Effects of 2,3-DPG knockout on SCD phenotype in Townes SCD model mice.

Sickle cell disease (SCD) is a severe, multisystemic hematological disorder that impacts nearly every major organ in adults. The current approved treatments for SCD directly target mutant hemoglobin or address downstream disease pathology. Several compounds targeting reduction of 2,3-DPG by activation of Pyruvate Kinase-R are currently being evaluated in SCD patients. In this study, we genetically engineered a mouse lacking 2,3-DPG on the Townes SCD mouse model background and evaluated the effects of 2,3-DPG loss on disease pathology. Animals lacking 2,3-DPG showed improvements in hematological markers and reductions in RBC sickling relative to native Townes mice, however, minimal difference in organ damage was observed in 2,3-DPG deficient mice compared to native Townes animals. When animals lacking 2,3-DPG were dosed with a compound designed to increase hemoglobin oxygen affinity, oxygen delivery related toxicity was observed.

The role of TLR4 and HO-1 in neuroinflammation after subarachnoid hemorrhage.

This review on the mechanisms of neuroinflammation following subarachnoid hemorrhage will focus mainly on toll-like receptor 4 (TLR4), Heme Oxygenase-1 (HO-1), and the role of microglia and macrophages in this process. Vasospasm has long been the focus of research in SAH; however, clinical trials have shown that amelioration of vasospasm does not lead to an improved clinical outcome. This necessitates the need for novel avenues of research. Our work has demonstrated that microglial TLR4 and microglial HO-1, not only affects cognitive dysfunction, but also circadian dysrhythmia in a mouse model of SAH. To attempt to translate these findings, we have also begun investigating macrophages in the cerebrospinal fluid of SAH patients. The goal of this review is to provide an update on the role of TLR4, HO-1, and other signal transduction pathways in SAH-induced neuroinflammation.