Regulation of Pulmonary Inflammation

肺部炎症的调节

• 批准号: 8392596
• 负责人: PETER M HENSON
• 金额: $ 6.2万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8392596
• 关键词: Address; Adjuvant; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Apoptosis; Apoptotic; Asthma; Autoimmune Responses; Autoimmunity; Binding; Cell membrane; Cells; Development; Disease; Environment; Event; Excision; Grant; Hypersensitivity; Immune; Immune response; Immunologics; Immunosuppression; Immunosuppressive Agents; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Investigation; Knowledge; Lead; Ligands; Liposomes; Lung; Mediating; Membrane; Mus; Nature; Necrosis; Phagocytes; Phagocytosis; Phosphatidylserines; Pilot Projects; Pneumonia; Population; Process; Reaction; Recruitment Activity; Regulation; Resolution; Role; Signal Pathway; Staging; System; T-Lymphocyte; Time; Tissues; Transforming Growth Factor beta; Work; immunogenicity; in vivo; novel; novel strategies; pathogen; phosphatidylserine receptor; prevent; receptor; response; subcutaneous; uptake

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.

识别和清除凋亡细胞是一个极其重要且高度保守的生物过程， ？沉默的？关于局部组织反应。我们之前已经证明，凋亡细胞会诱导 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通过响应进行识别 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。在肺部，与身体其他部位一样，这些效应被认为可以调节 通过消除凋亡炎症来解决正常的、保护性的和自限性的炎症反应 细胞，抑制持续的炎症，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) 的诱导和作用来介导的。 尽管如此，尽管我们和其他人已经收集了有关暴露 PS 的作用的信息，但我们仍然认为 对机制，特别是识别和识别的受体没有足够的了解 对 PS 做出反应，尤其是其驱动抑制过程的能力。近期有不少候选人 直接？受体？ PS 已被确定与先前描述的桥分子一起结合 一方面针对凋亡细胞上的PS，另一方面针对响应吞噬细胞上的受体。 因此，我们建议现在时机已经成熟，需要采取协调一致的方法来确定受体和 PS暴露细胞凋亡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，并按照我们通常的方法进行 涉及体外和体内研究。该提案包含两个具体目标，一是 炎症抑制和免疫抑制，重点是描述炎症抑制的作用 TGFa 并首先在体外然后在体内鉴定相关受体以及探索新的 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来故意 阻止肺部持续的炎症和/或免疫反应，实际上该提案包括早期 研究探索这种潜力。