Gram-positive endotoxemia and modulation of the innate immune response
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AbstractSepsis is a systemic inflammatory response caused by an infection. Although it is the leading cause of death in surgical intensive care units, limited progress has been made in recent decades to improve outcome and mortality. Gram-positive bacteria, such as Staphylococcus aureus, account for up to 50 % of all cases, but how this type of bacteria cause systemic inflammation has been scarcely studied.
This thesis aimed to explore the structural requirements of peptidoglycan, the major wall component of Gram-positive bacteria, to induce inflammation and organ injury, and the capacity of peptidoglycan to induce the release of inflammatory mediators considered to be important in the pathogenesis of sepsis. Further aims were to explore the potential of amelogenin, a protein known to promote periodontal wound healing, and liver X receptor, a nuclear nutrient receptor and transcription factor involved in multiple cellular functions, to modulate inflammation induced by bacterial endotoxins, such as peptidoglycan.
We discovered that peptidoglycan relies on its glycan backbone to induce organ injury and inflammation in rats, and that peptidoglycan is a potent inducer of several inflammatory mediators (specifically interleukin-8 and matrix metalloproteinase-9) from whole human blood and primary human monocytes and neutrophils. Amelogenin attenuated the release of pro-inflammatory cytokines caused by endotoxins in human blood, and this effect was probably mediated through induction of the second messenger cAMP. Finally, activation of the liver X receptor by synthetic ligands inhibited the release of a multitude of different cytokines from human monocytes. The precise mechanism, however, remains to be elucidated.
In summary, this thesis elucidates some mechanisms by which Gram-positive bacteria cause sepsis, as well as proposing new targets in modulating the exaggerated inflammation associated with sepsis, which might have therapeutic potentials.
LIST OF PAPERS:
Paper I Myhre AE, Stuestøl JF, Dahle MK, Øverland G, Thiemermann C, Foster SJ, Lilleaasen P, Aasen AO, Wang JE. Organ injury and cytokine release caused by peptidoglycan are dependent on the structural integrity of the glycan chain. Infect Immun. 2004 Mar;72(3):1311-7. Abstract.
Paper II Wang YY, Myhre AE, Pettersen SJ, Dahle MK, Foster SJ, Thiemermann C, Bjørnland K, Aasen AO, Wang JE. Peptidoglycan of Staphylococcus aureus induces enhanced levels of matrix metalloproteinase-9 in human blood originating from neutrophils. Shock. 2005 Sep;24(3):214-8. Abstract.
Paper III Myhre AE, Dahle MK, Foster SJ, Thiemermann C, Aasen AO, Wang JE. Peptidoglycan of Staphylococcus aureus enhances release of IL-8 and expression of NOD2 in human monocytes and neutrophilic granulocytes. 2007. Manuscript.
Paper IV Myhre AE, Lyngstadaas SP, Dahle MK, Stuestøl JF, Foster SJ, Thiemermann C, Lilleaasen P, Wang JE, Aasen AO. Anti-inflammatory properties of enamel matrix derivative in human blood. J Periodontal Res. 2006 Jun;41(3):208-13. Abstract.
Paper V Myhre AE, Ågren J, Dahle MK, Tamburstuen MV, Lyngstadaas SP, Collins JL, Foster SJ, Thiemermann C, Aasen AO, Wang JE. Liver X receptor is a key regulator of cytokine release in human monocytes. Shock. 2007. In press.