Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 4.198
Filter
1.
J Cancer Res Ther ; 20(3): 999-1005, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-39023609

ABSTRACT

AIMS: This study aims to investigate the incidence rate of pulmonary fibrosis as a late radiotherapy complication and identify the associated dosimetric and demographic factors using radiological findings between Iranian patients with breast cancer. METHODS AND MATERIAL: Breast cancer patients treated at the education hospital of Shohada-e Tajrish Hospital, Tehran, Iran, from 2017 to 2021 were considered. Patients have included for whom a secondary chest CT scan was available at least six months after radiotherapy. Dose-volume histogram (DVH) parameters of three-dimensional conformal radiotherapy (3D-CRT) treatment plans were exported. Demographic features and data on underlying lung diseases, diabetes, and smoking history were extracted. RESULTS: A total of 250 patients were included in the study with a mean age of 46.1 ± 7.5 yrs and a mean body mass index (BMI) of 24.5 ± 4.2 kg/m2. Pulmonary fibrosis was detected for sixty-two cases. A significant relationship was obtained between the ipsilateral lung DVH parameters of patients with pulmonary fibrosis (P value < 0.05). The V5Gy, V10Gy, V13Gy, V20Gy, V30Gy, MLD, and DMax for individuals with pulmonary fibrosis were significantly higher than those without this injury. CONCLUSIONS: Pulmonary fibrosis was distinguished for 25% of the breast cancer cases at least six months after adjuvant radiotherapy. A significant relationship between the DVH parameters, underlying lung disease, diabetes, radiotherapy fields (i.e., Breast + LN + SC or Breast/Chest-wall only), age, and BMI with the frequency of the ipsilateral pulmonary fibrosis was obtained. V13Gy and V30Gy of the ipsilateral lung may be the most predictor of pulmonary fibrosis incidence.


Subject(s)
Breast Neoplasms , Pulmonary Fibrosis , Humans , Female , Breast Neoplasms/radiotherapy , Breast Neoplasms/epidemiology , Breast Neoplasms/pathology , Middle Aged , Iran/epidemiology , Cross-Sectional Studies , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/epidemiology , Radiotherapy, Adjuvant/adverse effects , Prevalence , Adult , Radiotherapy, Conformal/adverse effects , Radiation Injuries/epidemiology , Radiation Injuries/etiology , Radiation Injuries/diagnosis , Radiotherapy Dosage , Incidence
2.
Int J Biol Sci ; 20(9): 3353-3371, 2024.
Article in English | MEDLINE | ID: mdl-38993568

ABSTRACT

Radiation-induced pulmonary fibrosis (RIPF) represents a serious complication observed in individuals undergoing thoracic radiation therapy. Currently, effective interventions for RIPF are unavailable. Prior research has demonstrated that nintedanib, a Food and Drug Administration (FDA)-approved anti-fibrotic agent for idiopathic pulmonary fibrosis, exerts therapeutic effects on chronic fibrosing interstitial lung disease. This research aimed to investigate the anti-fibrotic influences of nintedanib on RIPF and reveal the fundamental mechanisms. To assess its therapeutic impact, a mouse model of RIPF was established. The process involved nintedanib administration at various time points, both prior to and following thoracic radiation. In the RIPF mouse model, an assessment was conducted on survival rates, body weight, computed tomography features, histological parameters, and changes in gene expression. In vitro experiments were performed to discover the mechanism underlying the therapeutic impact of nintedanib on RIPF. Treatment with nintedanib, administered either two days prior or four weeks after thoracic radiation, significantly alleviated lung pathological changes, suppressed collagen deposition, and improved the overall health status of the mice. Additionally, nintedanib demonstrated significant mitigation of radiation-induced inflammatory responses in epithelial cells by inhibiting the PI3K/AKT and MAPK signaling pathways. Furthermore, nintedanib substantially inhibited fibroblast-to-myofibroblast transition by suppressing the TGF-ß/Smad and PI3K/AKT/mTOR signaling pathways. These findings suggest that nintedanib exerts preventive and therapeutic effects on RIPF by modulating multiple targets instead of a single anti-fibrotic pathway and encourage the further clinical trials to determine the efficacy of nintedanib in patients with RIPF.


