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BML-111 suppresses TGF-?1-induced lung ?broblast activation in vitro and decreases experimental pulmonary fibrosis in vivo.

ABSTRACT: Pulmonary fibrosis is an aggressive end?stage disease. Transforming growth factor??1 (TGF??1) mediates lung ?broblast activation and is essential for the progress of pulmonary fibrosis. BML?111, a lipoxinA4 (LXA4) receptor (ALX) agonist, has been reported to possess anti??brotic properties. The present study aimed to elucidate whether BML?111 inhibits TGF??1?induced mouse embryo lung ?broblast (NIH3T3 cell line) activation in vitro and bleomycin (BLM)?induced pulmonary fibrosis in vivo. In vitro experiments demonstrated that BML?111 treatment inhibits TGF??1?induced NIH3T3 cell viability and the expression of smooth muscle ? actin (??SMA), ?bronectin and total collagen. Furthermore, this suppressive effect was associated with mothers against decapentaplegic homolog (Smad)2/3, extracellular signal?regulated kinase (ERK) and Akt phosphorylation interference. In vivo experiments revealed that BML?111 treatment markedly improved survival rate and ameliorated the destruction of lung tissue structure. It also reduced interleukin?1? (IL?1?), tumor necrosis factor?? (TNF??) and TGF??1 expression in the BLM intratracheal mouse model. In addition, the expression of??SMA and extracellular matrix (ECM) deposition (total collagen, hydroxyproline and ?bronectin) were also suppressed following BML?111 treatment. However, BOC?2, an antagonist of ALX, partially weakened the effects of BML?111. In conclusion, these results indicated that BML?111 inhibits TGF??1?induced ?broblasts activation and alleviates BLM?induced pulmonary fibrosis. Therefore, BML?111 may be used as a potential therapeutic agent for pulmonary fibrosis treatment.

SUBMITTER: Ji YD

PROVIDER: S-EPMC6202103 | biostudies-other | 2018 Oct

REPOSITORIES: biostudies-other

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BML-111 suppresses TGF-β1-induced lung ﬁbroblast activation in vitro and decreases experimental pulmonary fibrosis in vivo.

Ji Yu-Dong YD Luo Zhen-Long ZL Chen Chun-Xiu CX Li Bo B Gong Jie J Wang Ya-Xin YX Chen Lin L Yao Shang-Long SL Shang You Y

International journal of molecular medicine 20181002 6

Pulmonary fibrosis is an aggressive end‑stage disease. Transforming growth factor‑β1 (TGF‑β1) mediates lung ﬁbroblast activation and is essential for the progress of pulmonary fibrosis. BML‑111, a lipoxinA4 (LXA4) receptor (ALX) agonist, has been reported to possess anti‑ﬁbrotic properties. The present study aimed to elucidate whether BML‑111 inhibits TGF‑β1‑induced mouse embryo lung ﬁbroblast (NIH3T3 cell line) activation in vitro and bleomycin (BLM)‑induced pulmonary fibrosis in vivo. In vitro ...[more]

