The mechanisms underlying fibroblast apoptosis regulated by growth factors during wound healing
The mechanisms underlying fibroblast apoptosis regulated by growth factors during wound healing
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DOI：
10.1002/path.2710
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发表时间：
2010-07-01
影响因子：
7.3
通讯作者：
Ishii, Toshiharu
中科院分区：
文献类型：
--
作者：
Akasaka, Yoshikiyo;Ono, Ichiro;Ishii, Toshiharu
在研究伤口愈合过程中细胞死亡的机制时，我们发现了碱性成纤维细胞生长因子（bFGF）在体外用转化生长因子（TGF）-β 1预处理后对肉芽组织成纤维细胞的促凋亡作用。bFGF诱导TGF-β 1预处理的肉芽组织来源的成纤维细胞（GF-1）在bFGF处理48和96 h后的caspase-3活化和凋亡。相比之下，以相同方式处理的并且源自未损伤真皮的成纤维细胞不显示细胞凋亡，表明源自正常真皮和伤口组织的成纤维细胞中细胞凋亡事件的潜在机制不同。在这个过程中，我们还发现，bFGF抑制Akt磷酸化丝氨酸473和诱导的快速损失的磷酸化的粘着斑激酶（FAK）在酪氨酸397在预处理的GF-1细胞，一个事件，与磷酸化FAK的解离从粘着斑。因此，通过破坏的粘着斑结构和bFGF处理后失活的Akt传递的存活信号的抑制可能导致用TGF-β 1预处理的GF-1细胞的凋亡。用TGF-β 1预处理GF-1，然后加入bFGF，与单独用TGF-β 1或bFGF处理相比，对Akt和FAK磷酸化的抑制显著更大。联合处理还导致GF-1细胞中FAK的蛋白水解和FAK和Akt蛋白表达的抑制。这些发现证明了两种细胞因子在创伤愈合过程中肉芽组织成纤维细胞凋亡中的重要作用。体内研究也证实了在bFGF注射的皮肤伤口中Akt和FAK的磷酸化和蛋白表达的显著下降。这些结果导致了这样的假设，即在损伤部位TGF-β 1和bFGF的暂时激活促进肉芽组织成纤维细胞的凋亡，这是终止增殖性肉芽组织形成的关键事件。版权所有（C）2010大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
While investigating the mechanisms underlying cell death during wound healing processes, we uncovered the proapoptotic effects of basic fibroblast growth factor (bFGF) on granulation tissue fibroblasts following pretreatment with transforming growth factor (TGF)-beta 1 in vitro. bFGF induced caspse-3 activation and apoptosis in TGF-beta 1-pretreated granulation tissue-derived fibroblasts (GF-1) following bFGF treatment for 48 and 96 h. In contrast, fibroblasts that had been treated in the same manner and that originated from the uninjured dermis did not display apoptosis, indicating that the mechanisms underlying apoptosis events in fibroblasts that originate from normal dermal and wound tissues differ. In this process, we also found that bFGF inhibited Akt phosphorylation at serine 473 and induced a rapid loss of phosphorylation of focal adhesion kinase (FAK) at tyrosine 397 in pretreated GF-1 cells, an event that coincided with the dissociation of phosphorylated FAK from the focal adhesions. Therefore, inhibition of survival signals relayed via the disrupted focal adhesion structures and inactivated Akt following bFGF treatment may lead to apoptosis in GF-1 cells pretreated with TGF-beta 1. Pretreatment of GF-1 with TGF-beta 1 followed by the addition of bFGF resulted in significantly greater inhibition of phosphorylation of Akt and FAK compared to treatment with TGF-beta 1 or bFGF alone. The combinatorial treatment also led to proteolysis of FAK and inhibition of FAK and Akt protein expression in GF-1 cells. These findings demonstrated a significant role for the two cytokines in apoptosis of granulation tissue fibroblasts during wound healing. In vivo studies also confirmed a marked decline in phosphorylation and protein expression of Akt and FAK in bFGF-injected skin wounds. These results led to the hypothesis that temporal activation of TGF-beta 1 and bFGF at the injury site promotes apoptosis in granulation tissue fibroblasts, an event that is critical for the termination of proliferative granulation tissue formation. Copyright (C) 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.