78.07 The Effects of Norepinephrine and Hypoxia on Bone Marrow Stromal Cytokine Expression

Posted on January 18, 2018

E. Miller1, T. Loftus1, K. Kannan1, I. Alamo1, J. Plazas1, J. Mira1, S. Brakenridge1, P. Efron1, A. Mohr1  1University Of Florida,Department Of Surgery,Gainesville, FLORIDA, USA

Introduction: Following severe trauma and hemorrhagic shock, the post-injury catecholamine surge and global hypoxia suppress erythroid progenitor cell growth in a process that is mediated by the bone marrow stroma.  We hypothesized that norepinephrine (NE) and dimethyloxaloylglycine (DMOG) would increase bone marrow fibroblast expression of IL-6, EPO, G-CSF, and SCF, and would decrease EPO-R expression.

Methods: Fibroblasts were cultured under four different conditions: NE administration to simulate hypercatecholaminemia, DMOG administration to simulate hypoxia, NE plus DMOG, and unmanipulated controls.  At 6, 24, and 48h, fibroblast cell death was assessed by flow cytometry and expression of IL-6, EPO, EPO-R, G-CSF, and SCF were measured by polymerase chain reaction. 

Results: NE and DMOG administration did not significantly increase fibroblast cell death.  IL-6 expression was increased at all time points following NE, DMOG, and NE+DMOG, and was highest 48h following NE (103% increase, p <0.001).  EPO was also significantly increased at all time points following administration of NE, DMOG, and NE+DMOG; DMOG had strongest effects (176% increase at 48h, p <0.001).  EPO-R was significantly increased 48h following NE+DMOG (18%, p =0.003).  G-CSF was suppressed by NE but remained close to control levels following DMOG and NE+DMOG.  SCF was not significantly affected by NE, but was significantly decreased 48h following DMOG (51% decrease, p <0.001) and NE+DMOG (47% decrease, p <0.001). 

Conclusion: Catecholamines and hypoxia affect bone marrow stromal expression of cytokines that influence erythropoiesis, with unique individual and combined effects. EPO-R dysregulation following severe trauma may be attributable to circulating factors or functional damage to bone marrow fibroblasts themselves. Downregulation of SCF by hypoxia may contribute to ineffective stress erythropoiesis.