A murine systemic bleomycin model of scleroderma
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE132869 | GEO | 2019/06/18
REPOSITORIES: GEO
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Project description:Systemic sclerosis (SSc) or scleroderma is a chronic multiorgan autoimmune disease of unknown etiology characterized by vascular, immunological and fibrotic abnormalities. Several lines of evidence have shown that the endocannabinoid system (ECS) may play a role in the pathophysiology of SSc. VCE-004.8, a CBD aminoquinone derivative, is a dual PPARγ/CB2 that alleviates bleomycin (BLM)-induced skin fibrosis. Herein we report that EHP-101, an oral lipidic formulation of VCE-004.8, prevents skin and lung fibrosis and collagen accumulation in BLM challenged mice. Immunohistochemistry analysis of the skin demonstrate that EHP-101 prevents macrophage infiltration, and the expression of Tenascin C (TNC), VCAM, and the α-smooth muscle actin (SMA). In addition, a reduced expression of vascular CD31, paralleling skin fibrosis, was also prevented by EHP-101. RNAseq analysis in skin biopsies showed a clear effect of EHP-101 in the inflammatory and epithelial-mesenchymal transition transcriptomic signatures. TGF-beta regulated genes such as matrix metalloproteinase-3 (Mmp3), cytochrome b-245 heavy chain (Cybb), lymphocyte antigen 6E (Ly6e), vascular cell adhesion molecule-1 (Vcam1) and the Integrin alpha-5 (Itga5) were induced in BLM mice and repressed by EHP-101 treatment. We also intersected differentially expressed genes in EHP-101-treated mice with dataset of human scleroderma intrinsic genes and found 53 overlapped genes, including the C-C motif chemokine 2 (Ccl2) and the interleukin 13 receptor subunit alpha 1 (IL-13Ra1) genes, which have been studied as biomarkers of SSc. Altogether the results indicate that this synthetic cannabinoid qualifies as a novel compound for the management and possible treatment of scleroderma and, potentially, other fibrotic diseases.
2018-10-02 | GSE115503 | GEO
Project description:To analyze the role of HSP27 in bleomycin (BLM)-induced pulmonary fibrosis in vivo, we used TG mice that conventionally overexpressed HSP27. Our previously reported that HSP27 plays an important role in pulmonary fibrosis. In mice overexpressing HSPB1, BLM-induced fibrotic regions and collagen deposits were increased compared with those in control BL6 mice. Following intratracheal treatment of BLM, the HSP25 TG mice showed an abundance of mononuclear and neutrophils cells in the alveoli, greater destruction of alveolar septa, intra-alveolar hyaline membrane formation, and a marked increase in collagen deposition compared with control BL6 mice.
2023-11-20 | GSE233735 | GEO
Project description:In this study, we analyzed the gene expression profiles of the lung in mouse bleomycin (BLM)-induced systemic sclerosis (SSc) model treated with MT-7117. Gene array analysis using the BLM-induced SSc model demonstrated changes in numerous categories related to macrophages, monocytes, and neutrophils, followed by endothelial cell-related categories after treatment with MT-7117 (Dersimelagon). In the analysis that focused on biological functions, categories of inflammatory response, activation of antigen-presenting cells, angiogenesis, atherosclerosis, vasculogenesis, and vaso-occlusion were suppressed by MT-7117. In the analysis that focused on molecular signaling pathways, triggering receptor expressed on myeloid cells-1, IL-6, and oncostatin M involved in inflammation, and peroxisome proliferator-activated receptor that is related to fibrosis were all affected by MT-7117.
2022-09-09 | GSE199581 | GEO
Project description:The NLRP3 inflammasome and IL-1β are essential for scleroderma pathogenesis. Nevertheless, the role of pyroptosis executor gasdermin D(GSDMD), which is a downstream molecule of NLRP3 and is required for IL-1β release in some situations, has not yet been well elucidated in scleroderma. The purpose of this study was to explore the differences in the degree of skin fibrosis between GSDMD-/- and wild type mice in a bleomycin-induced scleroderma model, and the molecular pathways that may be involved.Total RNA from skin biopsies from GSDMD-/- and wild type mice after subcutaneous injection of BLM to induce skin fibrosis was examined by nextGen RNA sequencing
2022-02-16 | GSE196637 | GEO
Project description:In addition to autoimmune and inflammatory diseases, variants of the TNFAIP3 gene encoding A20 are also associated with systemic sclerosis (SSc). However, it remains unclear how genetic factors contribute to fibrosis in SSc, and which cell types drive disease due to SSc-specific genetic alterations. We characterized the expression and function of A20, and its negative transcriptional regulator DREAM, in patient with SSc. We found that levels of A20 were significantly reduced in SSc skin and lung biopsies, while DREAM was elevated and showed anti-correlation with A20. Mice haploinsufficient for A20, or harboring fibroblasts-specific A20 deletion, recapitulated major pathological and genomic features of SSc, whereas DREAM-null mice showed elevated A20 expression and were protected from fibrosis. In fibroblasts, A20 mitigated ex vivo profibrotic responses. An anti-fibrotic small molecule targeting the adiponectin receptors stimulated A20 expression in vitro in wildtype but not A20-deficient fibroblasts, and in bleomycin-treated mice. Thus, A20 has a novel function in negative regulation of fibroblast responses, and together with DREAM, constitutes a critical regulatory network governing the fibrotic process in SSc, suggesting that A20 and DREAM represent novel druggable targets.
