Innate Immune Mechanisms in Non-infectious Lung Inflammation

描述（申请人提供）：肺泡巨噬细胞在调节宿主防御感染的先天宿主反应中起着重要作用。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，产生炎症趋化因子，从而介导肺部炎症，这种方式依赖于细胞内接头蛋白MyD88。此外，我们还意外地观察到，肺上皮细胞表面的高分子量HA以TLR2/4/MyD88的方式对非感染性肺损伤具有保护作用，这似乎与NF- B的组成性激活有关。这些数据表明，TLR2/4-MyD88通路通过不同的机制对巨噬细胞和上皮细胞起非感染性肺炎症的关键调节作用。我们还观察到TLR4通过一种可能涉及myd88独立通路的机制对肺纤维化具有保护作用。总的来说，这些数据使我们提出这样的假设，即细胞外基质通过与浸润性巨噬细胞和实质上皮细胞的TLRs的不同相互作用，在调节肺损伤、炎症和修复中起着重要作用。我们将在以下具体目标中检验这一假设：使用仅在肺上皮细胞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. 描述非感染性肺损伤后TLR4信号缺失情况下纤维增生的机制。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稳态的机制。公共卫生相关性。慢性肺部炎症导致肺纤维化、哮喘和慢性阻塞性肺病等肺部疾病的显著发病率。这项拨款提案是通过了解受伤的肺组织如何引起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.