American Society for Investigative Pathology, October 2009, Vol 1, No. 1

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Buhimschi, C.S., et al.,
Characterization of RAGE, HMGB1, and S100β in inflammation-induced preterm birth and fetal tissue injury.
Am J Pathol, 2009.175(3): p. 958-975.

A relatively new set of players in the complex, highly orchestrated series of events that occur during a host’s response to pathogens are the damage-associated molecular pattern molecules (DAMPs). In the presence of cell activation or injury, these “danger signals” [including high mobility group box-1 (HMGB1) and S100β proteins] are released into the extracellular compartment where they specifically activate the receptor of advanced glycation end-products (RAGE). In the most recent issue of The American Journal of Pathology, Buhimschi and colleagues begin to evaluate the role of soluble RAGE (sRAGE), HMGB1 and S100β in mediating fetal organ injury in the presence of inflammation.

The authors report a significant decrease in the level of sRAGE in the amniotic fluid of human fetuses delivered by women with severe inflammation. In addition, severe histological inflammation in either the maternal or fetal compartment was characterized by lower levels of sRAGE in cord blood samples. Although HMGB1 and S100β levels remained unaffected, levels of S100β correlated strongly with those of HMGB1. There was also a direct correlation between levels of interleukin-6 (IL-6), an acute cytokine, and HMGB1, a chronic cytokine, suggesting that although neonatal injury begins in utero, there is an important chronic component.

Using a mouse model of inflammation-induced preterm birth, the authors noted an increase in RAGE expression in both the brain and liver accompanied by shifts in the cellular distribution of HMGB1 in both organs. Moreover, the authors observed co-expression of RAGE and HMGB1 at sites with morphologically altered brain tissue architecture and subarachnoid hemorrhage suggesting a role for these proteins in the pathophysiology of ischemic brain injury in premature infants (i.e., periventricular leukomalacia and intraventricular hemorrhage).

This study is the first to provide information on the expression and subcellular localization of RAGE and two well-recognized DAMP molecules (HMGB1 and S100β) in the setting of human fetal inflammation and preterm birth. The authors hypothesize that RAGE and HMGB1 actively mediate the process of fetal and neonatal tissue injury which may extend well beyond the antenatal period. Along with further studies, it is possible that future therapeutic compounds targeting DAMPs and RAGE could prevent fetal and neonatal damage.