Hadden H L, Henke C A
Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
Am J Respir Crit Care Med. 2000 Oct;162(4 Pt 1):1553-60. doi: 10.1164/ajrccm.162.4.2001015.
Despite the importance of fibroproliferative lung disorders, no safe and effective therapies exist for reducing the size of the fibroblast population in existing fibrotic lesions. Recent work suggests that therapies that promote fibroblast apoptosis during the repair phase following lung injury may facilitate lung repair by eliminating excess fibrotic tissue. We report here our finding that three soluble fibronectin peptides (RGD, CS-1, and FN-C/H-V) induce apoptosis in lung fibroblasts. Fibroblast susceptibility to these peptides was dose and time dependent, with a maximal effect observed at 96 h (87 +/- 16% [mean +/- SEM] apoptosis). The peptides were able to induce fibroblast apoptosis in fibrin gels, an in vitro model of early fibroproliferative lesions. Fibroblasts were difficult to kill. All three peptides were required for maximal apoptosis of anchored cells. Apoptosis occurred by disruption of adhesion (anoikis). Treatment of fibroblasts with peptides caused proteolysis of pp125FAK, a tyrosine kinase involved in integrin-mediated signaling related to cell survival. These data show that soluble fibronectin peptides trigger nontransformed fibroblast apoptosis in routine culture and in fibrin gels by a mechanism that includes disruption of an integrin-mediated survival signaling pathway. The use of small fibronectin peptides to promote fibroblast apoptosis warrants further study as possible antifibrotic therapy.
尽管纤维增生性肺部疾病很重要，但目前尚无安全有效的疗法来减少现有纤维化病变中纤维母细胞的数量。最近的研究表明，在肺损伤后的修复阶段促进纤维母细胞凋亡的疗法，可能通过消除多余的纤维化组织来促进肺修复。我们在此报告我们的发现：三种可溶性纤连蛋白肽（RGD、CS-1和FN-C/H-V）可诱导肺纤维母细胞凋亡。纤维母细胞对这些肽的敏感性呈剂量和时间依赖性，在96小时时观察到最大效应（凋亡率为87±16%[平均值±标准误]）。这些肽能够在纤维蛋白凝胶（早期纤维增生性病变的体外模型）中诱导纤维母细胞凋亡。纤维母细胞很难被杀死。对于贴壁细胞的最大凋亡，三种肽均是必需的。凋亡是通过黏附破坏（失巢凋亡）发生的。用这些肽处理纤维母细胞会导致pp125FAK（一种参与整合素介导的与细胞存活相关信号传导的酪氨酸激酶）发生蛋白水解。这些数据表明，可溶性纤连蛋白肽通过一种包括破坏整合素介导的存活信号通路的机制，在常规培养和纤维蛋白凝胶中触发未转化的纤维母细胞凋亡。使用小的纤连蛋白肽来促进纤维母细胞凋亡作为一种可能的抗纤维化疗法值得进一步研究。
