The impact of a hypercatecholamine state on erythropoiesis following severe injury and the role of IL-6

BACKGROUND: Severe traumatic injury can lead to hemorrhagic shock-induced bone marrow (BM) dysfunction resulting in persistent anemia. The hypercatacholamine state that accompanies severe injury has been shown to impact the growth of erythroid progenitors. IL-6 has a role both in the acute phase response of trauma and has been implicated in the development of anemia. The aim of this study was to investigate the severity of a hyper-adrenergic stimulus on pluripotent progenitors (GEMM-CFU) as well as erythroid progenitors (BFU-E and CFU-E) and the potential regulatory role of IL-6. METHODS: Normal human BM mononuclear cells were isolated and erythropoiesis was assessed by the growth of GEMM-CFU, BFU-E and CFU-E in the presence of adrenergic agonists, norepinephrine (NE) and epinephrine (EPI), at increasing concentrations. Similarly, normal BM stroma cells were grown to confluence then incubated with NE and EPI. Supernatant was harvested and IL-6 levels were determined using ELISA. RESULTS: Under physiologic conditions (10(-7) M), NE and EPI increase BFU-E and CFU-E growth (374% and 177% versus 100% control). At severe stress levels (10(-3) M), NE and EPI completely inhibited BFU-E and CFU-E growth (5% and 4% versus 100% control). GEMM-CFU growth was increased by NE and not EPI at 10(-7) M. The presence of NE and EPI increased IL-6 levels in a dose-dependent fashion. CONCLUSIONS: The proliferative effect of adrenergic agonists at physiologic levels on normal erythropoiesis begins early during erythroid differentiation. At severe stress levels, BFU-E and CFU-E growth is inhibited. The erythropoietic dysfunction and resultant anemia seen following severe injury may be due to the presence of a severe hypercatecholamine state and may be mediated by IL-6.