scholarly journals Myeloid Fbxw7 Prevents Pulmonary Fibrosis by Suppressing TGF-β Production

2022 ◽  
Vol 12 ◽  
Author(s):  
Jia He ◽  
Yue Du ◽  
Gaopeng Li ◽  
Peng Xiao ◽  
Xingzheng Sun ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Mononuclear Cells ◽  
Transforming Growth Factor ◽  
Treatment Options ◽  
Myeloid Cell ◽  
Transforming Growth Factor Β ◽  
Peripheral Blood Mononuclear ◽  
Regulation Mechanisms ◽  
Insight Into

Idiopathic pulmonary fibrosis (IPF) is a group of chronic interstitial pulmonary diseases characterized by an inexorable decline in lung function with limited treatment options. The abnormal expression of transforming growth factor-β (TGF-β) in profibrotic macrophages is linked to severe pulmonary fibrosis, but the regulation mechanisms of TGF-β expression are incompletely understood. We found that decreased expression of E3 ubiquitin ligase Fbxw7 in peripheral blood mononuclear cells (PBMCs) was significantly related to the severity of pulmonary fibrosis in IPF patients. Fbxw7 is identified to be a crucial suppressing factor for pulmonary fibrosis development and progression in a mouse model induced by intratracheal bleomycin treatment. Myeloid cell-specific Fbxw7 deletion increases pulmonary monocyte-macrophages accumulation in lung tissue, and eventually promotes bleomycin-induced collagen deposition and progressive pulmonary fibrosis. Notably, the expression of TGF-β in profibrotic macrophages was significantly upregulated in myeloid cell-specific Fbxw7 deletion mice after bleomycin treatment. C-Jun has long been regarded as a critical transcription factor of Tgfb1, we clarified that Fbxw7 inhibits the expression of TGF-β in profibrotic macrophages by interacting with c-Jun and mediating its K48-linked ubiquitination and degradation. These findings provide insight into the role of Fbxw7 in the regulation of macrophages during the pathogenesis of pulmonary fibrosis.

scholarly journals Attenuated pulmonary fibrosis in sialidase-3 knockout (Neu3−/−) mice

2020 ◽  
Vol 318 (1) ◽  
pp. L165-L179 ◽  
Author(s):  
Tejas R. Karhadkar ◽  
Wensheng Chen ◽  
Richard H. Gomer
Keyword(s):  
Pulmonary Fibrosis ◽  
Mononuclear Cells ◽  
Transforming Growth Factor ◽  
Human Peripheral Blood ◽  
Lavage Fluid ◽  
Scar Tissue ◽  
Transforming Growth Factor Β1 ◽  
Peripheral Blood Mononuclear ◽  
Male And Female

Pulmonary fibrosis involves the formation of inappropriate scar tissue in the lungs, but what drives fibrosis is unclear. Sialidases (also called neuraminidases) cleave terminal sialic acids from glycoconjugates. In humans and mice, pulmonary fibrosis is associated with desialylation of glycoconjugates and upregulation of sialidases. Of the four mammalian sialidases, we previously detected only NEU3 in the bronchoalveolar lavage fluid from mice with bleomycin-induced pulmonary fibrosis. In this report, we show that NEU3 upregulates extracellular accumulation of the profibrotic cytokines IL-6 and IL-1β, and IL-6 upregulates NEU3 in human peripheral blood mononuclear cells, suggesting that NEU3 may be part of a positive feedback loop potentiating fibrosis. To further elucidate the role of NEU3 in fibrosis, we used bleomycin to induce lung fibrosis in wild-type C57BL/6 and Neu3−/− mice. At 21 days after bleomycin, compared with male and female C57BL/6 mice, male and female Neu3−/− mice had significantly less inflammation, less upregulation of other sialidases and the profibrotic cytokine active transforming growth factor β1, and less fibrosis in the lungs. Our results suggest that NEU3 participates in fibrosis and that NEU3 could be a target to develop treatments for fibrosis.

