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Therapeutic Advances in Respiratory... 2023It is unclear whether continuing anti-fibrotic therapy until the time of lung transplant increases the risk of complications in patients with idiopathic pulmonary... (Clinical Trial)
Clinical Trial
BACKGROUND
It is unclear whether continuing anti-fibrotic therapy until the time of lung transplant increases the risk of complications in patients with idiopathic pulmonary fibrosis.
OBJECTIVES
To investigate whether the time between discontinuation of anti-fibrotic therapy and lung transplant in patients with idiopathic pulmonary fibrosis affects the risk of complications.
METHODS
We assessed intra-operative and post-transplant complications among patients with idiopathic pulmonary fibrosis who underwent lung transplant and had been treated with nintedanib or pirfenidone continuously for ⩾ 90 days at listing. Patients were grouped according to whether they had a shorter (⩽ 5 medication half-lives) or longer (> 5 medication half-lives) time between discontinuation of anti-fibrotic medication and transplant. Five half-lives corresponded to 2 days for nintedanib and 1 day for pirfenidone.
RESULTS
Among patients taking nintedanib ( = 107) or pirfenidone ( = 190), 211 (71.0%) had discontinued anti-fibrotic therapy ⩽ 5 medication half-lives before transplant. Anastomotic and sternal dehiscence occurred only in this group (anastomotic: 11 patients [5.2%], = 0.031 vs patients with longer time between discontinuation of anti-fibrotic medication and transplant; sternal: 12 patients [5.7%], = 0.024). No differences were observed in surgical wound dehiscence, length of hospital stay, or survival to discharge between groups with a shorter versus longer time between discontinuation of anti-fibrotic therapy and transplant.
CONCLUSION
Anastomotic and sternal dehiscence only occurred in patients with idiopathic pulmonary fibrosis who discontinued anti-fibrotic therapy < 5 medication half-lives before transplant. The frequency of other intra-operative and post-transplant complications did not appear to differ depending on when anti-fibrotic therapy was discontinued.
REGISTRATION
clinicaltrials.gov NCT04316780: https://clinicaltrials.gov/ct2/show/NCT04316780.
Topics: Humans; Fibrosis; Idiopathic Pulmonary Fibrosis; Lung Transplantation; Treatment Outcome
PubMed: 37073794
DOI: 10.1177/17534666231165912 -
Aging Oct 2023G protein-coupled receptor kinase-2 (GRK2) is involved in TGF-β1-induced activation of lung fibroblasts, which could give rise to the pathogenesis of pulmonary...
G protein-coupled receptor kinase-2 (GRK2) is involved in TGF-β1-induced activation of lung fibroblasts, which could give rise to the pathogenesis of pulmonary fibrosis. Paroxetine (PRXT) serves as a selective GRK2 inhibitor which is widely used to treat anxiety and depression for several decades. However, whether PRXT could inhibit TGF-β1-induced activation of lung fibroblasts and combat bleomycin-induced pulmonary fibrosis remains unclear. Here, we investigated the effects of PRXT on pulmonary fibrosis in C57/BL6 caused by bleomycin as well as on the activation of murine primary lung fibroblasts stimulated with TGF-β1. The results demonstrated that PRXT markedly improved the pulmonary function and 21-day survival in bleomycin-induced mice. Meanwhile, PRXT significantly decreased collagen deposition, inflammation, and oxidative stress in lung tissues from bleomycin-induced mice. Furthermore, we found that PRXT could inhibit the protein and mRNA expression of GRK2 and Smad3 in lung tissues from bleomycin-induced mice. experiments also PRXT could inhibit cell activation and collagen synthesis in a concentration-dependent manner in TGF-β1-induced lung fibroblasts. In addition, we found that Smad3 overexpression by adenovirus transfection could offset anti-fibrotic and antioxidative effects from PRXT in TGF-β1-induced lung fibroblasts, which showed no effects on the protein expression of GRK2. In conclusion, PRXT mediates the inhibition of GRK2, which further blocks the transcription of Smad3 in TGF-β1-induced lung fibroblasts, providing an attractive therapeutic target for pulmonary fibrosis.
Topics: Mice; Animals; Pulmonary Fibrosis; Bleomycin; Transforming Growth Factor beta1; Paroxetine; Lung; Fibroblasts; Collagen; Mice, Inbred C57BL
PubMed: 37815883
DOI: 10.18632/aging.205092 -
International Journal of Chronic... 2023The comorbidity of pulmonary fibrosis and COPD/emphysema has garnered increasing attention. However, no bibliometric analysis of this comorbidity has been conducted thus...
