Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan and Dou-Liou, Dou-Liou, Taiwan.
Department of Orthopaedics, E-DA Hospital, Kaohsiung, Taiwan.
Sci Rep. 2019 Jul 16;9(1):10269. doi: 10.1038/s41598-019-46439-7.
Fibrosis has been considered as a major cause of capsular contracture. Hypoxia has widely emerged as one of the driving factors for fibrotic diseases. The aim of this study was to examine the association between hypoxia-induced fibrosis and breast capsular contracture formation. Fibrosis, epithelial-mesenchymal transition (EMT), expression levels of hypoxia-inducible factor-1α (HIF-1α), vimentin, fibronectin, and matrix metalloproteinase-9 (MMP-9) in tissues from patients with capsular contracture were determined according to the Baker classification system. Normal breast skin cells in patients with capsular contracture after implant-based breast surgery and NIH3T3 mouse fibroblasts were cultured with cobalt chloride (CoCl) to mimic hypoxic conditions. Treatment responses were determined by detecting the expression of HIF-1α, vimentin, fibronectin, N-cadherin, snail, twist, occludin, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1) and -2, as well as phosphorylated ERK. The expression levels of HIF-1α, vimentin, fibronectin, and fibrosis as well as EMT were positively correlated with the severity of capsular contracture. MMP-9 expression was negatively correlated the Baker score. Hypoxia up-regulated the expression of HIF-1α, vimentin, fibronectin, N-cadherin, snail, twist, TIMP-1 and -2, as well as phosphorylated ERK in normal breast skin cells and NIH3T3. Nonetheless, the expression levels of MMP-9 and occludin were down-regulated in response to CoCl treatment. This study is the first to demonstrate the association of hypoxia-induced fibrosis and capsular contracture.
纤维化被认为是包膜挛缩的主要原因。缺氧已广泛成为纤维化疾病的驱动因素之一。本研究旨在探讨缺氧诱导的纤维化与乳房包膜挛缩形成之间的关系。根据 Baker 分类系统，确定包膜挛缩患者组织中的纤维化、上皮-间充质转化（EMT）、缺氧诱导因子-1α（HIF-1α）、波形蛋白、纤维连接蛋白和基质金属蛋白酶-9（MMP-9）的表达水平。培养包膜挛缩患者乳房植入术后的正常乳房皮肤细胞和 NIH3T3 小鼠成纤维细胞，用氯化钴（CoCl）模拟缺氧条件。通过检测 HIF-1α、波形蛋白、纤维连接蛋白、N-钙粘蛋白、snail、twist、occludin、MMP-9、金属蛋白酶组织抑制剂-1（TIMP-1）和 -2 以及磷酸化 ERK 的表达来确定治疗反应。HIF-1α、波形蛋白、纤维连接蛋白和纤维化以及 EMT 的表达水平与包膜挛缩的严重程度呈正相关。MMP-9 的表达与 Baker 评分呈负相关。缺氧上调正常乳房皮肤细胞和 NIH3T3 中 HIF-1α、波形蛋白、纤维连接蛋白、N-钙粘蛋白、snail、twist、TIMP-1 和 -2 以及磷酸化 ERK 的表达。然而，CoCl 处理会下调 MMP-9 和 occludin 的表达。这项研究首次证明了缺氧诱导的纤维化与包膜挛缩之间的关联。
