Browse
Submit Data
Databases
API
Help

Dataset Information

24 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Tauroursodeoxycholic acid alleviates pulmonary endoplasmic reticulum stress and epithelial-mesenchymal transition in bleomycin-induced lung fibrosis.

ABSTRACT:

Background

Several studies demonstrate that endoplasmic reticulum (ER) stress-mediated epithelial-mesenchymal transition (EMT) is involved in the process of bleomycin (BLM)-induced pulmonary fibrosis. Tauroursodeoxycholic acid (TUDCA), a bile acid with chaperone properties, is an inhibitor of ER stress. This study aimed to investigate the preventive effects of TUDCA on BLM-induced EMT and lung fibrosis.

Methods

The model of lung fibrosis was established by intratracheal injection with a single dose of BLM (3.0 mg/kg). In TUDCA + BLM group, mice were intraperitoneally injected with TUDCA (250 mg/kg) daily.

Results

BLM-induced alveolar septal destruction and inflammatory cell infiltration were alleviated by TUDCA. BLM-induced interstitial collagen deposition, as determined by Sirius Red staining, was attenuated by TUDCA. BLM-induced elevation of pulmonary α-smooth muscle actin (α-SMA) and reduction of pulmonary E-cadherin were attenuated by TUDCA. BLM-induced pulmonary Smad2/3 phosphorylation was suppressed by TUDCA. BLM-induced elevation of Ki67 and PCNA was inhibited by TUDCA in mice lungs. In addition, BLM-induced elevation of HO-1 (heme oxygenase-1) and 3-NT (3-nitrotyrosine) was alleviated by TUDCA. Finally, BLM-induced upregulation of pulmonary GRP78 and CHOP was attenuated by TUDCA.

Conclusions

These results provide evidence that TUDCA pretreatment inhibits Smad2/3-medited EMT and subsequent lung fibrosis partially through suppressing BLM-induced ER stress and oxidative stress.

SUBMITTER: Tong B

PROVIDER: S-EPMC8097922 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Isorhamnetin protects against bleomycin-induced pulmonary fibrosis by inhibiting endoplasmic reticulum stress and epithelial-mesenchymal transition.

Project description:The present study aimed to determine whether isorhamnetin (Isor), a natural antioxidant polyphenol, has antifibrotic effects in a murine model of bleomycin?induced pulmonary fibrosis. A C57 mouse model of pulmonary fibrosis was established by intraperitoneal injection of a single dose of bleomycin (3.5 U/kg), and then Isor (10 and 30 mg/kg) was administered intragastrically. The level of fibrosis was assessed by hematoxylin and eosin and Sirius red staining. ??smooth muscle actin and type I collagen levels in lung tissues were determined by western blotting and immunohistochemistry (IHC). Epithelial?mesenchymal transition (EMT), endoplasmic reticulum stress (ERS) and related signaling pathways were examined by western blotting and IHC. In vitro, human bronchial epithelial cells (HBECs) and A549 cells were treated with transforming growth factor (TGF)?1 with or without Isor, and collagen deposition and the expression levels of EMT? and ERS?related genes or proteins were analyzed by reverse transcription?quantitative polymerase chain reaction, western blotting, and immunofluorescence. The results demonstrated that Isor inhibited bleomycin?induced collagen deposition, reduced type I collagen and ??SMA expression, and alleviated EMT and ERS in vivo. Furthermore, incubation of HBECs and A549 cells with TGF?1 activated EMT and ERS, and this effect was reversed by Isor. In conclusion, Isor treatment attenuated bleomycin?induced EMT and pulmonary fibrosis and suppressed bleomycin?induced ERS and the activation of PERK signaling.

| S-EPMC6257865 | biostudies-other

Endothelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis.

