Hyaluronan-Induced Signaling and Gene Regulation

很明显，组织微环境在调节炎症和组织中起着关键作用。 毁灭。慢性炎症和组织纤维化不仅导致细胞外翻转增加 基质也增加，炎性细胞和介质也增加。我们已经证明了 细胞外基质成分透明质酸，产生于组织炎症部位，在 通过TLR-2激活先天免疫系统。我们认为细胞外基质不仅是 炎症靶标，但以其低分子形式，作为内源性配体发挥核心作用 引发炎症。低分子透明质酸(LMW HA)在肺损伤中的重要性显而易见 在CD44受体缺失的小鼠中，小剂量博莱霉素暴露于泰国，泰国人死于压倒性炎症。 低分子腐植酸大量积累的背景。我们有支持性的数据表明低分子HA诱导其炎症 通过TLR-2和TLR-2缺失小鼠的信号可以免受博莱霉素的损伤。此外，没有TLR- 2逆转博莱霉素致CD44缺失小鼠死亡率升高的作用。但是，MyD88空值和TLR-4空值 小鼠博莱霉素肺损伤加重，表明LMW HA-TLR-2途径在小鼠肺损伤中的特异性 博莱霉素性肺损伤。因此，由于LMW HA片段在炎症中似乎是重要的， 调节低分子HA诱导的炎症反应在有效和特异性治疗中可能是重要的 炎症性疾病..。 我们假设，在组织微环境中，有一种关键机制 炎症是由低分子HA-TLR-2激活的先天免疫系统。为此，我们建议 以下是为期2年的ARRA资金的分配：具体目标I将削弱LMW HA-TLR-2信号在 博莱霉素肺损伤模型和特异靶II将确定骨髓来源细胞与： 受体缺陷小鼠骨髓移植治疗博莱霉素肺损伤中的常驻肺细胞。 通过研究和了解细胞外基质成分的炎症特性，我们将 最好能够确定特定的药理靶点作为潜在的治疗方法。我们相信这些研究 将为使用特定药物治疗炎症性肺病提供临床前基础。 如特发性肺纤维化、慢性支气管炎和肺气肿。

It is clear that the tissue microenvironment plays a critical role in regulating inflammation and tissue destruction. Chronic inflammation and tissue fibrosis lead not only to increased tumover of the extracellular matrix but also to an increase in inflammatory cells and mediators. We have shown that fragments of the extracellular matrix component hyaluronan, produced at sites of tissue inflammation, playa central role in the activation of the innate immune system via TLR-2. We propose that the extracellular matrix is not only the target of inflammation, but in its low molecular weight form, plays a central role as an endogenous ligand inducing inflammation. The importance of low molecular weight hyaluronan (LMW HA) in lung injury is evident in CD44 receptor null mice thai die of overwhelming inflammation upon exposure to low dose bleomycin in the setting of massive accumulation of LMW HA. We have supportive data that LMW HA induces its Inflammatory signals via TLR-2 and TLR-2 null mice are protected from bleomycin injury. Furthermore, the absence of TLR- 2 reverses the increased mortality of bleomycin injured CD44 null mice. However, MyD88 null and TLR-4 null mice have increased bleomycin lung injury indicating the specificity of the LMW HA-TLR-2 pathway in bleomycin-induced lung injury. Thus, as LMW HA fragments appears to be important in inflammation, regulation of LMW HA Induced inflammatory responses may be important in effectively and specifically treating inflammatory disorders.. . We hypothesize that within the tissue microenvironment a critical mechanism for mediating inflammation is the LMW HA-TLR-2 activation of the innate immune system. To this end, we propose the following alms for the 2-year ARRA funding: Specific Aim I will deflne the role of LMW HA-TLR-2 signaling in the bleomycin model of lung injury and Specific Aim II will define the role of bone marrow derived cells vs: resident lung cells in bleomycin lung injury using bone marrow transplantations in receptor deficient mice. By deflning and understanding the inflammatory properties of extracellular matrix components, we will better be able to identify specific pharmacologic targets as potential therapies. We believe that these studies will provide the pre-clinical basis for the use of specific agents in the treatment of inflammatory lung dis13ases such as idiopathic pulmonary fibrosis, chronic bronchitis and emphysema.