Subject(s)
Fibroblasts , Indoles , Pulmonary Fibrosis , Animals , Indoles/therapeutic use , Indoles/pharmacology , Mice , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/drug therapy , Fibroblasts/drug effects , Fibroblasts/metabolism , Epithelial Cells/drug effects , Myofibroblasts/drug effects , Myofibroblasts/metabolism , Mice, Inbred C57BL , Inflammation/drug therapy , Signal Transduction/drug effects
3.
J Am Heart Assoc ; 13(14): e034363, 2024 Jul 16.
Article in English | MEDLINE | ID: mdl-38979786

ABSTRACT

BACKGROUND: Aging-associated left ventricular dysfunction promotes cardiopulmonary fibrogenic remodeling, Group 2 pulmonary hypertension (PH), and right ventricular failure. At the time of diagnosis, cardiac function has declined, and cardiopulmonary fibrosis has often developed. Here, we sought to develop a molecular positron emission tomography (PET)-magnetic resonance imaging (MRI) protocol to detect both cardiopulmonary fibrosis and fibrotic disease activity in a left ventricular dysfunction model. METHODS AND RESULTS: Left ventricular dysfunction was induced by transverse aortic constriction (TAC) in 6-month-old senescence-accelerated prone mice, a subset of mice that received sham surgery. Three weeks after surgery, mice underwent simultaneous PET-MRI at 4.7 T. Collagen-targeted PET and fibrogenesis magnetic resonance (MR) probes were intravenously administered. PET signal was computed as myocardium- or lung-to-muscle ratio. Percent signal intensity increase and Δ lung-to-muscle ratio were computed from the pre-/postinjection magnetic resonance images. Elevated allysine in the heart (P=0.02) and lungs (P=0.17) of TAC mice corresponded to an increase in myocardial magnetic resonance imaging percent signal intensity increase (P<0.0001) and Δlung-to-muscle ratio (P<0.0001). Hydroxyproline in the heart (P<0.0001) and lungs (P<0.01) were elevated in TAC mice, which corresponded to an increase in heart (myocardium-to-muscle ratio, P=0.02) and lung (lung-to-muscle ratio, P<0.001) PET measurements. Pressure-volume loop and echocardiography demonstrated adverse left ventricular remodeling, function, and increased right ventricular systolic pressure in TAC mice. CONCLUSIONS: Administration of collagen-targeted PET and allysine-targeted MR probes led to elevated PET-magnetic resonance imaging signals in the myocardium and lungs of TAC mice. The study demonstrates the potential to detect fibrosis and fibrogenesis in cardiopulmonary disease through a dual molecular PET-magnetic resonance imaging protocol.


Subject(s)
Disease Models, Animal , Fibrosis , Magnetic Resonance Imaging , Positron-Emission Tomography , Ventricular Dysfunction, Left , Animals , Positron-Emission Tomography/methods , Ventricular Dysfunction, Left/diagnostic imaging , Ventricular Dysfunction, Left/physiopathology , Ventricular Dysfunction, Left/etiology , Ventricular Dysfunction, Left/metabolism , Magnetic Resonance Imaging/methods , Mice , Myocardium/pathology , Myocardium/metabolism , Pulmonary Fibrosis/diagnostic imaging , Pulmonary Fibrosis/physiopathology , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/etiology , Ventricular Function, Left , Male , Lung/diagnostic imaging , Lung/pathology , Lung/physiopathology , Lung/metabolism , Multimodal Imaging/methods , Collagen/metabolism , Ventricular Remodeling , Lysine/analogs & derivatives
4.
Front Immunol ; 15: 1372658, 2024.
Article in English | MEDLINE | ID: mdl-38827740

ABSTRACT

Background: Persistent radiological lung abnormalities are evident in many survivors of acute coronavirus disease 2019 (COVID-19). Consolidation and ground glass opacities are interpreted to indicate subacute inflammation whereas reticulation is thought to reflect fibrosis. We sought to identify differences at molecular and cellular level, in the local immunopathology of post-COVID inflammation and fibrosis. Methods: We compared single-cell transcriptomic profiles and T cell receptor (TCR) repertoires of bronchoalveolar cells obtained from convalescent individuals with each radiological pattern, targeting lung segments affected by the predominant abnormality. Results: CD4 central memory T cells and CD8 effector memory T cells were significantly more abundant in those with inflammatory radiology. Clustering of similar TCRs from multiple donors was a striking feature of both phenotypes, consistent with tissue localised antigen-specific immune responses. There was no enrichment for known SARS-CoV-2-reactive TCRs, raising the possibility of T cell-mediated immunopathology driven by failure in immune self-tolerance. Conclusions: Post-COVID radiological inflammation and fibrosis show evidence of shared antigen-specific T cell responses, suggesting a role for therapies targeting T cells in limiting post-COVID lung damage.