Project description:The pathological hallmark lesions in idiopathic pulmonary fibrosis are the fibroblastic foci, in which fibroblasts are thought to be involved in the tissue remodeling, matrix deposition, and cross-talk with alveolar epithelium. Recent evidence indicates that some fibroblasts in fibrosis may be derived from bone marrow progenitors as well as from epithelial cells through epithelial-mesenchymal transition. To evaluate whether endothelial cells could represent an additional source for fibroblasts, bleomycin-induced lung fibrosis was established in Tie2-Cre/CAG-CAT-LacZ double-transgenic mice, in which LacZ was stably expressed in pan-endothelial cells. Combined X-gal staining and immunocytochemical staining for type I collagen and alpha-smooth muscle actin revealed the presence of X-gal-positive cells in lung fibroblast cultures from bleomycin-treated mice. To explore the underlying mechanisms, by which loss of endothelial-specific markers and gain of mesenchymal phenotypes could be involved in microvascular endothelial cells, the effects of activated Ras and TGF-beta on the microvascular endothelial cell line MS1 were analyzed. Combined treatment with activated Ras and TGF-beta caused a significant loss of endothelial-specific markers, while inducing de novo mesenchymal phenotypes. The altered expression of these markers in MS1 cells with activated Ras persisted after withdrawal of TGF-beta in vitro and in vivo. These findings are the first to show that lung capillary endothelial cells could give rise to significant numbers of fibroblasts through an endothelial-mesenchymal transition in bleomycin-induced lung fibrosis model.

| S-EPMC2937229 | biostudies-literature

Bleomycin induces epithelial-to-mesenchymal transition via bFGF/PI3K/ESRP1 signaling in pulmonary fibrosis.

Project description:Idiopathic pulmonary fibrosis (IPF) is a fatal and chronic disease with a high rate of infection and mortality; however, its etiology and pathogenesis remain unclear. Studies have revealed that epithelial-mesenchymal transition (EMT) is a crucial cellular event in IPF. Here, we identified that the pulmonary fibrosis inducer bleomycin simultaneously increased the expression of bFGF and TGF-β1 and inhibited epithelial-specific regulatory protein (ESRP1) expression in vivo and in vitro. In addition, in vitro experiments showed that bFGF and TGF-β1 down-regulated the expression of ESRP1 and that silencing ESRP1 promoted EMT in A549 cells. Notably, we determined that bFGF activates PI3K/Akt signaling, and treatment with the PI3K/Akt inhibitor LY294002 inhibited bleomycin-induced cell morphology changes and EMT. In addition, the effects of LY294002 on bleomycin-induced EMT were inhibited by ESRP1 silencing in A549 cells. Taken together, these findings suggest that bleomycin induced EMT through down-regulating ESRP1 by simultaneously increasing bFGF and TGF-β1 in pulmonary fibrosis. Additionally, our findings indicated that bFGF inhibits ESRP1 by activating PI3K/Akt signaling.

| S-EPMC6960066 | biostudies-literature

NecroX-5 ameliorates bleomycin-induced pulmonary fibrosis via inhibiting NLRP3-mediated epithelial-mesenchymal transition.

Project description:BackgroundPulmonary fibrosis is a progressive and usually lethal pulmonary disease. Despite considerable research efforts, no effective therapeutic strategy for pulmonary fibrosis has been developed. NecroX-5 has been reported to possess anti-inflammatory, anti-oxidative and anti-tumor activities. In the present study, we aimed to determine whether NecroX-5 exhibits antifibrotic property in bleomycin (BLM)-induced pulmonary fibrosis.ResultsWe found that pre-treatment with NecroX-5 alleviated inflammatory response, reduced oxidative stress, inhibited epithelial-mesenchymal transition (EMT), and ameliorated pulmonary fibrosis in vivo and in vitro. Our data further indicated that NecroX-5 substantially reduced activation of NLRP3 inflammasome and TGF-β1/Smad2/3 signaling in vivo and in vitro. Additionally, NLRP3 overexpression significantly reversed the protective effects of NecroX-5 in lung epithelial cells exposed to BLM.ConclusionsOverall, our results demonstrate the potent antifibrotic properties of NecroX-5 and its therapeutic potential for pulmonary fibrosis.

| S-EPMC9121617 | biostudies-literature

Calpain inhibition attenuates bleomycin-induced pulmonary fibrosis via switching the development of epithelial-mesenchymal transition.

