Possible involvement of inflammatory/reparative processes in the development of uterine fibroids
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Uterine leiomyomas are benign tumors in the smooth muscle layer of the uterus. The most common histological type is the “usual leiomyoma”, characterized by overexpression of ECM proteins, whereas the “cellular type” has higher cellular content. Our objective is to investigate the involvement of inflammatory and reparative processes in leiomyoma pathobiology. Using a morphological approach, we investigate the presence of inflammatory cells. Next, we determine the localization of the ECM, the presence/absence of fibrotic cells via α-sma and desmin and the immunohistochemical profile of the mesenchymal cells with respect to CD34. Finally, we explore the effect of inflammatory mediators (TNF-α, IL-1β, IL-6, IL-15, GM-CSF and IFN-γ) on pro-fibrotic factor activin A mRNA expression in vitro. Higher numbers of macrophages were found inside and close to leiomyomas as compared to the more distant myometrium. Cellular leiomyomas showed more macrophages and mast cells than the “usual type”. Inside the fibroid tissue, we found cells positive for α-sma, but negative for desmin and a large amount of collagen surrounding the nodule, suggestive of myofibroblasts producing ECM. In the myometrium and leiomyomas of the “usual type”, we identified numerous CD34+ fibroblasts, which are known to give rise to myofibroblasts upon loss of CD34 expression. In leiomyomas of the “cellular type”, stromal fibroblasts were CD34-negative. Finally, we found that TNF-α increased activin A mRNA in myometrial and leiomyoma cells. In conclusion, this study demonstrates the presence of inflammatory cells in uterine leiomyomas, which may contribute to excessive ECM production, tissue remodeling and leiomyoma growth.
KeywordsUsual leiomyoma Cellular leiomyoma Inflammation ECM Myofibroblast CD34 TNF-α Activin A Myometrium
O.P. and M.J. are recipients of a fellowship from the Polytechnic University of Marche, reserved for PhD students coming from universities of the UNIADRION, a network of universities established with the purpose of creating a permanent connection among universities and research centers from the Adriatic-Ionian Region (Italy). M.S.I. is recipient of a fellowship from the Polytechnic University of Marche, reserved for PhD students from non-EU countries. We thank Dr. Francesco Piva (Bio-engineer, Department of Specialistic Clinical and Odontostomatological Sciences, Polytechnic University of Marche, Ancona, Italy) for his valuable help to perform statistical data analysis.
This work was supported by the “Fondazione Cassa di Risparmio di Fabriano e Cupramontana” (to M.C. and P.C.) and by the Italian Ministry of University and Research (PRIN 2010–2011, No. 20102CHST5_007, to S.R.G.). B.H is funded by grants from the Canadian Institutes of Health Research (#210820, #286720, #286920, #497202).
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