Subject(s)
COVID-19 , SARS-CoV-2 , Single-Cell Analysis , Humans , COVID-19/immunology , COVID-19/pathology , SARS-CoV-2/immunology , Male , Female , Middle Aged , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism , Receptors, Antigen, T-Cell/genetics , Pulmonary Fibrosis/immunology , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/pathology , CD8-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , Lung/immunology , Lung/pathology , Lung/diagnostic imaging , Aged , Adult , Inflammation/immunology , Inflammation/pathology , Bronchoalveolar Lavage Fluid/immunology , Bronchoalveolar Lavage Fluid/cytology , Memory T Cells/immunology , Transcriptome
5.
Adv Gerontol ; 37(1-2): 144-148, 2024.
Article in Russian | MEDLINE | ID: mdl-38944785

ABSTRACT

Research on the condition of the lungs in senile people is an urgent task. This is due to the fact that degenerative or age-associated changes in the respiratory system play an important role in the formation of senile asthenia syndrome and a decrease in the age-related viability of the body as a whole. CT-scans of patients aged 80-90 years were analyzed (n=31). Age-associated changes were evaluated: the presence of linear fibrosis, increased pulmonary pattern by the type of reticular (reticular) changes, the presence of gross fibrous reticular changes with cystic cavities and air bullae (by the type of «cellular lung¼), as well as the presence of pulmonary emphysema. Most naturally, senile people show changes characteristic of linear pulmonary fibrosis and emphysema. The progression of the process leads to diffuse reticular changes in the interalveolar and intersegmental septa and, in adverse cases, to the formation of gross changes in the type of «cellular lung¼. Fibro-emphysematous changes are significantly more common in men. A microbiological study of the microbiota of the lower respiratory tract in elderly people was also carried out (n=16). When studying the microbiocenosis of the lower respiratory tract in elderly people, the following data were obtained: resident microflora was found in 71% and clinically significant microorganisms were found in 29%.


Subject(s)
Microbiota , Pulmonary Emphysema , Humans , Aged, 80 and over , Male , Female , Pulmonary Emphysema/microbiology , Pulmonary Emphysema/physiopathology , Pulmonary Emphysema/diagnosis , Microbiota/physiology , Lung/microbiology , Tomography, X-Ray Computed/methods , Pulmonary Fibrosis/physiopathology , Pulmonary Fibrosis/microbiology , Pulmonary Fibrosis/diagnosis , Pulmonary Fibrosis/etiology , Aging/physiology
6.
Zhonghua Jie He He Hu Xi Za Zhi ; 47(6): 571-575, 2024 Jun 12.
Article in Chinese | MEDLINE | ID: mdl-38858210

ABSTRACT

COVID-19 is caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and manifests primarily as acute lung injury with diffuse interstitial lung disease evident in imaging. Patients often present with clinical features similar to those of autoimmune diseases and share imaging, treatment and serological similarities with autoimmune-related interstitial lung diseases. The association between autoimmune abnormalities and post-COVID-19 pulmonary fibrosis is also recognized. This article provided a comprehensive review of the pathogenic mechanisms, clinical manifestations, and therapeutic interventions associated with autoimmune abnormalities induced by SARS-CoV-2 infection.


Subject(s)
Autoimmune Diseases , COVID-19 , Lung Diseases, Interstitial , SARS-CoV-2 , Humans , COVID-19/complications , COVID-19/immunology , COVID-19/therapy , Lung Diseases, Interstitial/etiology , Lung Diseases, Interstitial/immunology , Lung Diseases, Interstitial/therapy , Autoimmune Diseases/therapy , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/therapy
7.
Int J Mol Sci ; 25(11)2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38892317

ABSTRACT

The bleomycin-induced scleroderma model is a well-established and dependable method for creating a mouse model of SSc (systemic sclerosis). In the field of skin connective tissue diseases, increasing evidence from clinical and animal experiments suggests that TLRs (Toll-like receptors) play an important role in several diseases. This study aimed to determine the role of TLR7 (Toll-like receptor 7) and TLR9 (Toll-like receptor 9) in the mechanisms of immune abnormalities and fibrosis in SSc. This study used TLR7-KO mice (TLR7-knockout mice with a balb/c background) and TLR9-KO mice (TLR9-knockout mice with a balb/c background) as well as WT mice (wild-type balb/c mice). All three kinds of mice were induced by BLM (bleomycin) in a scleroderma model as the experimental group; meanwhile, WT mice treated with PBS (phosphate-buffered saline) were used as the control group. We analyzed the fibrotic phenotype and the immunological abnormality phenotype of TLR7-deficient and TLR9-deficient mice in the SSc disease model using flow cytometry, RT-PCR (reverse transcription-polymerase chain reaction), a histological examination, and IHC (immunohistochemical staining). In a mouse model of SSc disease, the deletion of TLR7 attenuated skin and lung fibrosis, while the deletion of TLR9 exacerbated skin and lung fibrosis. The deletion of TLR7 resulted in a relative decrease in the infiltration and expression of various pro-inflammatory and fibrotic cells and cytokines in the skin. On the other hand, the deletion of TLR9 resulted in a relative increase in the infiltration and expression of various pro-inflammatory and cytokine-inhibiting cells and cytokines in the skin. Under the influence of pDCs (plasmacytoid dendritic cells), the balances of Beff/Breg (IL-6 + CD19 + B cell/IL-10 + CD19 + B cell), Th17/Treg (IL-17A + CD4 + T cell/Foxp3 + CD25 + CD4 + T cell), M1/M2 (CD86 + macrophage/CD206 + macrophage), and Th1/Th2 (TNFα + CD3 + CD4 + T cell/IL-4 + CD3 + CD4 + T cell) were biased towards the suppression of inflammation and fibrosis as a result of the TLR7 deletion. Comparatively, the balance was biased towards promoting inflammation and fibrosis due to the TLR9 deletion. In the SSc model, TLR7 promoted inflammation and fibrosis progression, while TLR9 played a protective role. These results suggest that TLR7 and TLR9 play opposite roles in triggering SSc to produce immune system abnormalities and skin fibrosis.