Project description:Calpains are intracellular calcium-dependent cysteine proteases, which cleave several substrates proteins, have been proven to play important roles in lung fibrosis. The aim of this study was to investigate the effects of calpain on bleomycin (BLM)-induced pulmonary fibrosis. A lung fibrosis mice model was established successfully by intraperitoneal injection of bleomycin. Calpeptin, a highly selective inhibitor of calpain activation, was administered three times weekly after bleomycin injection. Histological examination was used to assess the fibrosis. Quantitative-PCR and Western blotting were used to assess the development of epithelial-mesenchymal transition (EMT). We found calpeptin treatment decreased the BLM-induced EMT-associated markers, such as muscle actin (α-SMA) and collagen-I, while increased E-cadherin (E-cad). Calpeptin also suppressed the activation of transforming growth factor β1 (TGFβ1)-Smad2/3 signaling pathway, which plays crucial role in lung fibrosis and EMT. Furthermore, we found differentiated embryonic chondrocyte-expressed gene 1 (DEC1), an important transcription factor, was upregulated in both patients with idiopathic pulmonary fibrosis and in bleomycin-induced lung fibrosis. DEC1 was suppressed by calpeptin in bleomycin-induced mice model. Collectively, these findings indicated that calpeptin had a potential anti-fibrosis effect, which focus on the development of EMT.

| S-EPMC5994212 | biostudies-literature

Atractylodin Suppresses TGF-β-Mediated Epithelial-Mesenchymal Transition in Alveolar Epithelial Cells and Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice.

Project description:Idiopathic pulmonary fibrosis (IPF) is characterized by fibrotic change in alveolar epithelial cells and leads to the irreversible deterioration of pulmonary function. Transforming growth factor-beta 1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) in type 2 lung epithelial cells contributes to excessive collagen deposition and plays an important role in IPF. Atractylodin (ATL) is a kind of herbal medicine that has been proven to protect intestinal inflammation and attenuate acute lung injury. Our study aimed to determine whether EMT played a crucial role in the pathogenesis of pulmonary fibrosis and whether EMT can be utilized as a therapeutic target by ATL treatment to mitigate IPF. To address this topic, we took two steps to investigate: 1. Utilization of anin vitro EMT model by treating alveolar epithelial cells (A549 cells) with TGF-β1 followed by ATL treatment for elucidating the underlying pathways, including Smad2/3 hyperphosphorylation, mitogen-activated protein kinase (MAPK) pathway overexpression, Snail and Slug upregulation, and loss of E-cadherin. Utilization of an in vivo lung injury model by treating bleomycin on mice followed by ATL treatment to demonstrate the therapeutic effectiveness, such as, less collagen deposition and lower E-cadherin expression. In conclusion, ATL attenuates TGF-β1-induced EMT in A549 cells and bleomycin-induced pulmonary fibrosis in mice.

| S-EPMC8570326 | biostudies-literature

Sorafenib ameliorates bleomycin-induced pulmonary fibrosis: potential roles in the inhibition of epithelial-mesenchymal transition and fibroblast activation.

Project description:Idiopathic pulmonary fibrosis (IPF) is a serious progressive and irreversible lung disease with unknown etiology and few treatment options. This disease was once thought to be a chronic inflammatory-driven process, but it is increasingly recognized that the epithelial-mesenchymal transition (EMT) contributes to the cellular origin of fibroblast accumulation in response to injury. During the pathogenesis of pulmonary fibrotic diseases, transforming growth factor-β (TGF-β) signaling is considered a pivotal inducer of EMT and fibroblast activation, and a number of therapeutic interventions that interfere with TGF-β signaling have been developed to reverse established fibrosis. However, efficient and well-tolerated antifibrotic agents are not currently available. Previously, we reported the identification of sorafenib to antagonize TGF-β signaling in mouse hepatocytes in vitro. In this manuscript, we continued to evaluate the antifibrotic effects of sorafenib on bleomycin (BLM)-induced pulmonary fibrosis in mice. We further demonstrated that sorafenib not only profoundly inhibited TGF-β1-induced EMT in alveolar epithelial cells, but also simultaneously reduced the proliferation and collagen synthesis in fibroblasts. Additionally, we presented in vivo evidence that sorafenib inhibited the symptoms of BLM-mediated EMT and fibroblast activation in mice, warranting the therapeutic potential of this drug for patients with IPF.

| S-EPMC3698540 | biostudies-literature

Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis.

