Abstract
Intrauterine adhesion (IUA) is a serious complication caused by excessive fibrosis resulting from endometrial repair after trauma. The traditional Chinese medicine Tiaoshen Tongluo recipe (TTR) contains ingredients associated with the alleviation of fibrosis. The transforming growth factor-β1 (TGF-β1)/Smad pathway is thought to mediate fibrosis in IUA. In this study, we evaluated the influence of TTR on endometrial fibrosis in a rat model of IUA and in TGF-β1-stimulated endometrial stromal cells (ESCs). TTR was found to alleviate the level of endometrial fibrosis in a rat model of IUA. A higher number of collagen fibers and greater damage were observed in the endometrial tissue of untreated rats compared to those treated with TTR. The expression of TGF-β1, Smad2, Smad3, and Smad4 was upregulated following IUA, whereas Smad7 expression was downregulated. TTR lowers the expression of TGF-β1, Smad2, Smad3, and Smad4 but increases the expression of Smad7 in vivo, indicating that TTR can modulate the expression of the TGF-β1/Smad pathway to mediate fibrosis. In ESCs, the phosphorylation of Smad2 and Smad3 and upregulation of Smad4 were induced by TGF-β1 whereas the expression of Smad7 was inhibited. Administration of TTR reduces the phosphorylation of Smad2 and Smad3, increases Smad4 expression induced by TGF-β1, and promotes the expression of Smad7. TTR modulates the TGF-β1/Smad pathway to alleviate the generation of fibrotic tissue in response to IUA.
Highlights
Intrauterine adhesion (IUA) can occur in patients with endometrial repair disorder following the uterine wall and endometrial trauma during pregnancy and is frequently associated with infertility and an increased risk of miscarriage [1, 2]. erapeutic options are limited but include high doses of estrogen because hormonal changes in the uterus are thought to increase susceptibility to injury [3, 4]
We first assessed whether Tiaoshen Tongluo recipe (TTR) could alleviate IUA in a rat model by examining the level of fibrosis in endometrial tissue (Figure 1(a)). e number of endometrial glands was significantly reduced in the IUA model compared with the shamoperated rats (P < 0.01, Figure 1(b))
To establish whether TTR influenced proteins that are upregulated in fibrosis, we examined the activity of the transforming growth factor-β1 (TGF-β1)/ Smad pathway in the rat endometrium following IUA and in rats treated with various doses of TTR (2.88, 5.75, and 11.50 g/ kg)
Summary
Intrauterine adhesion (IUA) can occur in patients with endometrial repair disorder following the uterine wall and endometrial trauma during pregnancy and is frequently associated with infertility and an increased risk of miscarriage [1, 2]. erapeutic options are limited but include high doses of estrogen because hormonal changes in the uterus are thought to increase susceptibility to injury [3, 4]. Erefore, the expression of endometrial stem cell markers and those associated with fibrosis are upregulated in endometrial tissue with IUA [6]. E multifunctional cytokine transforming growth factor-β1 (TGF-β1) plays a major role in the stimulation of extracellular matrix (ECM) proteins and inhibition of ECM degradation during the process of fibrosis in IUA [7]. The levels of TGF-β1 and the Smad pathway proteins it regulates are correlated with IUA [7]. Stem cellderived exosomes were found to reverse the elevated expression of TGF-β1 and Smad mRNA in endometrial epithelial cells and an animal model of IUA [8]. Erefore, TGF-β1 can be used to induce IUA in endometrial stromal cells (ESCs) and provide a target for the alleviation of endometrial fibrosis TGF-β1 is activated in the human endometrium by serine kinases; once activated, it, in turn, activates Smad, Smad, and Smad4 [10], which mediate most profibrotic activities [11]. erefore, TGF-β1 can be used to induce IUA in endometrial stromal cells (ESCs) and provide a target for the alleviation of endometrial fibrosis
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