Novel therapeutic approaches for shock and systemic inflammation

Sepsis is the leading cause of mortality in non-coronary intensive care units and its incidence is set to rise. Despite advances in patient care, novel therapeutic interventions (with the exception of activated protein C) have failed to demonstrate benefit in clinical trials. High density lipoprotein has been widely reported to possess immunomodulatory properties and has been shown to be beneficial in animal models of systemic inflammation and sepsis. This thesis investigates the hypothesis that lysophospholipids, which are derivatives of high density lipoprotein, and other lipoproteins, display similar immunomodulatory properties. I have administered Gram-negative (lipopolysaccharide) or Gram-positive (peptidoglycan and lipoteichoic acid) cell wall components in anaesthetised rats to cause shock, organ injury/dysfunction and systemic inflammation. Subsequently, I have investigated the effects of various lysophospholipids in these models. I have demonstrated that therapeutic administration of lysophosphatidylcholine (LPC) dose-dependently attenuates the organ injury/dysfunction caused by administration of lipopolysaccharide. Furthermore, I have shown that LPC is also protective in a model of systemic inflammation caused by eo-administration of peptidoglycan and lipoteichoic acid. Lastly, I have reported that the beneficial effects of LPC discovered here can be demonstrated with an LPC derived from a natural source or with synthetic LPC. In addition, I have found that both saturated and unsaturated lysophosphatidic acid (LP A) significantly reduces the organ injury associated with systemic inflammation associated with endotoxic shock. The observed beneficial effects of LP A are dependant on acyl chain saturation, as saturated LP A only activates specific G-protein coupled receptors, while unsaturated LP A activates both G-protein coupled receptors and peroxisome proliferator-activated receptor-y. Finally, I have established that sphingosylphosphorylcholine attenuates the organ injury/dysfunction caused by administration of lipopolysaccharide. These beneficial effects were associated with potent anti-inflammatory effects, which include the reduction in the formation of pro-inflammatory cytokines, adhesion molecules, COX- 2 and iNOS expression and the recruitment of neutrophils.EThOS - Electronic Theses Online ServiceGBUnited Kingdo