SP-A as an immune modulator

固有的和适应性的宿主反应的基本作用是识别和消除入侵的抗原、病原体或改变的自身成分，以恢复组织的完整性和动态平衡。虽然在宿主反应正常时可以解决，但当关键宿主因子失活、失调或遗传和/或环境因素共同导致慢性肺时，外源性损害就不能得到遏制。 疾病。在我们的建议中，这个关键的宿主因子是表面活性蛋白A(SP-A)，这是一种排列在肺上皮表面的蛋白质。正常的SP-A可以减轻变态反应性炎症，但由于基因多态和/或氧化改变而改变或异常的SP-A丧失了保护宿主免受环境侮辱导致的过度支气管收缩和过敏的能力 发炎。我们在体外、呼吸道炎症动物模型和哮喘患者中的初步研究发现，SP-A在先天免疫反应中的作用存在特定缺陷，导致哮喘和过敏性疾病的持续或加重。需要检验的中心假设是，SP-A在哮喘中是功能失调的。SP-A通常调节先天免疫并保护宿主免受哮喘的持续和恶化。这些项目将采用特定的环境 挑战(感染和臭氧暴露)，以测试SP-A调节哮喘过敏性炎症的能力，以及SP-A的等位基因变体、数量不足或氧化是否导致哮喘SP-A功能障碍。项目1将评估来自哮喘患者的人SP-A和等位基因变体SP-A分别调节人类巨噬细胞和呼吸道上皮细胞对感染和臭氧暴露的先天和适应性反应的能力。项目2将使用小鼠模型 卵清蛋白致敏和激发以确定哮喘SP-A和SP-A的等位基因变异体是否有效地调节由感染性激发引起的炎症。项目3将确定特定的SP-A基因多态性是否调节哮喘患者对臭氧暴露的不同敏感性(生理和机械方面)，以及在人体哮喘患者体内臭氧暴露期间，SP-A本身是否经历氧化。

The fundamental roles of innate and adaptive host responses are to recognize and eradicate invading antigens, pathogens or altered self components to restore tissue integrity and homeostasis. 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 genetic and/or environmental factors conspire to result in chronic lung disease. In our proposal, this critical host factor is surfactant protein A (SP-A), a protein that lines the epithelial surfaces in the lung. Normal SP-A can attenuate allergic inflammation, but SP-A that is altered or abnormal as a consequence of genetic polymorphisms and/or oxidative changes has abrogated ability to defend the host from environmental insults leading to excessive bronchoconstriction and allergic inflammation. Our preliminary studies in vitro, in animal models of airway inflammation and in patients with asthma have identified specific defects in the role of SP-A in the innate immune response that contribute to the persistence or exacerbation of asthma and allergic disease. The central hypothesis to be tested is that SP-A, which normally regulates innate immunity and protects the host from persistence and exacerbation of asthma, is dysfunctional in asthma. These projects will employ specific environmental challenges (infection and ozone exposure) to test the ability of SP-A to modulate allergic inflammation in asthma, and whether allelic variants of SP-A, insufficient quantities or oxidation are responsible for dysfunction of SP-A in asthma. Project 1 will evaluate the ability of human SP-A from asthmatic subjects and allelic variant SP-A to modulate the innate and adaptive responses to infection and ozone exposure, respectively, in the human macrophage and airway epithelial cell. Project 2 will employ murine models of ovalbumin sensitization and challenge to determine if asthmatic SP-A and allelic variants of SP-A effectively modulate inflammaton induced by an infectious challenge. Project 3 will determine whether a specific SP-A polymorphisms modulate differential sensitivity to ozone exposure in asthma (physiologic and mechanical), and whether SP-A itself undergoes oxidation during in vivo ozone exposure in human asthma.