OBJECTIVE
The comorbidity of pulmonary fibrosis and COPD/emphysema has garnered increasing attention. However, no bibliometric analysis of this comorbidity has been conducted thus far. This study aims to perform a bibliometric analysis to explore the current status and cutting-edge trends in the field, and to establish new directions for future research.
METHODS
Statistical computing, graphics, and data visualization tools such as VOSviewer, CiteSpace, Biblimatrix, and WPS Office were employed.
RESULTS
We identified a total of 1827 original articles and reviews on the comorbidity of pulmonary fibrosis and COPD/emphysema published between 2004 and 2023. There was an observed increasing trend in publications related to this comorbidity. The United States, Japan, and the United Kingdom were the countries with the highest contributions. Professor Athol Wells and the University of Groningen had the highest h-index and the most articles, respectively. Through cluster analysis of co-cited documents, we identified the top 17 major clusters. Keyword analysis predicted that NF-κB, oxidative stress, physical activity, and air pollution might be hot spots in this field in the future.
CONCLUSION
This bibliometric analysis demonstrates a continuous increasing trend in literature related to the comorbidity of pulmonary fibrosis and COPD/emphysema. The research hotspots and trends identified in this study provide a reference for in-depth research in this field, aiming to promote the development of the comorbidity of pulmonary fibrosis and COPD/emphysema.
Topics: Humans; Pulmonary Fibrosis; Pulmonary Disease, Chronic Obstructive; Comorbidity; Emphysema; Pulmonary Emphysema
PubMed: 37720874
DOI: 10.2147/COPD.S426763 -
Acta Medica Indonesiana Apr 2021Since December 2019, COVID-19 caused by SARS-CoV-2 infection has been spread rapidly in the world. Beside acute respiratory distress syndrome found in acute phase of...
Since December 2019, COVID-19 caused by SARS-CoV-2 infection has been spread rapidly in the world. Beside acute respiratory distress syndrome found in acute phase of infection, there is also pulmonary fibrosis as a chronic complication due to COVID-19. With the global pandemic of COVID-19, more and more autopsy and puncture histopathological results have been published.Until now there is no specific therapy to handle post-inflammatory pulmonary fibrosis due to COVID-19 infection. Several studies are ongoing to determine an effective treatment for this chronic complication. While ARDS appears to be the main cause of pulmonary fibrosis in COVID-19, the pathogenesis of ARDS caused by SARS-CoV-2 is different from the typical ARDS. Some therapies may be considered for reducing the fibrosis process in lung after COVI-19 infection namely pirfenidone, nintedanib and mesenchymal stem cells. Many patients are still recovering spontaneously in the first six weeks after acute COVID-19 infection and do not generally require fast-track entry into a pulmonary rehabilitation programme. However, those who have significantly persistent respiratory illness may need to be supported by pulmonary rehabilitation. Multidisciplinary intervention based on personalized evaluation and treatment which includes exercise training, education and behavioral modification can be given to improve the physical and psychological condition of patients with post-COVID pulmonary fibrosis.
Topics: COVID-19; Humans; Pandemics; Patient Discharge; Pneumonia, Viral; Pulmonary Fibrosis; SARS-CoV-2
PubMed: 34251340
DOI: No ID Found -
American Journal of Respiratory and... Mar 2023
Topics: Humans; Pulmonary Fibrosis; Incidence; Lung
PubMed: 36154916
DOI: 10.1164/rccm.202209-1769ED -
Respiratory Research Mar 2023Lower body mass index (BMI) and weight loss have been associated with worse outcomes in some studies in patients with pulmonary fibrosis. We analyzed outcomes in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Lower body mass index (BMI) and weight loss have been associated with worse outcomes in some studies in patients with pulmonary fibrosis. We analyzed outcomes in subgroups by BMI at baseline and associations between weight change and outcomes in subjects with progressive pulmonary fibrosis (PPF) in the INBUILD trial.
METHODS
Subjects with PPF other than idiopathic pulmonary fibrosis were randomized to receive nintedanib or placebo. In subgroups by BMI at baseline (< 25, ≥ 25 to < 30, ≥ 30 kg/m), we analyzed the rate of decline in FVC (mL/year) over 52 weeks and time-to-event endpoints indicating disease progression over the whole trial. We used a joint modelling approach to assess associations between change in weight and the time-to-event endpoints.
