Oxidized Phospholipids as inhibitors of inflammation

Oxidatively modified phospholipids (OxPL) are increasingly recognized as important modulators of inflammation. While earlier studies focused mainly on OxPL`s pro-inflammatory role in atherosclerosis, evidence is accumulating that OxPL are also potent anti-inflammatory mediators. OxPL both inhibit major pro-inflammatory signalling pathways (e.g. Toll-like receptor (TLR) 4 pathway) and activate anti-inflammatory factors (e.g. the PPARs transcription factors or enzymes like heme oxygenase-1). Since inflammation is accompanied by the generation of OxPL, we hypothesize that OxPL may play an important role as physiologic modifiers that blunt acute inflammation and assist in the resolution of the inflammatory response. The major aim of this project is to study the biological effects of OxPL during acute inflammation and their potential importance in the resolution process. Specific aim 1 is to study the anti-inflammatory potential of OxPL on gene transcription level utilizing microchip and microarray technologies. The biological importance of newly identified OxPL-responsive genes with potential anti-inflammatory activities (e.g. signaling inhibitors, decoy receptors, cytokines and enzymes) will be further investigated with the help of inhibitors and blocking antibodies in vivo using the mouse air pouch model. Furthermore, the signaling and transcriptional mechanisms regulating expression of already identified OxPL -responsive mediators like apo E and COX-2 will be examined as well as their relevance for the resolution of inflammation in vivo. Specific aim 2 is to study the role and precise mechanism of OxPL as antagonists of innate immune receptors. It is planned to investigate whether OxPL inhibit the TLR4 pathway via LPS scavenging or receptor antagonism. Furthermore, we plan to use a number of experimental approaches in order to demonstrate that LPS-binding proteins and receptors such as LBP, CD14 and TLR4/MD-2 are inactivated in human disease during local acute inflammation or sepsis. Finally, the in vivo effects of OxPL on the course of murine Gram-negative peritonitis induced by viable bacteria will be studied to clarify the pathophysiological and clinical importance as well as the therapeutic potential of the negative feedback loops mediated by OxPL during acute bacterial inflammation. To summarize, this project will provide important insights into the role of OxPL as lipid mediators in the resolution process of acute bacterial inflammation both in vitro and in vivo. Moreover, these data might help to identify new pharmacological approaches to treat the overwhelming inflammatory response during sepsis.

Oxidatively modified phospholipids (OxPL) are increasingly recognized as important modulators of inflammation. While earlier studies focused mainly on OxPLés pro-inflammatory role in atherosclerosis, evidence is accumulating that OxPL are also potent anti-inflammatory mediators. OxPL both inhibit major pro-inflammatory signalling pathways (e.g. Toll-like receptor (TLR) 4 pathway) and activate anti-inflammatory factors (e.g. the PPARs transcription factors or enzymes like heme oxygenase-1). Since inflammation is accompanied by the generation of OxPL, we hypothesize that OxPL may play an important role as physiologic modifiers that blunt acute inflammation and assist in the resolution of the inflammatory response. The major aim of this project is to study the biological effects of OxPL during acute inflammation and their potential importance in the resolution process. Specific aim 1 is to study the anti-inflammatory potential of OxPL on gene transcription level utilizing microchip and microarray technologies. The biological importance of newly identified OxPL-responsive genes with potential anti-inflammatory activities (e.g. signaling inhibitors, decoy receptors, cytokines and enzymes) will be further investigated with the help of inhibitors and blocking antibodies in vivo using the mouse air pouch model. Furthermore, the signaling and transcriptional mechanisms regulating expression of already identified OxPL -responsive mediators like apo E and COX-2 will be examined as well as their relevance for the resolution of inflammation in vivo. Specific aim 2 is to study the role and precise mechanism of OxPL as antagonists of innate immune receptors. It is planned to investigate whether OxPL inhibit the TLR4 pathway via LPS scavenging or receptor antagonism. Furthermore, we plan to use a number of experimental approaches in order to demonstrate that LPS-binding proteins and receptors such as LBP, CD14 and TLR4/MD-2 are inactivated in human disease during local acute inflammation or sepsis. Finally, the in vivo effects of OxPL on the course of murine Gram-negative peritonitis induced by viable bacteria will be studied to clarify the pathophysiological and clinical importance as well as the therapeutic potential of the negative feedback loops mediated by OxPL during acute bacterial inflammation. To summarize, this project will provide important insights into the role of OxPL as lipid mediators in the resolution process of acute bacterial inflammation both in vitro and in vivo. Moreover, these data might help to identify new pharmacological approaches to treat the overwhelming inflammatory response during sepsis.