2022-02-01 | GSE194380 | GEO
Project description:Bleomycin-induced pulmonary fibrosis in mice mimics major hallmarks of idiopathic pulmonary fibrosis, yet in this model it spontaneously resolves over time. We studied molecular mechanisms of fibrosis resolution and lung repair, focusing on transcriptional and proteomic signatures and the effect of aging. Young (3 months) and old (21 months) mice were treated with Bleomycin or with control saline solution and analyzed transcript and protein expression over 8 weeks (Day 0, 14, 21, 28, 35, 42, 49, 56).
2023-08-09 | PXD041050 | Pride
Project description:Backgroud: Idiopathic pulmonary fibrosis (IPF) is an irreversible disorder with a poor clinical outcome. The partial understanding of IPF pathogenesis and, consequently, the lack of appropriate relevant animal models is limiting the development of effective treatments. In this context, the intratracheal bleomycin (BLM) administration murine model is regarded as the most reliable preclinical approximation of human IPF. We present, here, the results of an integrated histological and transcriptome analysis that was used to monitor the time-course of BLM-induced lung fibrosis development in a rat model of disease and to assess its overlap with IPF. Methods: Male rats were injected intratracheally (IT) with a double dose of BLM or saline (day 0 – 4) and sacrificed at day 7, 14, 21, 28 and 56. Histomorphometric analysis of lung fibrosis was performed on Masson’s trichrome stained sections on the left lung lobe. Transcriptome profiling by RNAseq was performed on total RNA extracted from the right lung lobe Results and Conclusions: Transcriptomic analysis provided a detailed overview of BLM-induced lung fibrosis development and identified three clusters of differentially co-regulated genes whose expression was modulated in a time-dependent manner in response to BLM. One of these clusters centred on extracellular matrix-related pathways and process was found to be significantly correlated with histological parameters and gene sets derived from human IPF studies, thus indicating its translational potential as a signature biomarker for future IPF-related target validation and drug discovery studies.
2023-09-20 | GSE212141 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a type of pulmonary fibrosis, a disease that results in scarring and stiffness of lung tissue affecting over 5 million people globally, while the underlying disease mechanisms in IPF are largely unknown. As an animal model of IPF, a single intratracheal injection of bleomycin (BLM) is generally employed, in which cell death of type II alveolar epithelial cells (AEC II) is a trigger of pulmonary fibrosis. One of mitogen-activated protein kinases, p38 is well known as an important regulator of inflammatory responses and cell fate such as apoptosis, differentiation and tumorgenesis. Given that mice with different intrinsic activity of p38 in AEC II were subjected to BLM instillation and investigated, candidate genes in the development of pulmonary fibrosis would be screened. Here, we provide gene expression profiling of lung tissues using the RNA sequencing for identifying changes in gene expression.
2020-09-09 | GSE154074 | GEO
Project description:Pulmonary fibrosis is a devatating lung disease with limited effective treatment. Because fibrotic responses are considered to be regulated by complex cellular and molecular circuits, it is difficult to demonstrate a causal relationship of cells, molecules, and cell-cell interactions with diseases in vivo. To overcome this issue, we established bleomycin (BLM)-stimulated alveolosphere model as an ex vivo culture model. To clarify whether our ex vivo model recapitulates the cellular and molecular response to BLM-induced lung injury, we performed RNA-seq (Bulk RNA-seq) analysis of the BLM-stimulated alveolospheres generated by co-culturing murine lung epithelial cells and lung fibroblasts.
2024-04-01 | GSE200297 | GEO
Project description:Several lines of evidence have shown that the endocannabinoid system (ECS) may play a role in the pathophysiology of systemic sclerosis (SSc). Thereby, structurally different dual PPARγ/CB2 agonists such as VCE-004.8 and Ajulemic acid (AjA) have been shown to alleviate skin fibrosis and inflammation in experimental models of SSc. Since both compounds are currently being tested in humans, we were interested to identify similarities and differences in a murine model of SSc. One method available to assess this is the pharmacotranscriptomic signature of the individual compounds. To analyze the pharmacotranscriptomic signature, we used RNA-Seq to analyze the skin gene expression changes from bleomycin-induced fibrosis in mice treated orally with either AjA or EHP-101, a lipidic formulation of VCE-004.8. While both compounds prevented the upregulation of a common group of genes involved in the inflammatory and fibrotic components of the disease and the pharmacotranscriptomic signatures were similar for both compounds in some pathways, we found key differences between the compounds in several functional groups, including genes related the hypoxia, interferon-α and interferon-γ response. Additionally, we found 28 specific genes with translation potential by comparing our results with a list of intrinsic human scleroderma genes. Inmunohistochemical analysis revealed that both EHP-101 and AjA prevented bleomycin-induced skin fibrosis, collagen accumulation, and TNC and VCAM expression. However, only EHP-101 normalized the reduced expression of vascular CD31, CD34 and Von Willebrand factor markers, which parallels skin fibrosis, while AjA did not affect these markers. Finally, clear differences were also found in the plasmatic biomarker analysis, in which we found that EHP-101, but not AjA, enhanced the expression of some factors related to angiogenesis and vasculogenesis. Altogether the results indicate that dual PPARγ/CB2 agonists qualify as a novel therapeutic approach for the treatment of SSc and other fibrotic diseases as well, and that EHP-101 has unique mechanisms of action related to the pathophysiology of SSc which could be beneficial in treatment of this complex disease with no current therapeutic options.
2019-03-31 | GSE121659 | GEO