matrix to promote their invasive phenotype. In this regard, we hypothesized that invadosome formation may be increased in lung fibroblasts from patients with IPF. Public RNAseq datasets from control and IPF lung tissues were used to identify differentially expressed genes associated with invadosomes. Lung fibroblasts isolated from bleomycin-exposed mice and IPF patients were seeded with and without the two approved drugs for treating IPF, nintedanib or pirfenidone on fluorescent gelatin-coated coverslips for invadosome assays. Several matrix and invadosome-associated genes were increased in IPF tissues and in IPF fibroblastic foci. Invadosome formation was significantly increased in lung fibroblasts isolated from bleomycin-exposed mice and IPF patients. The degree of lung fibrosis found in IPF tissues correlated strongly with invadosome production by neighboring cells. Nintedanib suppressed IPF and PDGF-activated lung fibroblast invadosome formation, an event associated with inhibition of the PDGFR/PI3K/Akt pathway and TKS5 expression. Fibroblasts derived from IPF lung tissues express a pro-invadosomal phenotype, which correlates with the severity of fibrosis and is responsive to antifibrotic treatment.

PMID:36613948 | DOI:10.3390/ijms24010499

Int J Mol Sci. 2022 Dec 25;24(1):326. doi: 10.3390/ijms24010326.

ABSTRACT

Diffuse parenchymal lung diseases (DPLD) or Interstitial lung diseases (ILD) are a heterogeneous group of lung conditions with common characteristics that can progress to fibrosis. Within this group of pneumonias, idiopathic pulmonary fibrosis (IPF) is considered the most common. This disease has no known cause, is devastating and has no cure. Chronic lesion of alveolar type II (ATII) cells represents a key mechanism for the development of IPF. ATII cells are specialized in the biosynthesis and secretion of pulmonary surfactant (PS), a lipid-protein complex that reduces surface tension and minimizes breathing effort. Some differences in PS composition have been reported between patients with idiopathic pulmonary disease and healthy individuals, especially regarding some specific proteins in the PS; however, few reports have been conducted on the lipid components. This review focuses on the mechanisms by which phospholipids (PLs) could be involved in the development of the fibroproliferative response.

PMID:36613771 | DOI:10.3390/ijms24010326

Int J Mol Sci. 2022 Dec 23;24(1):239. doi: 10.3390/ijms24010239.

ABSTRACT

Fibrosing diseases are a major medical problem, and are associated with more deaths per year than cancer in the US. Sialidases are enzymes that remove the sugar sialic acid from glycoconjugates. In this review, we describe efforts to inhibit fibrosis by inhibiting sialidases, and describe the following rationale for considering sialidases to be a potential target to inhibit fibrosis. First, sialidases are upregulated in fibrotic lesions in humans and in a mouse model of pulmonary fibrosis. Second, the extracellular sialidase NEU3 appears to be both necessary and sufficient for pulmonary fibrosis in mice. Third, there exist at least three mechanistic ways in which NEU3 potentiates fibrosis, with two of them being positive feedback loops where a profibrotic cytokine upregulates NEU3, and the upregulated NEU3 then upregulates the profibrotic cytokine. Fourth, a variety of NEU3 inhibitors block pulmonary fibrosis in a mouse model. Finally, the high sialidase levels in a fibrotic lesion cause an easily observed desialylation of serum proteins, and in a mouse model, sialidase inhibitors that stop fibrosis reverse the serum protein desialylation. This then indicates that serum protein sialylation is a potential surrogate biomarker for the effect of sialidase inhibitors, which would facilitate clinical trials to test the exciting possibility that sialidase inhibitors could be used as therapeutics for fibrosis.

PMID:36613682 | DOI:10.3390/ijms24010239

Cells. 2022 Dec 29;12(1):145. doi: 10.3390/cells12010145.

ABSTRACT

DNA damage is the major cause of senescence and apoptosis; however, the manner by which DNA-damaged cells become senescent remains unclear. We demonstrate that DNA damage leads to a greater level of senescence rather than apoptosis in DBC1-deficient cells. In addition, we show that BLM becomes degraded during DNA damage, which induces p21 expression and senescence. DBC1 binds to and shields BLM from degradation, thus suppressing senescence. ML216 promotes DBC1-BLM interaction, which aids in the preservation of BLM following DNA damage and suppresses senescence. ML216 enhances pulmonary function by lowering the levels of senescence and fibrosis in both aged mice and a mouse model of bleomycin-induced idiopathic pulmonary fibrosis. Our data reveal a unique mechanism preventing DNA-damaged cells from becoming senescent, which may be regulated by the use of ML216 as a potential treatment for senescence-related diseases.

