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.
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