Sequential Analysis of Myofibroblast Differentiation and Transforming Growth Factor-β1/Smad Pathway Activation in Murine Pulmonary Fibrosis

Abstract Objective Previously, the protective effect of microRNA (miR)-145-5p has been discovered in acute lung injury (ALI). Thus, this study attempts to further discuss the mechanism of miR-145-5p in ALI through the downstream E26 transformation-specific proto-oncogene 2 (ETS2)/transforming growth factor β1 (TGF-β1)/Smad pathway. Methods A lipopolysaccharide (LPS)-induced rat ALI model was established. Recombinant adenovirus miR-145-5p and/or ETS2 overexpression plasmid was administrated into rats. Afterwards, pathological damage in the lung tissue, wet/dry (W/D) ratio, apoptosis and contents of serum inflammatory factors were observed. miR-145-5p, ETS2, TGF-β1, Smad2/3, phosphorylated Smad2/3 levels were measured in rats. Results miR-145-5p was down-regulated, ETS2 was up-regulated and TGF-β1/Smad pathway was activated in LPS-suffered rats. Overexpression of miR-145-5p inactivated the TGF-β1/Smad pathway and attenuated ALI, as reflected by relived pathological damage, and decreased W/D ratio, apoptosis and inflammatory response. Oppositely, loss of miR-145-5p or enhancement of ETS2 worsened ALI and activated the TGF-β1/Smad pathway. Moreover, elevation of ETS2 decreased miR-145-5p-mediated protection against ALI. Conclusion Evidently, miR-145-5p negatively regulates ETS2 expression and inactivates TGF-β1/Smad pathway to ameliorate ALI in rats.

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Glutaminolysis is required for transforming growth factor-β1–induced myofibroblast differentiation and activation

Journal of Biological Chemistry ◽

10.1074/jbc.ra117.000444 ◽

2017 ◽

Vol 293 (4) ◽

pp. 1218-1228 ◽

Cited By ~ 40

Author(s):

Karen Bernard ◽

Naomi J. Logsdon ◽

Gloria A. Benavides ◽

Yan Sanders ◽

Jianhua Zhang ◽

...

Keyword(s):

Growth Factor ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β1 ◽

Myofibroblast Differentiation

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Lung Fibrosis-associated Surfactant Protein A1 and C Variants Induce Latent Transforming Growth Factor β1 Secretion in Lung Epithelial Cells

Journal of Biological Chemistry ◽

10.1074/jbc.m113.475335 ◽

2013 ◽

Vol 288 (38) ◽

pp. 27159-27171 ◽

Cited By ~ 5

Author(s):

Meenakshi Maitra ◽

Moushumi Dey ◽

Wen-Cheng Yuan ◽

Peter W. Nathanielsz ◽

Christine Kim Garcia

Keyword(s):

Growth Factor ◽

Pulmonary Fibrosis ◽

Lung Fibrosis ◽

Transforming Growth Factor ◽

Surfactant Protein ◽

Transforming Growth Factor Β1 ◽

Lung Epithelial Cells ◽

Missense Mutations ◽

Lung Epithelial ◽

Tgf Β1

Missense mutations of surfactant proteins are recognized as important causes of inherited lung fibrosis. Here, we study rare and common surfactant protein (SP)-A1 and SP-C variants, either discovered in our familial pulmonary fibrosis cohort or described by others. We show that expression of two SP-A1 (R219W and R242*) and three SP-C (I73T, M71V, and L188Q) variant proteins lead to the secretion of the profibrotic latent transforming growth factor (TGF)-β1 in lung epithelial cell lines. The secreted TGF-β1 is capable of autocrine and paracrine signaling and is dependent upon expression of the latent TGF-β1 binding proteins. The dependence upon unfolded protein response (UPR) mediators for TGF-β1 induction differs for each variant. TGF-β1 secretion induced by the expression of the common SP-A1 R219W variant is nearly completely blocked by silencing the UPR transducers IRE-1α and ATF6. In contrast, the secretion of TGF-β1 induced by two rare SP-C mutant proteins (I73T and M71V), is largely unaffected by UPR silencing or by the addition of the small molecular chaperone 4-phenylbutyric acid, implicating a UPR-independent mechanism for these variants. Blocking TGF-β1 secretion reverses cell death of RLE-6TN cells expressing these SP-A1 and SP-C variants suggesting that anti-TGF-β therapeutics may be beneficial to this molecularly defined subgroup of pulmonary fibrosis patients.

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