PMID: 30280199

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Project description:AimPaeoniflorin has shown to attenuate bleomycin-induced pulmonary fibrosis (PF) in mice. Because the epithelial-mesenchymal transition (EMT) in type 2 lung endothelial cells contributes to excessive fibroblasts and myofibroblasts during multiple fibrosis of tissues, we investigated the effects of paeoniflorin on TGF-? mediated pulmonary EMT in bleomycin-induced PF mice.MethodsPF was induced in mice by intratracheal instillation of bleomycin (5 mg/kg). The mice were orally treated with paeoniflorin or prednisone for 21 d. After the mice were sacrificed, lung tissues were collected for analysis. An in vitro EMT model was established in alveolar epithelial cells (A549 cells) incubated with TGF-?1 (2 ng/mL). EMT identification and the expression of related proteins were performed using immunohistochemistry, transwell assay, ELISA, Western blot and RT-qPCR.ResultsIn PF mice, paeoniflorin (50, 100 mg·kg(-1)·d(-1)) or prednisone (6 mg·kg(-1)·d(-1)) significantly decreased the expression of FSP-1 and ?-SMA, and increased the expression of E-cadherin in lung tissues. In A549 cells, TGF-?1 stimulation induced EMT, as shown by the changes in cell morphology, the increased cell migration, and the increased vimentin and ?-SMA expression as well as type I and type III collagen levels, and by the decreased E-cadherin expression. In contrast, effects of paeoniflorin on EMT disappeared when the A549 cells were pretreated with TGF-?1 for 24 h. TGF-?1 stimulation markedly increased the expression of Snail and activated Smad2/3, Akt, ERK, JNK and p38 MAPK in A549 cells. Co-incubation with paeoniflorin (1-30 ?mol/L) dose-dependently attenuated TGF-?1-induced expression of Snail and activation of Smad2/3, but slightly affected TGF-?1-induced activation of Akt, ERK, JNK and p38 MAPK. Moreover, paeoniflorin markedly increased Smad7 level, and decreased ALK5 level in A549 cells.ConclusionPaeoniflorin suppresses the early stages of TGF-? mediated EMT in alveolar epithelial cells, likely by decreasing the expression of the transcription factors Snail via a Smad-dependent pathway involving the up-regulation of Smad7.

Project description:BACKGROUND:Idiopathic Pulmonary Fibrosis (IPF) is a progressive inflammatory disorder driven by a fibrotic cascade of events such as epithelial to mesenchymal transition, extracellular matrix production and collagen formation in the lungs in a sequential manner. IPF incidences were raising rapidly across the world. FDA approved pirfenidone and nintedanib (tyrosine kinase inhibitors) are being used as a first-line treatment drugs for IPF, however, neither the quality of life nor survival rates have been improved because of patient noncompliance due to multiple side effects. Thus, the development of novel therapeutic approaches targeting TGF-? mediated cascade of fibrotic events is urgently needed to improve the survival of the patients suffering from devastating disease. PURPOSE:The aim of this study was to investigate and validate the anti-fibrotic properties of Biochanin-A (isoflavone) against TGF-? mediated fibrosis in in vitro, ex vivo, in vivo models and to determine the molecular mechanisms that mediate these anti-fibrotic effects. METHODS:The therapeutic activity of BCA was determined in in vitro/ex vivo models. Cells were pre-treated with BCA and incubated in presence or absence of recombinant-TGF-? to stimulate the fibrotic cascade of events. Pulmonary fibrosis was developed by intratracheal administration of bleomycin in rats. BCA treatment was given for 14 days from post bleomycin instillation and then various investigations (collagen content, fibrosis gene/protein expression and histopathological changes) were performed to assess the anti-fibrotic activity of BCA. RESULTS:In vitro/ex vivo (Primary normal, IPF cell line and primary IPF cells/ Precision cut mouse lung slices) experiments revealed that, BCA treatment significantly (p < 0.001) reduced the expression of TGF-? modulated fibrotic genes/protein expressions (including their functions) which are involved in the cascade of fibrotic events. BCA treatment significantly (p < 0.01) reduced the bleomycin-induced inflammatory cell-infiltration, inflammatory markers expression, collagen deposition and expression of fibrotic markers in lung tissues equivalent or better than pirfenidone treatment. In addition, BCA treatment significantly (p < 0.001) attenuated the TGF-?1/BLM-mediated increase of TGF-?/Smad2/3 phosphorylation and resulted in the reduction of pathological abnormalities in lung tissues determined by histopathology observations. CONCLUSION:Collectively, BCA treatment demonstrated the remarkable therapeutic effects on TGF-?/BLM mediated pulmonary fibrosis using IPF cells and rodent models. This current study may offer a novel treatment approach to halt and may be even rescue the devastating lung scarring of IPF.

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BML-111 suppresses TGF-?1-induced lung ?broblast activation in vitro and decreases experimental pulmonary fibrosis in vivo.

Publications

BML-111 suppresses TGF-β1-induced lung ﬁbroblast activation in vitro and decreases experimental pulmonary fibrosis in vivo.

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