Innate Immune Mechanisms in Non-infectious Lung Inflammation

描述(由申请人提供)：肺泡巨噬细胞在调节宿主抵抗感染的先天宿主反应中具有基础作用。然而，也有慢性炎症和纤维化在没有感染的情况下持续存在的情况。我们发现细胞外基质糖胺聚糖透明质酸(HA)是肺损伤、炎症和纤维化的关键调节因子。我们发现，HA片段通过与巨噬细胞上的Toll样受体2和4相互作用，以依赖于细胞内适配器蛋白MyD88的方式产生炎性趋化因子，从而介导肺部炎症。此外，我们还意外地观察到肺上皮细胞表面的高分子HA以TLR2/4/MyD88的方式对非感染性肺损伤具有保护作用，这似乎涉及到NF-β的结构性激活。这些数据表明，TLR2/4-MyD88途径是通过巨噬细胞和上皮细胞上的不同机制而对非感染性肺炎症起关键调节作用的。我们还观察到，TLR4对肺纤维化具有保护作用，其机制可能涉及MyD88不依赖的途径。综上所述，这些数据使我们得出这样的假设，即细胞外基质通过与浸润的巨噬细胞和实质上皮细胞上的TLRs相互作用，在调节肺损伤、炎症和修复中发挥重要作用。我们将在以下特定目标中验证这一假说：1.利用仅在肺上皮或组织巨噬细胞中表达MyD88的基因靶向小鼠，确定肺上皮细胞和巨噬细胞中MyD88信号在调节非感染性肺损伤和修复中的作用。2.探讨非感染性肺损伤后TLR4信号缺失时过度纤维化的发生机制。3.明确透明质酸-TLR相互作用在非感染性肺损伤时维持肺泡动态平衡的机制。与公共卫生相关。慢性肺部炎症是肺纤维化、哮喘和慢性阻塞性肺病等肺部疾病的重要致病因素。这项拨款建议是为了通过了解肺组织损伤如何导致慢性肺部炎症来寻找治疗肺部炎症的方法。

DESCRIPTION (provided by applicant): Alveolar macrophages have a fundamental role in regulating the innate host response in host defense against infection. However, there are also circumstances where chronic inflammation and fibrosis persist in the absence of infection. We have found that the extracellular matrix glycosaminoglycan hyaluronan (HA) is a critical regulator of lung injury, inflammation and fibrosis. We have found that HA fragments mediate lung inflammation by interacting with Toll-like receptors 2 and 4 on macrophages to produce inflammatory chemokines in a manner that depends upon the intracellular adaptor protein MyD88. In addition, we have made the unexpected observation that high molecular mass HA on the cell surface of lung epithelial cells is protective against non-infectious lung injury in a TLR2/4/MyD88 manner that appears to involve the constitutive activation of NF-?B. These data suggest that the TLR2/4-MyD88 pathway is a critical regulator of non-infectious lung inflammation through distinct mechanisms on macrophages and epithelial cells. We have also made the observation that TLR4 is protective against lung fibrosis by a mechanism that may involve a MyD88-independent pathway. Collectively, these data have led us to the hypothesis that extracellular matrix has a fundamental role in regulating lung injury, inflammation and repair by distinct interactions with TLRs on infiltrating macrophages and parenchymal epithelial cells. We will test this hypothesis in the following Specific Aims: 1. Define the role of MyD88 signaling in lung epithelial cells and macrophages in regulating non- infectious lung injury and repair using gene targeted mice that only express MyD88 in either the lung epithelium or in tissue macrophages. 2. Characterize the mechanisms of exaggerated fibrogenesis in the absence of TLR4 signaling following non-infectious lung injury. 3. Define the mechanisms by which hyaluronan-TLR interactions maintain alveolar homeostasis in response to non-infectious lung injury. PUBLIC HEALTH RELEVANCE. Chronic lung inflammation contributes to significant morbidity in lung diseases such as pulmonary fibrosis, asthma and COPD. This grant proposal is to find to treatments for lung inflammation by understanding how injured lung tissue causes chronic lung inflammation.