Subject(s)
Disease Models, Animal , Mice, Knockout , Scleroderma, Systemic , Toll-Like Receptor 7 , Toll-Like Receptor 9 , Animals , Toll-Like Receptor 7/metabolism , Toll-Like Receptor 7/genetics , Scleroderma, Systemic/metabolism , Scleroderma, Systemic/pathology , Scleroderma, Systemic/immunology , Scleroderma, Systemic/genetics , Toll-Like Receptor 9/metabolism , Toll-Like Receptor 9/genetics , Mice , Bleomycin/adverse effects , Mice, Inbred BALB C , Cytokines/metabolism , Skin/pathology , Skin/metabolism , Skin/immunology , Fibrosis , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/etiology , Membrane Glycoproteins
8.
Int J Rheum Dis ; 27(5): e15174, 2024 May.
Article in English | MEDLINE | ID: mdl-38720423

ABSTRACT

OBJECTIVES: This study investigates the role of TNF-induced protein 3 (TNFAIP3) and CCAAT/enhancer-binding protein ß (C/EBPß) in alveolar macrophages (AMs) of patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) and their influence on pulmonary fibrosis. METHODS: Transfection of HEK293T cells and AMs with plasmids carrying TNFAIP3 and C/EBPß was performed, followed by co-culturing AMs with pulmonary fibroblasts. Immunoblotting analysis was then utilized to assess the expression of TNFAIP3, C/EBPß, and collagen type 1 (Col1). Quantitative PCR analysis was conducted to quantify the mRNA levels of C/EBPß, IL-10, and TGF-ß1. STRING database analysis, and immunoprecipitation assays were employed to investigate the interactions between TNFAIP3 and C/EBPß. RESULTS: TNFAIP3 expression was significantly reduced in SSc-ILD AMs, correlating with increased Col1 production in fibroblasts. Overexpression of TNFAIP3 inhibited this pro-fibrotic activity. Conversely, C/EBPß expression was elevated in SSc-ILD AMs, and its reduction through TNFAIP3 restoration decreased pro-fibrotic cytokines IL-10 and TGFß1 levels. Protein-protein interaction studies confirmed the regulatory relationship between TNFAIP3 and C/EBPß. CONCLUSIONS: This study highlights the important role of TNFAIP3 in regulating pulmonary fibrosis in SSc-ILD by modulating C/EBPß expression in AMs. These findings suggest that targeting TNFAIP3 could be a potential therapeutic strategy for managing SSc-ILD patients.


Subject(s)
CCAAT-Enhancer-Binding Protein-beta , Coculture Techniques , Fibroblasts , Lung Diseases, Interstitial , Macrophages, Alveolar , Scleroderma, Systemic , Tumor Necrosis Factor alpha-Induced Protein 3 , Female , Humans , Male , Middle Aged , CCAAT-Enhancer-Binding Protein-beta/metabolism , CCAAT-Enhancer-Binding Protein-beta/genetics , Collagen Type I/metabolism , Collagen Type I/genetics , Fibroblasts/metabolism , HEK293 Cells , Interleukin-10/metabolism , Interleukin-10/genetics , Lung/metabolism , Lung/pathology , Lung Diseases, Interstitial/metabolism , Lung Diseases, Interstitial/etiology , Macrophages, Alveolar/metabolism , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/etiology , Scleroderma, Systemic/metabolism , Scleroderma, Systemic/complications , Signal Transduction , Transforming Growth Factor beta1/metabolism , Tumor Necrosis Factor alpha-Induced Protein 3/metabolism , Tumor Necrosis Factor alpha-Induced Protein 3/genetics , Adult , Aged
9.
Ter Arkh ; 96(3): 298-302, 2024 Apr 16.
Article in Russian | MEDLINE | ID: mdl-38713047

ABSTRACT

Fibrosis is a dynamic process characterized by a typical cascade of events as a result of overexpressed repair of connective tissue in response to injury, and manifested by excessive accumulation of extracellular matrix. The development of fibrosis is a determining factor in the pathogenesis, clinical course and prognosis of many diseases, among which interstitial lung diseases occupy a special place. According to a large Russian registry (ClinicalTrials.gov: NCT04492384), in a third of patients with COVID-19, the volume of lung parenchyma involvement exceeds 50% (CT 3-4). The rapid growth in the number of patients who have had a coronavirus infection with lung damage has raised the issues of its long-term consequences to the number of the most relevant in internal medicine of the current time. Often, in the outcome of a coronavirus infection, patients retain clinical and functional changes that are similar to interstitial lung diseases of a different origin, the prognosis of which is determined by the development of interstitial fibrosis and the rate of its progression. This article is an attempt to consider topical issues of fibrogenesis in patients who have undergone a new coronavirus infection through the prism of polar data on immunobiology, clinical course and prognosis.


