Date of Award

9-28-2009

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

First Advisor

Irina Buhimschi, MD

Second Advisor

Errol Norwitz, MD

Abstract

The receptor for advanced glycation end products (RAGE) is a multiligand pattern recognition receptor involved in transducing endogenous damage associated stimuli into inflammatory responses. Advanced glycation end products (AGEs), HMGB1 (amphoterin) and S100 proteins, such as S100B, are prototype RAGE ligands, while soluble RAGE (sRAGE), a product of RAGE activation, acts as a ligand scavenger and RAGE inhibitor. We propose that RAGE may play important yet distinct pathogenic roles in both inflammation-induced preterm birth and preeclampsia and that, while inflammation-induced preterm birth associates with fetal RAGE activation, preeclampsia induces a maternal state of RAGE activation. We sought to identify the putative stimuli and implications for the opposing types of RAGE activation in these two leading causes of prematurity. Biological samples from two cohorts of prospectively enrolled women were analyzed. In women with symptoms of preterm birth who were assessed to rule out intra-amniotic infection, we measured amniotic fluid for HMGB1 and cord blood for HMGB1 and S100B. For ex vivo validation of our findings, HMGB1 was also measured in tissue explants subjected to endotoxin. From women assessed clinically to rule out preeclampsia, blood and urine of three subgroups (severe preeclampsia, healthy controls, and chronic hypertension but no preeclampsia) were used to determine levels of AGE and HMGB1 as potential stimuli for RAGE activation. Immunohistochemistry on reproductive tissues was used on select cases in both cohorts for cellular localization and validation of immunoassay findings. We found that HMGB1 levels are increased in amniotic fluid of women with intra-amniotic inflammation and preterm birth, and the likely source is the damaged amniochorion, as demonstrated by explant experiments and immunohistochemistry. Cord blood levels of HMGB1 correlate with the extent of fetal inflammation and S100B but not with either the level of intra-amniotic infection or amniotic fluid HMGB1, indicating that other RAGE axis modulating molecules may play a role. We confirmed that severe preeclampsia is associated with elevated sRAGE, a product of RAGE activation, but that neither serum AGE nor HMGB1 levels mirrored the changes in sRAGE. In contrast, women with severe preeclampsia and especially those with HELLP and/or eclampsia had significantly elevated HMGB1 excretions that correlated directly with circulating sRAGE. In conclusion, this research provides evidence for a biologically relevant role of HMGB1 in driving the distinct types of RAGE activation in two major obstetrical complications leading to prematurity. Heightened fetal HMGB1-RAGE axis activation may play a role in intra-amniotic inflammation while a maternal HMGB1-RAGE system may contribute to pathogenesis of preeclampsia.

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This is an Open Access Thesis.

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