RESULTS
Among 662 subjects, 28.4%, 36.6% and 35.0% had BMI < 25, ≥ 25 to < 30 and ≥ 30 kg/m, respectively. The rate of decline in FVC over 52 weeks was numerically greater in subjects with baseline BMI < 25 than ≥ 25 to < 30 or ≥ 30 kg/m (nintedanib: - 123.4, - 83.3, - 46.9 mL/year, respectively; placebo: - 229.5; - 176.9; - 171.2 mL/year, respectively). No heterogeneity was detected in the effect of nintedanib on reducing the rate of FVC decline among these subgroups (interaction p = 0.83). In the placebo group, in subjects with baseline BMI < 25, ≥ 25 to < 30 and ≥ 30 kg/m, respectively, 24.5%, 21.4% and 14.0% of subjects had an acute exacerbation or died, and 60.2%, 54.5% and 50.4% of subjects had ILD progression (absolute decline in FVC % predicted ≥ 10%) or died over the whole trial. The proportions of subjects with these events were similar or lower in subjects who received nintedanib versus placebo across the subgroups. Based on a joint modelling approach, over the whole trial, a 4 kg weight decrease corresponded to a 1.38-fold (95% CI 1.13, 1.68) increase in the risk of acute exacerbation or death. No association was detected between weight loss and the risk of ILD progression or the risk of ILD progression or death.
CONCLUSIONS
In patients with PPF, lower BMI at baseline and weight loss may be associated with worse outcomes and measures to prevent weight loss may be required.
TRIAL REGISTRATION
https://clinicaltrials.gov/ct2/show/NCT02999178 .
Topics: Humans; Vital Capacity; Disease Progression; Double-Blind Method; Idiopathic Pulmonary Fibrosis; Body Mass Index; Treatment Outcome
PubMed: 36894966
DOI: 10.1186/s12931-023-02371-z -
Gene Apr 2023Mesenchymal cells in the lung are crucial during development, but also contribute to the pathogenesis of fibrotic disorders, including idiopathic pulmonary fibrosis... (Review)
Review
Mesenchymal cells in the lung are crucial during development, but also contribute to the pathogenesis of fibrotic disorders, including idiopathic pulmonary fibrosis (IPF), the most common and deadly form of fibrotic interstitial lung diseases. Originally thought to behave as supporting cells for the lung epithelium and endothelium with a singular function of producing basement membrane, mesenchymal cells encompass a variety of cell types, including resident fibroblasts, lipofibroblasts, myofibroblasts, smooth muscle cells, and pericytes, which all occupy different anatomic locations and exhibit diverse homeostatic functions in the lung. During injury, each of these subtypes demonstrate remarkable plasticity and undergo varying capacity to proliferate and differentiate into activated myofibroblasts. Therefore, these cells secrete high levels of extracellular matrix (ECM) proteins and inflammatory cytokines, which contribute to tissue repair, or in pathologic situations, scarring and fibrosis. Whereas epithelial damage is considered the initial trigger that leads to lung injury, lung mesenchymal cells are recognized as the ultimate effector of fibrosis and attempts to better understand the different functions and actions of each mesenchymal cell subtype will lead to a better understanding of why fibrosis develops and how to better target it for future therapy. This review summarizes current findings related to various lung mesenchymal cells as well as signaling pathways, and their contribution to the pathogenesis of pulmonary fibrosis.
Topics: Humans; Lung; Fibrosis; Pulmonary Fibrosis; Mesenchymal Stem Cells; Myofibroblasts; Fibroblasts; Extracellular Matrix Proteins; Idiopathic Pulmonary Fibrosis
PubMed: 36603696
DOI: 10.1016/j.gene.2022.147142 -
Scientific Reports Apr 2023Pulmonary fibrosis (PF) is a special type of pulmonary parenchymal disease, with chronic, progressive, fibrosis, and high mortality. There is a lack of safe, effective,...
Pulmonary fibrosis (PF) is a special type of pulmonary parenchymal disease, with chronic, progressive, fibrosis, and high mortality. There is a lack of safe, effective, and affordable treatment methods. Qilongtian (QLT) is a traditional Chinese prescription that is composed of Panax notoginseng, Earthworm, and Rhodiola, and shows the remarkable clinical curative effect of PF. However, the mechanism of QLT remains to be clarified. Therefore, we studied the effectivity of QLT in treating Bleomycin (BLM) induced PF mice. 36 C57BL/6 J mice were randomized into the control group, the model group, the low-, medium- and high-dose QLT group, and Pirfenidone group. After establishing a model of pulmonary fibrosis in mice, the control and model groups were infused with a normal saline solution, and the delivery group was infused with QLT. Pulmonary function in the mice from each group was detected. Pulmonary tissue morphologies and collagen deposition were stained by HE and Masson. The content of hydroxyproline (HYP) was detected by alkaline hydrolysis and the mRNA and protein expression of related genes in pulmonary tissues were detected by using q-PCR, ELISA, and Western blot. Our studies have shown that QLT significantly reduced the inflammatory injury, hydroxy-proline content, and collagen deposition of pulmonary tissue in BLM-induced PF mice and down-regulated the cytokine related to inflammation and fibrosis and PF expression on the mRNA and protein level in PF mice. To identify the mechanism of QLT, the Transcriptome was measured and the IL-17 signal pathway was screened out for further research. Further studies indicated that QLT reduced the mRNAs and protein levels of interleukin 17 (IL-17), c-c motif chemokine ligand 12 (CCL12), c-x-c motif chemokine ligand 5 (CXCL5), fos-like antigen 1 (FOSL1), matrix metalloproteinase-9 (MMP9), and amphiregulin (AREG), which are inflammation and fibrosis-related genes in the IL-17 signal pathway. The results indicated that the potential mechanism for QLT in the prevention of PF progression was by inhibiting inflammation resulting in the IL-17 signal pathway. Our study provides the novel scientific basis of QLT and represents new therapeutics for PF in clinical.