Subject(s)
COVID-19 , Pulmonary Fibrosis , Humans , COVID-19/complications , Pulmonary Fibrosis/etiology , SARS-CoV-2 , Prognosis , Disease Progression
10.
EBioMedicine ; 104: 105135, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38718684

ABSTRACT

Interstitial lung diseases (ILDs) in adults and children (chILD) are a heterogeneous group of lung disorders leading to inflammation, abnormal tissue repair and scarring of the lung parenchyma often resulting in respiratory failure and death. Inherited factors directly cause, or contribute significantly to the risk of developing ILD, so called familial pulmonary fibrosis (FPF), and monogenic forms may have a poor prognosis and respond poorly to current treatments. Specific, variant-targeted or precision treatments are lacking. Clinical trials of repurposed drugs, anti-fibrotic medications and specific treatments are emerging but for many patients no interventions exist. We convened an expert working group to develop an overarching framework to address the existing research gaps in basic, translational, and clinical research and identified areas for future development of preclinical models, candidate medications and innovative clinical trials. In this Position Paper, we summarise working group discussions, recommendations, and unresolved questions concerning precision treatments for FPF.


Subject(s)
Precision Medicine , Humans , Precision Medicine/methods , Animals , Disease Management , Pulmonary Fibrosis/therapy , Pulmonary Fibrosis/genetics , Pulmonary Fibrosis/etiology , Clinical Trials as Topic
11.
Front Immunol ; 15: 1404828, 2024.
Article in English | MEDLINE | ID: mdl-38745647

ABSTRACT

Objectives: Interstitial lung disease (ILD) is one of the common extramuscular involvement in idiopathic inflammatory myopathies (IIMs) (1). Several patients develop a progressive fibrosing ILD (PF-ILD) despite conventional treatment, resulting in a progressive deterioration in their quality of life (2). Here, we investigated the clinical and immune characteristics of IIM-ILD and risk factors for PF-ILD in IIM, mainly in anti-melanoma differentiation-associated protein 5 (anti-MDA5+) dermatomyositis (DM) and anti-synthetase syndrome (ASS). Methods: Here, a prospective cohort of 156 patients with IIM-ILD were included in the longitudinal analysis and divided into the PF-ILD (n=65) and non-PF-ILD (n=91) groups, and their baseline clinical characteristics were compared. Univariate and multivariate Cox analyses were performed to identify the variables significantly associated with pulmonary fibrosis progression in the total cohort, then anti-MDA5+ DM and ASS groups separately. Results: Peripheral blood lymphocyte counts, including T, B, and NK cell counts, were significantly lower in the PF-ILD group than in the non-PF-ILD group. This characteristic is also present in the comparison between patients with anti-MDA5+ DM and ASS. The multivariate Cox regression analysis revealed that age > 43.5 years [HR: 7.653 (95% CI: 2.005-29.204), p = 0.003], absolute NK cell count < 148 cells/µL [HR: 6.277 (95% CI: 1.572-25.067), p = 0.009] and absolute Th cell count < 533.2 cells/µL [HR: 4.703 (95% CI: 1.014-21.821), p = 0.048] were independent predictors of progressive fibrosing during 1-year follow-up for patients with anti-MDA5+ DM, while absolute count of NK cells < 303.3 cells/µL [HR: 19.962 (95% CI: 3.108-128.223), p = 0.002], absolute count of lymphocytes < 1.545×109/L [HR: 9.684 (95% CI: 1.063-88.186), p = 0.044], and ferritin > 259.45 ng/mL [HR: 6 (95% CI: 1.116-32.256), p = 0.037] were independent predictors of PF-ILD for patients with ASS. Conclusions: Patients with anti-MDA5+ DM and ASS have independent risk factors for PF-ILD. Lymphocyte depletion (particularly NK cells) was significantly associated with PF-ILD within 1-year of follow-up for IIM-ILD.


