Regulation of pulmonary inflammation

描述(申请人提供)：本研究的目标是阐明肺对凋亡或坏死细胞存在的一些复杂的抗炎和促炎反应。一般说来，已知凋亡细胞可以刺激抗炎反应，部分原因是它们诱导和释放了活性的转化生长因子β。这种作用似乎是通过识别暴露在凋亡细胞表面的磷脂酰丝氨酸(PS)来实现的。因此，研究细胞凋亡诱导的产物(转录和翻译调节)、分泌和激活这一多功能介质将是本文的主要重点。一个有待探索的假设是，在这个系统中，RhoA的激活在TGFbeta的产生中可能起到了作用。然而，也有越来越多的证据表明，凋亡细胞可能通过不涉及TGFβ的过程启动抗炎效应，该提案包括对其中一些过程的检查，以及它们与TGFa作用的后果的区别。除了识别PS外，表面钙网蛋白是凋亡细胞上的另一个主要配体，在这种情况下，刺激LRP(低密度脂蛋白受体相关蛋白，CD91)来诱导其清除。然而，LRP的激活会导致促炎介质的产生。对凋亡细胞的抗炎和促炎反应之间的平衡提出了建议，并将探索这两种受体之间相互作用的参数及其信号转导。同样，“坏死性”细胞通常被认为是促炎细胞。在这里，我们将检查凋亡后细胞的抗炎刺激(PS)和促炎症LRP配体的假定平衡的变化，并通过信号来检验这一假设，即在很大程度上是这种平衡的改变在相反的方向上驱动了凋亡-坏死细胞的二分法。最后，这些反应将在活体模型系统中进行探索，在该模型系统中，将凋亡或坏死细胞(或单独的刺激)注入急性炎症的小鼠肺中，在促进或延迟炎症消退的过程中改变局部炎症介质的产生。

DESCRIPTION (provided by applicant): The objectives of this proposed set of studies are to elucidate some of the complex anti- and pro-inflammatory responses of the lung to the presence of apoptotic or necrotic cells. In general apoptotic cells are known to stimulate an anti-inflammatory response, in part due to their induction and release of active TGFbeta. This effect seems to be driven by recognition of exposed phosphatidylserine (PS) on the surface of apoptotic cells. Accordingly, study of apoptotic cell-induced production (transcriptional and translational regulation), secretion and activation of this multifunctional mediator will represent a major emphasis herein. One hypothesis to be explored is a potential role for activation of RhoA in the production of TGFbeta in this system. However, there is also increasing evidence that apoptotic cells may initiate anti-inflammatory effects by processes that do not involve TGFbeta and the proposal includes examination of some of these and their distinction from the consequences of TGFa action. In addition to recognition of PS, surface calreticulin is another major ligand on the apoptotic cell, in this case stimulating LRP (LDL receptor related protein, CD91) to induce its clearance. LRP activation however leads to the production of proinflammatory mediators. A balance between anti- and pro-inflammatory responses to apoptotic cells is suggested and the parameters of interaction between these two receptors and their signaling will be explored. In like manner, "necrotic" cells are generally considered to be proinflammatory. Here we will examine post apoptotic cells for alterations in the presumed balance of anti-inflammatory stimuli (PS) versus proinflammatory LRP ligands and signaling to test the hypothesis that it is largely an alteration of this balance in the opposite direction that drives the apoptotic-necrotic cell dichotomy. Finally, these responses will be explored in vivo in a model system wherein instillation of apoptotic or necrotic cells (or isolated stimuli) into acutely inflamed mouse lungs alters local inflammatory mediator production on the way to either enhancing or delaying resolution of the inflammation.