Regulation of Pulmonary Inflammation

识别和清除凋亡细胞是一个极其重要和高度保守的生物过程，即 ？沉默？关于局部组织反应。我们之前已经表明，凋亡细胞诱导了 主动抗炎反应，很大程度上是由磷脂酰丝氨酸(PS)的重新分布介导的 从质膜的内叶到外叶及其随后的响应识别 吞噬细胞和其他细胞。最近我们发现PS对凋亡细胞也有抑制作用。 适应性免疫反应。在肺中，就像身体的其他部位一样，这些效应被认为是调节 通过清除凋亡性炎症反应来解决正常的、保护性的和自限性的炎症反应 细胞，抑制正在进行的炎症，同时防止不适当的免疫 反应。我们还表明，许多炎症抑制和免疫抑制是由 PS的识别是通过转化生长因子β(TGFa)的诱导和作用来实现的。 然而，尽管我们和其他人收集了关于暴露的PS的作用的信息，我们仍然这样做 没有足够的了解机制，特别是识别和受体 对PS做出反应，特别是在其驱动抑制过程的能力方面。最近，一些候选人 直接？受体？因为PS已被发现与先前描述的结合桥式分子 一方面作用于凋亡细胞上的PS，另一方面作用于反应吞噬细胞上的受体。 因此，我们认为，现在是时候采取协调一致的方法来确定受体和 PS暴露的细胞凋亡抑制炎症和免疫抑制作用的机制 细胞。这些研究将在肺部环境中进行，按照我们通常的方法将 包括体外和体内的研究。该提案包含两个具体目标，一个是关于 一种是关于炎症抑制，另一种是关于免疫抑制，主要侧重于表征 TGFa和相关受体的鉴定，先在体外，然后在体内以及探索新的 调节肺部免疫反应的机制。 这项工作的含义和更广泛的目标是能够利用所获得的知识故意 阻断肺部正在进行的炎症和/或免疫反应，事实上，该提议包括早期 探索这一潜力的研究。

Recognition and removal of apoptotic cells is a critically important and highly conserved biologic process that is ?silent? with regard to local tissue responses. We have previously shown that the apoptotic cells induce an active anti-inflammatory response that is mediated in large part by the redistribution of phosphatidylserine (PS) from the inner to the outer leaflet of the plasma membrane and its subsequent recognition by responding phagocytes and other cells. More recently we have shown that PS on the apoptotic cells can also suppress the adaptive immune response. In the lung, as elsewhere in the body, these effects are suggested to mediate the resolution of normal, protective and self-limited inflammatory responses by removing apoptotic inflammatory cells, suppressing the ongoing inflammation while at the same time preventing inappropriate immune reactions. We have also shown that much of the inflammosuppression and immunosuppression initiated by recognition of the PS is mediated through the induction and effects of transforming growth factor beta (TGFa). Nevertheless, despite the information that we and others have gathered on the role of exposed PS, we still do not have an adequate understanding of the mechanisms and particularly, the receptors that recognize and respond to the PS, especially in its ability to drive the suppressive processes. Recently a number of candidate direct ?receptors? for PS have been identified to go along with previously described bridge molecules that bind on the one hand to PS on the apoptotic cells and on the other to receptors on the responding phagocyte. Accordingly, we suggest that the time is now ripe for a concerted approach to determine the receptors and mechanisms underlying the inflammosuppressive and immunosuppressive effects of PS-exposing apoptotic cells. These studies will be carried out in the pulmonary environment and following our usual approach will involve investigations both in vitro and in vivo. The proposal encompasses two specific aims, one on the inflammosuppression and one on immunosuppression, with major emphases on characterizing the role for TGFa and identifying the relevant receptors, first in vitro and then in vivo as well as exploring novel mechanisms by which immune responses in the lung are modulated. Implications and broader objectives of this work are the ability to use the knowledge obtained to deliberately block ongoing inflammatory and/or immunologic reactions in the lung and indeed the proposal includes early studies to explore this potential.