Subject(s)
Disease Progression , Killer Cells, Natural , Lung Diseases, Interstitial , Myositis , Humans , Female , Male , Middle Aged , Lung Diseases, Interstitial/immunology , Lung Diseases, Interstitial/diagnosis , Lung Diseases, Interstitial/etiology , Killer Cells, Natural/immunology , Myositis/immunology , Myositis/blood , Myositis/diagnosis , Prognosis , Aged , Prospective Studies , Adult , Lymphocyte Depletion , Interferon-Induced Helicase, IFIH1/immunology , Risk Factors , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/immunology , Lymphocyte Count , Longitudinal Studies
12.
Clin Transl Med ; 14(5): e1690, 2024 May.
Article in English | MEDLINE | ID: mdl-38760896

ABSTRACT

INTRODUCTION: Radiation-induced pulmonary fibrosis (RIPF) is a chronic, progressive, irreversible lung interstitial disease that develops after radiotherapy. Although several previous studies have focused on the mechanism of epithelial-mesenchymal transition (EMT) in lung epithelial cells, the essential factors involved in this process remain poorly understood. The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) exhibits strong repair capacity when cells undergo radiation-induced damage; whether DNA-PKcs regulates EMT during RIPF remains unclear. OBJECTIVES: To investigate the role and molecular mechanism of DNA-PKcs in RIPF and provide an important theoretical basis for utilising DNA-PKcs-targeted drugs for preventing RIPF. METHODS: DNA-PKcs knockout (DPK-/-) mice were generated via the Cas9/sgRNA technique and subjected to whole chest ionizing radiation (IR) at a 20 Gy dose. Before whole chest IR, the mice were intragastrically administered the DNA-PKcs-targeted drug VND3207. Lung tissues were collected at 1 and 5 months after IR. RESULTS: The expression of DNA-PKcs is low in pulmonary fibrosis (PF) patients. DNA-PKcs deficiency significantly exacerbated RIPF by promoting EMT in lung epithelial cells. Mechanistically, DNA-PKcs deletion by shRNA or inhibitor NU7441 maintained the protein stability of Twist1. Furthermore, AKT1 mediated the interaction between DNA-PKcs and Twist1. High Twist1 expression and EMT-associated changes caused by DNA-PKcs deletion were blocked by insulin-like growth factor-1 (IGF-1), an AKT1 agonist. The radioprotective drug VND3207 prevented IR-induced EMT and alleviated RIPF in mice by stimulating the kinase activity of DNA-PKcs. CONCLUSION: Our study clarified the critical role and mechanism of DNA-PKcs in RIPF and showed that it could be a potential target for preventing RIPF.


Subject(s)
DNA-Activated Protein Kinase , Epithelial-Mesenchymal Transition , Nuclear Proteins , Proto-Oncogene Proteins c-akt , Pulmonary Fibrosis , Twist-Related Protein 1 , Epithelial-Mesenchymal Transition/drug effects , Animals , DNA-Activated Protein Kinase/metabolism , DNA-Activated Protein Kinase/genetics , Mice , Proto-Oncogene Proteins c-akt/metabolism , Nuclear Proteins/metabolism , Nuclear Proteins/genetics , Twist-Related Protein 1/metabolism , Twist-Related Protein 1/genetics , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/etiology , Ubiquitination , Humans , Mice, Knockout , DNA-Binding Proteins
13.
Mol Med ; 30(1): 72, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38822247

ABSTRACT

BACKGROUND: 8-Oxoguanine DNA glycosylase (OGG1), a well-known DNA repair enzyme, has been demonstrated to promote lung fibrosis, while the specific regulatory mechanism of OGG1 during pulmonary fibrosis remains unclarified. METHODS: A bleomycin (BLM)-induced mouse pulmonary fibrosis model was established, and TH5487 (the small molecule OGG1 inhibitor) and Mitochondrial division inhibitor 1 (Mdivi-1) were used for administration. Histopathological injury of the lung tissues was assessed. The profibrotic factors and oxidative stress-related factors were examined using the commercial kits. Western blot was used to examine protein expression and immunofluorescence analysis was conducted to assess macrophages polarization and autophagy. The conditional medium from M2 macrophages was harvested and added to HFL-1 cells for culture to simulate the immune microenvironment around fibroblasts during pulmonary fibrosis. Subsequently, the loss- and gain-of function experiments were conducted to further confirm the molecular mechanism of OGG1/PINK1. RESULTS: In BLM-induced pulmonary fibrosis, OGG1 was upregulated while PINK1/Parkin was downregulated. Macrophages were activated and polarized to M2 phenotype. TH5487 administration effectively mitigated pulmonary fibrosis, M2 macrophage polarization, oxidative stress and mitochondrial dysfunction while promoted PINK1/Parkin-mediated mitophagy in lung tissues of BLM-induced mice, which was partly hindered by Mdivi-1. PINK1 overexpression restricted M2 macrophages-induced oxidative stress, mitochondrial dysfunction and mitophagy inactivation in lung fibroblast cells, and OGG1 knockdown could promote PINK1/Parkin expression and alleviate M2 macrophages-induced mitochondrial dysfunction in HFL-1 cells. CONCLUSION: OGG1 inhibition protects against pulmonary fibrosis, which is partly via activating PINK1/Parkin-mediated mitophagy and retarding M2 macrophage polarization, providing a therapeutic target for pulmonary fibrosis.