scholarly journals LncRNA SNHG16 promotes pulmonary fibrosis by targeting miR-455-3p to regulate the Notch2 pathway

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Panpan Liu ◽  
Lei Zhao ◽  
Yuxia Gu ◽  
Meilan Zhang ◽  
Hongchang Gao ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interstitial Lung Diseases ◽  
Luciferase Reporter ◽  
Qrt Pcr ◽  
Rna Immunoprecipitation ◽  
And Migration

Abstract Background Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung diseases with a poor prognosis. Long non-coding RNAs (lncRNAs) have been reported to be involved in IPF in several studies. However, the role of lncRNA SNHG16 in IPF is largely unknown. Methods Firstly, experimental pulmonary fibrosis model was established by using bleomycin (BML). Histology and Western blotting assays were used to determine the different stages of fibrosis and expression of several fibrosis biomarkers. The expression of SNHG16 was detected by quantitative real-time polymerase chain reaction (qRT‐PCR). EdU staining and wound-healing assay were utilized to analyze proliferation and migration of lung fibroblast cells. Molecular mechanism of SNHG16 was explored by bioinformatics, dual-luciferase reporter assay, RNA immunoprecipitation assay (RIP), and qRT-PCR. Results The expression of SNHG16 was significantly up-regulated in bleomycin-(BLM) induced lung fibrosis and transforming growth factor-β (TGF-β)-induced fibroblast. Knockdown of SNHG16 could attenuate fibrogenesis. Mechanistically, SNHG16 was able to bind and regulate the expression of miR-455-3p. Moreover, SNHG16 also regulated the expression of Notch2 by targeting miR-455-3p. Finally, SNHG16 could promote fibrogenesis by regulating the expression of Notch2. Conclusion Taken together, our study demonstrated that SNHG16 promoted pulmonary fibrosis by targeting miR-455-3p to regulate the Notch2 pathway. These findings might provide a novel insight into pathologic process of lung fibrosis and may provide prevention strategies in the future.

Fibroblasts positive for meflin have anti-fibrotic property in pulmonary fibrosis

2021 ◽  
pp. 2003397
Author(s):  
Yoshio Nakahara ◽  
Naozumi Hashimoto ◽  
Koji Sakamoto ◽  
Atsushi Enomoto ◽  
Taylor S. Adams ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Single Cell ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Normal Lung ◽  
Potential Marker ◽  
Rna Hybridisation ◽  
Secretory Phenotype

The prognosis of elderly individuals with idiopathic pulmonary fibrosis (IPF) remains poor. Fibroblastic foci, in which aggregates of proliferating fibroblasts and myofibroblasts are involved, are the pathological hallmark lesions in IPF to represent focal areas of active fibrogenesis. Fibroblast heterogeneity in fibrotic lesions hampers the discovery of the pathogenesis of pulmonary fibrosis. Therefore, to determine of the pathogenesis of IPF, identification of functional fibroblasts is warranted. This study was aimed to determine the role of fibroblasts positive for meflin, identified as a potential marker for mesenchymal stromal cells, during the development of pulmonary fibrosis. We characterised meflin-positive cells in a single cell atlas established by single-cell RNA sequencing (scRNA-seq)-based profiling of 243 472 cells from 32 IPF lungs and 29 normal lung samples. scRNA-seq combined with in situ RNA hybridisation identified proliferating fibroblasts positive for meflin in fibroblastic foci, not dense fibrosis, of fibrotic lungs in IPF patients. We determined the role of fibroblasts positive for meflin using bleomycin (BLM)-induced pulmonary fibrosis. A BLM-induced lung fibrosis model for meflin-deficient mice showed that fibroblasts positive for meflin had anti-fibrotic property to prevent pulmonary fibrosis. Although transforming growth factor-β-induced fibrogenesis and cell senescence with senescence-associated secretory phenotype were exacerbated in fibroblasts via the repression or lack of meflin, these were inhibited in meflin-deficient fibroblasts with meflin reconstitution. These findings provide evidence to show the biological importance of meflin expression on fibroblasts and myofibroblasts in the active fibrotic region of pulmonary fibrosis.

