Regulation of pulmonary inflammation

描述（由申请人提供）：本研究的目的是阐明肺对凋亡或坏死细胞的一些复杂的抗炎和促炎反应。一般来说，已知凋亡细胞刺激抗炎反应，部分原因是它们诱导和释放活性tgf - β。这种效应似乎是由凋亡细胞表面暴露的磷脂酰丝氨酸（PS）的识别驱动的。因此，研究凋亡细胞诱导的产生（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RhoA激活在该系统中tgf - β产生中的潜在作用。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的过程启动抗炎作用，该建议包括检查其中一些过程及其与TGFa作用后果的区别。除了识别PS外，表面钙调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 （LDL受体相关蛋白，CD91）诱导其清除。然而，LRP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被提出，这两个受体及其信号传导之间相互作用的参数将被探索。同样，“坏死”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）与促炎LRP配体和信号的假设平衡的改变，以验证这一假设，即在很大程度上是这种平衡的相反方向的改变，推动了凋亡-坏死细胞的二分法。最后，这些反应将在一个模型系统中进行体内研究，其中将凋亡或坏死细胞（或孤立刺激）灌注到急性炎症小鼠肺部，在增强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.