Host Defense Mechanisms in Chronic Lung Disease

本SCCOR提案的总体目标是阐明先天免疫和适应性免疫在慢性肺病发病机制中的作用。SCCOR提案包括四个相互关联的研究项目，重点关注两种慢性肺部疾病：哮喘和闭塞性细支气管炎综合征（BOS），共同的潜在主题是上皮损伤，炎症，修复和纤维增生。待检验的中心假设是，慢性肺病的发生是由于宿主对挑战肺部的常见环境损伤的破坏性或适应不良反应。先天性和适应性宿主反应的基本作用是识别入侵的抗原、病原体或改变的自身成分，目的是根除入侵因子并恢复组织完整性。虽然当宿主反应正常时可以发生消退，但是当关键宿主因子失活、失调或变得功能障碍时，不能包含外源性损伤。这种适应不良的宿主反应导致慢性肺病。 本SCCOR提案中的项目特定假设为： 项目一：由肺泡和气道细胞产生的表面活性剂蛋白SP-A和SP-D与适应性和先天免疫系统的细胞相互作用，以协调地最大化对吸入的过敏原的防御，并引起和加剧哮喘，同时最小化可能导致炎症，组织损伤和慢性肺部疾病的过度旺盛的免疫应答。 项目二：白细胞介素13（IL-13）通过血小板衍生生长因子（PDGF）表达增加、适应性宿主反应以及随后通过成纤维细胞增殖、胶原蛋白表达和弹性蛋白表达减少的气道重塑来调节人哮喘中的气道成纤维细胞功能。 项目三：通过移植肺中的Toll样受体（TLR）激活先天免疫促进适应性同种免疫应答，导致急性排斥和BOS。 项目四：先天免疫机制调节慢性炎症和组织重塑，具体而言，宿主透明质酸和TLR相互作用是非感染性肺损伤、BOS和慢性哮喘中损伤和修复反应的关键组成部分。 这些研究将有助于我们了解正常和改变的宿主对肺结构和功能的反应，并将为研究和开发治疗慢性肺部疾病的新疗法提供基础。

The overall goal of this SCCOR proposal is to elucidate the roles of innate and adaptive immunity in the pathogenesis of chronic lung disease. The SCCOR proposal consists of four interrelated research projects that are focused on two chronic lung diseases: asthma and bronchiolitis obliterans syndrome (BOS) with a common underlying theme of epithelial injury, inflammation, repair and fibroproliferation. The central hypothesis to be tested is that chronic lung disease occurs as a consequence of destructive or maladaptive host responses to common environmental insults that challenge the lung. The fundamental roles of innate and adaptive host responses are to recognize invading antigens, pathogens or altered self components with the purpose of eradicating the offending agents and restoring tissue integrity. While resolution can occur when the host response is normal, an exogenous insult cannot be contained when a critical host factor is inactivated, dysregulated, or becomes dysfunctional. Such maladaptive host responses lead to chronic lung disease. The project specific hypotheses within this SCCOR proposal are: Project 1: Surfactant proteins SP-A and SP-D, which are produced by both alveolar and airway cells, interact with cells of both the adaptive and innate immune systems to coordinately maximize defense against inhaled allergens and that cause and exacerbate asthma, while minimizing an over exuberant immune response that could result in inflammation, tissue damage and chronic lung disease. Project 2: Interleukin 13 (IL-13) modulates airway fibroblast function in human asthma via increased expression of platelet-derived growth factor (PDGF), an adaptive host response, and subsequent airway remodeling via fibroblast proliferation, collagen expression and decreased elastin expression. Project 3: Activation of innate immunity through toll like receptors (TLRs) in the transplanted lung promotes the adaptive alloimmune response leading to acute rejection and BOS. Project 4: Innate immune mechanisms regulate chronic inflammation and tissue remodeling and specifically, host hyaluronan and TLR interactions are critical components of the injury and repair response in non-infectious lung injury, BOS and chronic asthma. These studies will contribute to our understanding of normal and altered host responses on lung structure and function and will provide a basis for investigation and development of new therapies for the treatment of chronic lung diseases.