Project description:The molecular pathomechanisms underlying idiopathic pulmonary fibrosis (IPF) are elusive, but chronic epithelial injury has recently been suggested as key event.We investigated the possible implication of endoplasmic reticulum (ER) stress-mediated apoptosis in sporadic IPF.We analyzed peripheral explanted lung tissues from patients with sporadic IPF (n = 24), chronic obstructive pulmonary disease (COPD) (n = 9), and organ donors (n = 12) for expression of major ER stress mediators and apoptosis markers by means of immunoblotting, semiquantitative reverse transcription-polymerase chain reaction, immunohistochemistry, and the TUNEL method.Compared with COPD and donor lungs, protein levels of ER stress mediators, such as processed p50 activating transcription factor (ATF)-6 and ATF-4 and the apoptosis-inductor CHOP (C/EBP-homologous protein), as well as transcript levels of spliced X-box binding protein (XBP)-1, were significantly elevated in lung homogenates and type II alveolar epithelial cells (AECIIs) of IPF lungs. Proapoptotic, oligomeric forms of Bax, which play a key role in ER stress-mediated apoptosis downstream of CHOP induction, as well as caspase-3 cleavage, could be detected in IPF lungs. By means of immunohistochemistry, exclusive induction of active ATF-6, ATF-4, and CHOP in AECIIs was encountered in IPF but not in COPD or donor lungs. Immunoreactivity was most prominent in the epithelium near dense zones of fibrosis and fibroblast foci, where these ER stress markers colocalized with markers of apoptosis (TUNEL, cleaved caspase-3).Severe ER stress response in the AECIIs of patients with sporadic IPF may underlie the apoptosis of this cell type and development of fibrosis in this disease.

| S-EPMC2566794 | biostudies-literature

Tauroursodeoxycholic acid (TUDCA) alleviates endoplasmic reticulum stress of nuclear donor cells under serum starvation.

Project description:Serum starvation is a routine protocol for synchronizing nuclear donor cells to G0/G1 phase during somatic cell nuclear transfer (SCNT). However, abrupt serum deprivation can cause serious stress to the cells cultured in vitro, which might result in endoplasmic reticulum (ER) stress, chromosome damage, and finally reduce the success rate of SCNT. In the present study, the effects of tauroursodeoxycholic acid (TUDCA), an effective ER stress-relieving drug, on the nuclear donor cells under serum deprivation condition as well as following SCNT procedures were first assessed in the bovine. The results showed that TUDCA significantly reduced ER stress and cell apoptosis in those nuclear donor cells. Moreover, it significantly decreased the expression of Hdac1 and Dnmt1, and increased the level of H3K9 acetylation in nuclear donor cells compared with control group. SCNT reconstructed embryos cloned from TUDCA-treated donor cells showed significantly higher fusion, cleavage, blastocyst formation rate, total cell number in day 7 blastocysts, and lower apoptotic index than that from control group. In addition, the expression of Hdac1, Dnmt1 and Bax was significantly lower in blastocysts derived from TUDCA-treated donor cells than that from control group. In conclusion, TUDCA significantly reduced the ER stress of nuclear donor cells under serum starvation condition, and significantly improved the developmental competence of following SCNT reconstructed embryos when these TUDCA-treated cells were used as the nuclear donors.

| S-EPMC5931650 | biostudies-literature

Alveolar epithelial cells undergo epithelial-to-mesenchymal transition in response to endoplasmic reticulum stress.

Project description:Expression of mutant surfactant protein C (SFTPC) results in endoplasmic reticulum (ER) stress in type II alveolar epithelial cells (AECs). AECs have been implicated as a source of lung fibroblasts via epithelial-to-mesenchymal transition (EMT); therefore, we investigated whether ER stress contributes to EMT as a possible mechanism for fibrotic remodeling. ER stress was induced by tunicamyin administration or stable expression of mutant (L188Q) SFTPC in type II AEC lines. Both tunicamycin treatment and mutant SFTPC expression induced ER stress and the unfolded protein response. With tunicamycin or mutant SFTPC expression, phase contrast imaging revealed a change to a fibroblast-like appearance. During ER stress, expression of epithelial markers E-cadherin and Zonula occludens-1 decreased while expression of mesenchymal markers S100A4 and ?-smooth muscle actin increased. Following induction of ER stress, we found activation of a number of pathways, including MAPK, Smad, ?-catenin, and Src kinase. Using specific inhibitors, the combination of a Smad2/3 inhibitor (SB431542) and a Src kinase inhibitor (PP2) blocked EMT with maintenance of epithelial appearance and epithelial marker expression. Similar results were noted with siRNA targeting Smad2 and Src kinase. Together, these studies reveal that induction of ER stress leads to EMT in lung epithelial cells, suggesting possible cross-talk between Smad and Src kinase pathways. Dissecting pathways involved in ER stress-induced EMT may lead to new treatment strategies to limit fibrosis.

| S-EPMC3162456 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data