Project 2: Environmental Determinants of Early Host Response to RSV

众所周知，吸入的空气污染物（如臭氧）会加重哮喘，并可能在生命早期的反应性气道疾病的发病中发挥潜在作用。虽然臭氧可对大多数接触臭氧的人造成严重的呼吸系统健康问题，但幼儿因接触臭氧而产生严重不良健康影响的风险尤其大。这是因为他们的肺部仍在快速发育，在这一敏感性的关键窗口期暴露可能会改变肺部发育，导致永久性呼吸系统健康问题。空气污染物还可能影响幼儿免疫系统的发育，增加对感染的易感性，并促进呼吸道对常见空气过敏原的敏感性。该项目的总体目标是确定臭氧如何影响出生后早期的肺部发育和宿主免疫反应。我们的一般假设是，在出生后早期阶段的臭氧暴露改变肺的发育和修改宿主的免疫反应，早期生命的病毒感染和过敏原暴露，从而有助于反应性气道疾病的发展。为了检验这一假设，我们将追求以下目标： 1.明确臭氧对先天免疫反应、气道结构和功能的影响。研究旨在确定哪些Toll样受体（TLR）在出生后臭氧暴露后被修饰，以定义气道结构和功能的变化，并确定TLR-4在这些反应中的作用。 2.确定臭氧对呼吸道合胞病毒（RSV）感染和屋尘螨（HDM）过敏原暴露的早期宿主反应的影响。拟议的研究将确定臭氧如何在出生后阶段改变宿主对RSV和HDM的反应，并将确定气道结构和功能的相关变化以及TLR-4在这些反应中的作用。 3.确定脂多糖（LPS），一种与TLR-4相互作用的空气污染物，如何改变出生后臭氧暴露后宿主对RSV和HDM的反应。我们将确定LPS如何改变出生后臭氧暴露后宿主对RSV和HDM的早期反应，以及气道结构和功能的相关变化。

Inhaled air pollutants such as ozone are known to exacerbate asthma and may play a potential role in the inception of reactive airway disease in early life. While ozone can cause significant respiratory health problems in the majority of exposed individuals, young children are particularly at greater risk for developing serious adverse health effects from ozone exposure. This is because their lungs are still developing rapidly, and exposures during this critical window of susceptibility may alter lung development, resulting in permanent respiratory health problems. Air pollutants may also influence the developing immune system in young children, increasing susceptibility to infection and promoting airway sensitization to common aeroallergens. The overall objective of this project is to define how ozone influences lung development and host immune response in early postnatal life. Our general hypothesis is that ozone exposure in the early postnatal phase alters lung development and modifies the host immune response to early life viral infection and allergen exposure, thereby contributing to the development of reactive airway disease. To test this hypothesis, we will pursue the following aims: 1. To define the influence of ozone on innate immune response, airway structure and function. Studies are designed to identify which toll-like receptors (TLRs) are modified following postnatal ozone exposure, to define the changes in airway structure and function, and to determine the role of TLR-4 in these responses. 2. To define the influence of ozone on the early host response to respiratory syncytial virus (RSV) infection and house dust mite (HDM) allergen exposure. The proposed studies will determine how ozone modifies the host response to RSV and HDM during the postnatal phase and will define the associated changes in airway structure and function and the role of TLR-4 in these responses. 3. To determine how lipopolysaccharide (LPS), an air contaminant that interacts with TLR-4, modifies the host response to RSV and HDM following postnatal ozone exposure. We will determine how LPS modifies the early host response to RSV and HDM, and associated changes in airway structure and function, following postnatal ozone exposure.