115 EXPRESSION OF RADICAL S-ADENOSYL METHIONINE DOMAIN CONTAINING-2 (RSAD2) AND TRANSFORMING GROWTH FACTOR β (TGF-β) IN BOVINE PERIPHERAL BLOOD MONONUCLEAR CELLS DURING PREGNANCY: IDENTIFICATION OF POTENTIAL BIOMARKERS TO DETERMINE PREGNANCY STATUS

2011 ◽  
Vol 23 (1) ◽  
pp. 162
Author(s):  
N. Mansouri-Attia ◽  
L. J. Oliveira ◽  
F. Carter ◽  
N. Forde ◽  
P. Lonergan ◽  
...  
Keyword(s):  
Dairy Cows ◽  
Mrna Expression ◽  
Mixed Model ◽  
Mononuclear Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Peripheral Blood Mononuclear ◽  
Dairy Heifers ◽  
Pregnancy Status ◽  
Adenosyl Methionine

During the bovine peri-implantation period, immune cells are exposed to endocrine and paracrine signals, which support feto-placental development. Recent studies in cattle have shown that the antiviral factor Mx2, known to be up-regulated by conceptus-derived interferon-τ in pregnancy, is detected in peripheral blood mononuclear cells (PBMC) and can be used for pregnancy detection on Day 18. The objectives of the current study were to correlate mRNA expression levels of pregnancy associated factors and immune modulators RSAD2 (radical S-adenosyl methionine domain containing-2) and TGF-β (transforming growth factor β) in circulating PBMCs, with pregnancy status in dairy cows and heifers. Holstein-Friesian heifers (n = 12) and lactating dairy cows (n = 17) were synchronised to estrus and artificially inseminated (bred) or not (non bred, n = 4). Blood samples were collected on Day 0 (day of AI or estrus), 5, 7, 13, 16, 20, and 25 for PBMC isolation. Pregnancy was diagnosed retrospectively by transrectal ultrasonography at Days 30 and 60 after breeding. The relative quantification of RSAD2 and TGF-β transcript abundance, analysed by qPCR, was normalised against PPIA and calculated according to the relative standard curve method. Data from duplicates were pooled, and a mixed model was run on the pooled Cq values for each stage. Genes were considered as differentially expressed if the mixed model P value was <0.05. RSAD2 mRNA abundance was 2-fold higher in pregnant heifers compared with non-bred heifers on Day 20 (P < 0.01) and Day 25 (P < 0.03) post AI. Likewise, RSAD2 mRNA expression was greater (2.25 fold) in pregnant heifers compared with heifers that were inseminated but not pregnant (P < 0.007). In contrast, RSAD2 expression was not significantly different in pregnant cows compared to non-bred or bred but non-pregnant cows. TGF-β mRNA abundance was significantly lower in both pregnant cows (3.5-fold, P < 0.04) and pregnant heifers (4.5-fold, P < 0.01) compared to non-bred animals as early as Day 13. This suppression of expression was maintained until Day 20 in heifers (3.9-fold, P < 0.02). In addition, PBMC TGF-β mRNA expression was lower in pregnant cows compared with bred non-pregnant cows (1.65-fold, P < 0.06). In conclusion, Day 20 PBMC RSAD2 expression may be a useful predictor of pregnancy maintenance in dairy heifers. However, decreased TGF-β expression as early as Day 13 appears to be a more powerful indicator of the presence of a viable embryo in both dairy heifers and cows and may play a role in the establishment and maintenance of pregnancy through the restriction of monocyte recruitment or activation during the time of maternal recognition of pregnancy. Research supported by Science Foundation Ireland (PICA-B813)

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