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防御感染的先天性宿主反应中具有重要作用。然而，也存在慢性炎症和纤维化在没有感染的情况下持续存在的情况。我们已经发现，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。我们已经发现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衔接蛋白MyD 88的方式产生炎性趋化因子来介导肺部炎症。此外，我们已经取得了意想不到的观察，高分子量HA的细胞表面的肺上皮细胞是保护非感染性肺损伤的TLR 2/4/MyD 88的方式，似乎涉及组成性激活NF-？B。这些数据表明，TLR 2/4-MyD 88途径是通过对巨噬细胞和上皮细胞的不同机制的非感染性肺部炎症的关键调节剂。我们还观察到TLR 4通过可能涉及MyD 88非依赖性途径的机制对肺纤维化具有保护作用。总的来说，这些数据使我们假设细胞外基质在调节肺损伤，炎症和修复中具有重要作用，通过与浸润巨噬细胞和实质上皮细胞上的TLR的不同相互作用。我们将在以下具体目标中检验这一假设：1。使用仅在肺上皮或组织巨噬细胞中表达MyD 88的基因靶向小鼠，确定肺上皮细胞和巨噬细胞中MyD 88信号传导在调节非感染性肺损伤和修复中的作用。2.描述非感染性肺损伤后在缺乏TLR 4信号传导的情况下过度纤维化的机制。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内环境稳定的机制。公共卫生相关性。慢性肺部炎症导致肺部疾病如肺纤维化、哮喘和COPD的显著发病率。这项拨款提案是通过了解受伤的肺组织如何导致慢性肺部炎症来寻找肺部炎症的治疗方法。

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.