Subject(s)
Bleomycin , DNA Glycosylases , Disease Models, Animal , Macrophages , Mitophagy , Protein Kinases , Pulmonary Fibrosis , Animals , Mitophagy/drug effects , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/pathology , DNA Glycosylases/metabolism , DNA Glycosylases/genetics , Mice , Macrophages/metabolism , Protein Kinases/metabolism , Bleomycin/adverse effects , Male , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/genetics , Oxidative Stress/drug effects , Mice, Inbred C57BL , Macrophage Activation , Humans , Quinazolinones
14.
Respir Res ; 25(1): 170, 2024 Apr 18.
Article in English | MEDLINE | ID: mdl-38637860

ABSTRACT

While the COVID-19 outbreak and its complications are still under investigation, post-inflammatory pulmonary fibrosis (PF) has already been described as a long-term sequela of acute respiratory distress syndrome (ARDS) secondary to SARS-CoV2 infection. However, therapeutical strategies for patients with ARDS and PF are still limited and do not significantly extend lifespan. So far, lung transplantation remains the only definitive treatment for end-stage PF. Over the last years, numerous preclinical and clinical studies have shown that allogeneic mesenchymal stromal cells (MSCs) might represent a promising therapeutical approach in several lung disorders, and their potential for ARDS treatment and PF prevention has been investigated during the COVID-19 pandemic. From April 2020 to April 2022, we treated six adult patients with moderate COVID-19-related ARDS in a late proliferative stage with up to two same-dose infusions of third-party allogeneic bone marrow-derived MSCs (BM-MSCs), administered intravenously 15 days apart. No major adverse events were registered. Four patients completed the treatment and reached ICU discharge, while two received only one dose of MSCs due to multiorgan dysfunction syndrome (MODS) and subsequent death. All four survivors showed improved gas exchanges (PaO2/FiO2 ratio > 200), contrary to the others. Furthermore, LDH trends after MSCs significantly differed between survivors and the deceased. Although further investigations and shared protocols are still needed, the safety of MSC therapy has been recurrently shown, and its potential in treating ARDS and preventing PF might represent a new therapeutic strategy.


Subject(s)
COVID-19 , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Pulmonary Fibrosis , Respiratory Distress Syndrome , Adult , Humans , Pulmonary Fibrosis/therapy , Pulmonary Fibrosis/etiology , Pandemics , RNA, Viral , Respiratory Distress Syndrome/therapy , Respiratory Distress Syndrome/etiology , COVID-19/therapy , Mesenchymal Stem Cell Transplantation/methods
15.
Pediatr Blood Cancer ; 71(7): e31004, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38637875

ABSTRACT

Pleuroparenchymal fibroelastosis (PPFE) is a rare interstitial pneumonia with distinct clinicopathologic features. It has been associated with exposure to hematopoietic stem cell transplantation (HSCT) and classical alkylating agents. Here, we highlight PPFE as a late complication of childhood cancer therapy by describing the cases of four survivors of childhood cancer with a diagnosis of treatment-related PPFE. All patients received high-dose alkylating agents. PPFE should be considered in the differential diagnosis of restrictive lung disease in patients with history of exposure to alkylating agents or HSCT. Development of PPFE-specific, noninvasive diagnostic tools and disease-modifying therapies will clinically benefit these patients.


Subject(s)
Lung Diseases, Interstitial , Adolescent , Child , Child, Preschool , Female , Humans , Male , Antineoplastic Agents, Alkylating/adverse effects , Hematopoietic Stem Cell Transplantation/adverse effects , Lung Diseases, Interstitial/pathology , Lung Diseases, Interstitial/etiology , Lung Diseases, Interstitial/chemically induced , Lung Diseases, Interstitial/therapy , Neoplasms/drug therapy , Neoplasms/complications , Neoplasms/pathology , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/pathology
17.
Front Immunol ; 15: 1328781, 2024.
Article in English | MEDLINE | ID: mdl-38550597

ABSTRACT

Metabolic changes are coupled with alteration in protein glycosylation. In this review, we will focus on macrophages that are pivotal in the pathogenesis of pulmonary fibrosis and sarcoidosis and thanks to their adaptable metabolism are an attractive therapeutic target. Examples presented in this review demonstrate that protein glycosylation regulates metabolism-driven immune responses in macrophages, with implications for fibrotic processes and granuloma formation. Targeting proteins that regulate glycosylation, such as fucosyltransferases, neuraminidase 1 and chitinase 1 could effectively block immunometabolic changes driving inflammation and fibrosis, providing novel avenues for therapeutic interventions.


