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至关重要的作用。 杀伤性慢性炎症和组织纤维化不仅导致细胞外基质的tumor增加， 基质，而且炎症细胞和介质的增加。我们已经证明， 细胞外基质成分透明质酸，产生于组织炎症部位，在炎症过程中起核心作用。 通过TLR-2激活先天免疫系统。我们认为细胞外基质不仅是 炎症靶点，但以其低分子量形式，作为内源性配体发挥核心作用 引起炎症。低分子量透明质酸在肺损伤中的重要性是显而易见的 在暴露于低剂量博来霉素后死于严重炎症的CD 44受体缺失小鼠中， LMW HA大量蓄积的背景。我们有支持性数据表明LMW HA诱导其炎症反应， 通过TLR-2和TLR-2缺失小鼠的信号被保护免受博来霉素损伤。此外，缺乏TLR- 2逆转博来霉素损伤的CD 44缺失小鼠的死亡率增加。然而，MyD 88和TLR-4均为空， 小鼠具有增加的博来霉素肺损伤，表明LMW HA-TLR-2途径在肺损伤中的特异性。 博莱霉素引起的肺损伤因此，由于LMW HA片段似乎在炎症中很重要， LMW HA诱导的炎症反应的调节可能在有效和特异性治疗中是重要的 炎症性疾病. 我们假设，在组织微环境中， 炎症是先天免疫系统的LMW HA-TLR-2激活。为此，我们建议 具体目标I将定义LMW HA-TLR-2信号传导在以下方面的作用： 肺损伤的博来霉素模型和特异性Aim II将确定骨髓来源的细胞相对于以下细胞的作用： 受体缺陷小鼠骨髓移植中博来霉素肺损伤的常驻肺细胞 通过定义和了解细胞外基质成分的炎症特性，我们将 能够更好地确定作为潜在疗法的特定药理学靶点。我们相信这些研究 将为使用特异性药物治疗炎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.