PMID:36611939 | DOI:10.3390/cells12010145

J Biomed Sci. 2023 Jan 7;30(1):2. doi: 10.1186/s12929-023-00896-5.

ABSTRACT

BACKGROUND: Heat shock protein 27 (HSP27) is overexpressed during pulmonary fibrosis (PF) and exacerbates PF; however, the upregulation of HSP27 during PF and the therapeutic strategy of HSP27 inhibition is not well elucidated.

METHODS: We have developed a mouse model simulating clinical stereotactic body radiotherapy (SBRT) with focal irradiation and validated the induction of RIPF. HSP25 (murine form of HSP27) transgenic (TG) and LLC1-derived orthotropic lung tumor models were also used. Lung tissues of patients with RIPF and idiopathic pulmonary fibrosis, and lung tissues from various fibrotic mouse models, as well as appropriated cell line systems were used. Public available gene expression datasets were used for therapeutic response rate analysis. A synthetic small molecule HSP27 inhibitor, J2 was also used.

RESULTS: HSP27 expression with its phosphorylated form (pHSP27) increased during PF. Decreased mRNA expression of SMAD-specific E3 ubiquitin-protein ligase 2 (Smurf2), which is involved in ubiquitin degradation of HSP27, was responsible for the increased expression of pHSP27. In addition, increased expression of miRNA15b was identified with decreased expression of Smurf2 mRNA in PF models. Inverse correlation between pHSP27 and Smurf2 was observed in the lung tissues of PF animals, an irradiated orthotropic lung cancer models, and PF tissues from patients. Moreover, a HSP27 inhibitor cross-linked with HSP27 protein to ameliorate PF, which was more effective when targeting the epithelial to mesenchymal transition (EMT) stage of PF.

CONCLUSIONS: Our findings identify upregulation mechanisms of HSP27 during PF and provide a therapeutic strategy for HSP27 inhibition for overcoming PF.

PMID:36611161 | DOI:10.1186/s12929-023-00896-5

Phytomedicine. 2022 Dec 13;109:154604. doi: 10.1016/j.phymed.2022.154604. Online ahead of print.

ABSTRACT

BACKGROUND: Jinshui Huanxian formula (JHF) ameliorates idiopathic pulmonary fibrosis patients. Active compounds, including icariin, isoliquiritigenin, nobiletin, peimine, and paeoniflorin, deriving from JHF were combined as effective-component compatibility ECC of JHF II (ECC-JHF II), which is an effective therapeutic strategy for pulmonary fibrosis (PF) induced by bleomycin (BLM) in rats.

PURPOSE: This study aimed to explore the underlying mechanism of ECC-JHF II on pulmonary fibrosis.

METHODS: A model of PF in rats was established through intratracheal instillation of BLM. Pulmonary function, pathological changes, and collagen deposition were examined. The gene and protein expressions in fibroblast activation were detected by quantitative real-time PCR and western blotting respectively.

RESULTS: ECC-JHF II significantly improved BLM-induced PF in rats, manifested as decreased collagen deposition, reduced pathological damage and improved pulmonary function. Furthermore, ECC-JHF II inhibited fibroblast activation by reducing the expression of α-smooth muscle actin (α-SMA) and fibronectin. We analyzed the targets of ECC-JHF II and differentially expressed genes (DEGs) of fibroblast activation induced by transforming growth factor-β1 (TGF-β1) and found that ECC-JHF II might regulate fibroblast activation by EGFR, PI3K-Akt or mTOR signaling pathway. In vitro experiments, we also found that ECC-JHF II suppressed the mTOR pathway, such as downregulating the phosphorylation levels of p70S6K in fibroblast activation induced by TGF-β1. After activating mTOR signaling, the inhibition of ECC-JHF II on fibroblast activation was blocked. These results suggested that ECC-JHF II potently ameliorated pulmonary fibrosis in rats and effectively suppressed fibroblast activation by interfering with mTOR signaling.

CONCLUSION: We combined transcriptomics with the network analysis to predict the mechanism underlying ECC-JHF II suppression of fibroblast activation. In summary, ECC-JHF II improved BLM-induced pulmonary fibrosis, which might be associated with the suppression of fibroblast activation by inhibiting the mTOR signaling.

PMID:36610143 | DOI:10.1016/j.phymed.2022.154604