Subject(s)
Lung Diseases, Interstitial , Pulmonary Fibrosis , Sarcoidosis , Humans , Glycosylation , Lung Diseases, Interstitial/metabolism , Pulmonary Fibrosis/etiology , Sarcoidosis/metabolism , Fibrosis
18.
Sci Adv ; 10(13): eadj9559, 2024 Mar 29.
Article in English | MEDLINE | ID: mdl-38552026

ABSTRACT

Pulmonary fibrosis is an often fatal lung disease. Immune cells such as macrophages were shown to accumulate in the fibrotic lung, but their contribution to the fibrosis development is unclear. To recapitulate the involvement of macrophages in the development of pulmonary fibrosis, we developed a fibrotic microtissue model with cocultured human macrophages and fibroblasts. We show that profibrotic macrophages seeded on topographically controlled stromal tissues became mechanically activated. The resulting co-alignment of macrophages, collagen fibers, and fibroblasts promoted widespread fibrogenesis in micro-engineered lung tissues. Anti-fibrosis treatment using pirfenidone disrupts the polarization and mechanical activation of profibrotic macrophages, leading to fibrosis inhibition. Pirfenidone inhibits the mechanical activation of macrophages by suppressing integrin αMß2 and Rho-associated kinase 2. These results demonstrate a potential pulmonary fibrogenesis mechanism at the tissue level contributed by macrophages. The cocultured microtissue model is a powerful tool to study the immune-stromal cell interactions and the anti-fibrosis drug mechanism.


Subject(s)
Pulmonary Fibrosis , Humans , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/etiology , Lung/pathology , Fibrosis , Macrophages , Coculture Techniques
19.
Thorax ; 79(5): 472-475, 2024 Apr 15.
Article in English | MEDLINE | ID: mdl-38514184

ABSTRACT

We conducted a prospective single-centre cohort study of 104 multi-ethnic severe COVID-19 survivors from the first wave of the pandemic 15 months after hospitalisation. Of those who were assessed at 4 and 15 months, improvement of ground glass opacities correlated with worsened fibrotic reticulations. Despite a high prevalence of fibrotic patterns (64%), pulmonary function, grip strength, 6 min walk distance and frailty normalised. Overall, dyspnoea, cough and exhaustion did not improve and were not correlated with pulmonary function or radiographic fibrosis at 15 months, suggesting non-respiratory aetiologies. Monitoring persistent, and often subclinical, fibrotic interstitial abnormalities will be needed to determine their potential for future progression.


Subject(s)
COVID-19 , Pulmonary Fibrosis , Humans , Pulmonary Fibrosis/diagnostic imaging , Pulmonary Fibrosis/etiology , Exercise Tolerance , Prospective Studies , Cohort Studies
20.
Radiat Res ; 201(5): 460-470, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38376474

ABSTRACT

With the current volatile geopolitical climate, the threat of nuclear assault is high. Exposure to ionizing radiation from either nuclear incidents or radiological accidents often lead to major harmful consequences to human health. Depending on the absorbed dose, the symptoms of the acute radiation syndrome and delayed effects of acute radiation exposure (DEARE) can appear within hours, weeks to months. The lung is a relatively radiosensitive organ with manifestation of radiation pneumonitis as an acute effect, followed by apparent fibrosis in weeks or even months. A recently developed, first-of-its-kind murine model for partial-body irradiation (PBI) injury, which can be used to test potential countermeasures against multi-organ damage such as gastrointestinal (GI) tract and lungs was used for irradiation, with 2.5% bone marrow spared (BM2.5-PBI) from radiation exposure. Long-term damage to lungs from radiation was evaluated using µ-CT scans, pulmonary function testing, histopathological parameters and molecular biomarkers. Pulmonary fibrosis was detected by ground glass opacity observed in µ-CT scans of male and female C57BL/6J mice 6-7 months after BM2.5-PBI. Lung mechanics assessments pertaining to peripheral airways suggested fibrotic lungs with stiffer parenchymal lung tissue and reduced inspiratory capacity in irradiated animals 6-7 months after BM2.5-PBI. Histopathological evaluation of the irradiated lungs revealed presence of focal and diffuse pleural, and parenchymal inflammatory and fibrotic lesions. Fibrosis was confirmed by elevated levels of collagen when compared to lungs of age-matched naïve mice. These findings were validated by findings of elevated levels of pro-fibrotic biomarkers and reduction in anti-inflammatory proteins. In conclusion, a long-term model for radiation-induced pulmonary fibrosis was established, and countermeasures could be screened in this model for survival and protection/mitigation or recovery from radiation-induced pulmonary damage.


Subject(s)
Disease Models, Animal , Mice, Inbred C57BL , Pulmonary Fibrosis , Animals , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/pathology , Mice , Male , Female , Lung/radiation effects , Lung/pathology , Radiation Pneumonitis/pathology , Radiation Pneumonitis/etiology , Radiation Injuries, Experimental/pathology , Radiation Injuries, Experimental/etiology
SELECTION OF CITATIONS
SEARCH DETAIL