Am J Pathol：揭示治疗硬皮病的新型靶点

2012年11月26日 讯 /生物谷BIOON/ --近日，刊登在国际杂志the American Journal of Pathology上的一篇研究报告中，来自美国西北大学的研究者进行了一项国际多学科的研究，揭开了蛋白质Toll样受体4（TLR4）在组织纤维化以及结疤发展过程中所扮演的重要角色。相关研究或许为开发硬皮病的疗法提供一些希望。

硬皮病是一种慢性的自体免疫疾病，其可以引发皮肤进行性的紧皱以及引发组织器官损伤，最终导致患者死亡，在美国，硬皮病每年可以影响大约300，000人的健康情况，大多数患者为年轻-中年的女性，但是其发病原因并不清楚。

TLR4以前被证明和炎症相关，但其在组织纤维化上扮演的角色却并不知道，组织纤维化是硬皮病的标志，其可以引发一系列疾病，如肺纤维化、肾脏纤维化、肝硬化以及辐射诱发的结疤。

研究者表示，当小鼠机体中负责表达TLR4的基因突变后，小鼠就会对实验性的硬皮病产生抗性。而硬皮病病人往往在其纤维化皮肤以及肺部组织中存在异常水平的TLR4。及时仔细的个体检查可以帮助病人了解疾病发展，对于开发新型疗法也很关键。

目前用于治疗人类炎症及败血症的堵塞TLR4的制剂已经开发出来了，TLR4的抑制剂药物或许可以钝化、逆转硬皮病患者的病情，然而研究者表示，早期的试验中由于药物的毒性宣告失败了。

如今研究者知道了TLR4在硬皮病的发病中扮演着重要角色，但是未来很多研究需要进行以开发出安全有效地抑制疾病发病的疗法。当前研究者用小鼠模型进行研究，来更好地揭示TLR4在纤维化组织中的作用，未开发新型的抑制TLR4的药物以及新型的疗法的开发提供了一定的建议和帮助。

Toll-like receptor 4 signaling augments transforming growth factor-β responses: a novel mechanism for maintaining and amplifying fibrosis in scleroderma.
Abstract
Because recent studies implicate Toll-like receptors (TLRs) in the pathogenesis of fibrosis, we sought to investigate the in vitro and in vivo role and mechanism of TLR4-mediated fibroblast responses in fibrogenesis. We found that TLR4 was constitutively expressed, and accumulation of endogenous TLR4 ligands significantly elevated, in lesional skin and lung tissues from patients with scleroderma. Activation of TLR4 signaling in explanted fibroblasts resulted in enhanced collagen synthesis and increased expression of multiple genes involved in tissue remodeling and extracellular matrix homeostasis. Moreover, TLR4 dramatically enhanced the sensitivity of fibroblasts to the stimulatory effect of transforming growth factor-β1. These profibrotic responses were abrogated by both genetic and pharmacological disruption of TLR4 signaling in vitro, and skin fibrosis induced by bleomycin in vivo was attenuated in mice harboring a mutated TLR4. Activation of TLR4 in fibroblasts augmented the intensity of canonical Smad signaling, and was accompanied by suppression of anti-fibrotic microRNA expression. Together, these results suggest a novel model to account for persistent fibrogenesis in scleroderma, in which activation of fibroblast TLR4 signaling, triggered by damage-associated endogenous TLR4 ligands, results in augmented transforming growth factor-β1 sensitivity with increased matrix production and progressive connective tissue remodeling. Under these conditions, fibroblast TLR4 serves as the switch for converting self-limited tissue repair into intractable fibrosis.