Project 2: Environmental Determinants of Early Host Response to RSV

众所周知，臭氧等吸入空气污染物会加剧哮喘，并可能在生命早期出现反应性呼吸道疾病方面发挥潜在作用。虽然臭氧可在大多数接触臭氧的人中造成严重的呼吸道健康问题，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。这是因为他们的肺仍在快速发育，在这一关键的易感窗口期间暴露可能会改变肺的发育，导致永久性的呼吸道健康问题。空气污染物还可能影响幼儿发育中的免疫系统，增加感染的敏感性，并促进对常见空气过敏原的呼吸道敏化。这个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，出生后早期臭氧暴露改变了肺部发育，改变了宿主对早期生命病毒感染和过敏原暴露的免疫反应，从而促进了反应性呼吸道疾病的发展。为了验证这一假设，我们将追求以下目标： 1.明确臭氧对先天免疫反应、呼吸道结构和功能的影响。研究旨在确定在出生后臭氧暴露后，哪些Toll样受体(TLRs)被修饰，以确定呼吸道结构和功能的变化，并确定TLR-4在这些反应中的作用。 2.明确臭氧对呼吸道合胞病毒(RSV)感染和屋尘螨(HDM)变应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，并将确定相关的呼吸道结构和功能变化以及TLR-4在这些反应中的作用。 3.为了确定一种与TLR-4相互作用的空气污染物脂多糖(LPS)如何改变出生后臭氧暴露后宿主对RSV和HDM的反应。我们将确定内毒素如何改变早期宿主对RSV和HDM的反应，以及出生后臭氧暴露后呼吸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.