Topics: Mice; Animals; Pulmonary Fibrosis; Bleomycin; Interleukin-17; Ligands; Mice, Inbred C57BL; Inflammation; Fibrosis; Collagen; Signal Transduction; RNA, Messenger; Chemokines
PubMed: 37045911
DOI: 10.1038/s41598-023-31439-5 -
International Journal of Molecular... May 2023The pathological features of pulmonary fibrosis (PF) are the abnormal activation and proliferation of myofibroblasts and the extraordinary deposition of the... (Review)
Review
The pathological features of pulmonary fibrosis (PF) are the abnormal activation and proliferation of myofibroblasts and the extraordinary deposition of the extracellular matrix (ECM). However, the pathogenesis of PF is still indistinct. In recent years, many researchers have realized that endothelial cells had a crucial role in the development of PF. Studies have demonstrated that about 16% of the fibroblasts in the lung tissue of fibrotic mice were derived from endothelial cells. Endothelial cells transdifferentiated into mesenchymal cells via the endothelial-mesenchymal transition (E(nd)MT), leading to the excessive proliferation of endothelial-derived mesenchymal cells and the accumulation of fibroblasts and ECM. This suggested that endothelial cells, a significant component of the vascular barrier, played an essential role in PF. Herein, this review discusses E(nd)MT and its contribution to the activation of other cells in PF, which could provide new ideas for further understanding the source and activation mechanism of fibroblasts and the pathogenesis of PF.
Topics: Mice; Animals; Pulmonary Fibrosis; Endothelial Cells; Fibrosis; Fibroblasts; Myofibroblasts; Risk Factors
PubMed: 37240093
DOI: 10.3390/ijms24108749 -
Human Vaccines & Immunotherapeutics Dec 2024Mimotope, a kind of peptide vaccine, is developed to bind natural receptor and inhibit the downstream signaling. We have demonstrated that the vaccination of Tocilizumab...
Mimotope, a kind of peptide vaccine, is developed to bind natural receptor and inhibit the downstream signaling. We have demonstrated that the vaccination of Tocilizumab mimotopes could alleviate the renal fibrosis by interfering with both IL-6 and ferroptosis signaling. However, the effect of the vaccination of Tocilizumab mimotopes on the fibroblast was not investigated in previous study. Thus, we sought to explore the changes in the fibroblast induced by the Tocilizumab mimotopes vaccination. Bleomycin instillation was performed to construct the pulmonary fibrosis model after the immunization of Tocilizumab mimotopes. Lung histological analysis showed that the Tocilizumab mimotopes could significantly reduce the maladaptive repairment and abnormal remodeling. Immunoblotting assay and fluorescence staining showed that Immunization with the Tocilizumab mimotopes reduces the accumulation of fibrosis-related proteins. High level of lipid peroxidation product was observed in the animal model, while the Tocilizumab mimotopes vaccination could reduce the generation of lipid peroxidation product. Mechanism analysis further showed that Nrf-2 signaling, but not GPX-4 and FSP-1 signaling, was upregulated, and reduced the lipid peroxidation. Our results revealed that in the BLM-induced pulmonary fibrosis, high level of lipid peroxidation product was significantly accumulation in the lung tissues, which might lead to the occurrence of ferroptosis. The IL-6 pathway block therapy could inhibit lipid peroxidation product generation in the lung tissues by upregulating the Nrf-2 signaling, and further alleviate the pulmonary fibrosis.
Topics: Animals; Pulmonary Fibrosis; Interleukin-6; Bleomycin; Lung; Vaccination; Antibodies, Monoclonal, Humanized
PubMed: 38408907
DOI: 10.1080/21645515.2024.2319965