Regulation of Pulmonary Inflammation

凋亡细胞的识别和去除是一个非常重要和高度保守的生物过程， ?沉默？关于局部组织反应。我们以前已经证明凋亡细胞诱导了一种新的免疫反应。 在很大程度上由磷脂酰丝氨酸（PS）的再分布介导的主动抗炎反应 从质膜的内叶到外叶，以及随后通过响应 吞噬细胞和其他细胞。最近，我们发现凋亡细胞上的PS也可以抑制凋亡细胞的凋亡。 适应性免疫反应在肺中，与身体其他部位一样，这些作用被认为是介导 通过去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启动 PS的识别通过转化生长因子β（TGF α）的诱导和作用介导。 然而，尽管我们和其他人已经收集了关于暴露的PS的作用的信息， 没有充分了解的机制，特别是，受体，认识和 对PS作出反应，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？对于PS，已经鉴定出与先前描述的桥分子沿着， 一方面与凋亡细胞上的PS结合，另一方面与应答吞噬细胞上的受体结合。 因此，我们认为，现在时机已经成熟，可以采取协调一致的方法来确定受体， 暴露于PS的凋亡细胞的炎症抑制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，并按照我们的常规方法进行， 包括体外和体内研究。该提案包括两个具体目标，一个是 炎症抑制和免疫抑制，主要重点是表征的作用， TGF α和识别相关受体，首先在体外，然后在体内，以及探索新的 调节肺中免疫反应的机制。 这项工作的意义和更广泛的目标是利用所获得的知识， 阻断肺部正在进行的炎症和/或免疫反应， 研究探索这种潜力。

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.