Daily propranolol administration reduces persistent injury-associated anemia after severe trauma and chronic stress

Abstract

Background Following severe trauma, patients develop a norepinephrine-mediated persistent, injury-associated anemia. This anemia is associated with suppression of bone marrow erythroid colony growth, along with decreased iron levels, and elevated erythropoietin (EPO) levels, which are insufficient to promote effective erythropoiesis. The impact of norepinephrine on iron regulators such as ferroportin, transferrin and transferrin receptor-1 (TFR-1) are unknown. Using a clinically relevant rodent model of lung contusion (LC), hemorrhagic shock (HS), and chronic stress (CS), we hypothesize that daily propranolol (BB), a non-selective beta-blocker, restores bone marrow function and improves iron homeostasis. Methods Male Sprague-Dawley rats were subjected to LCHS±BB and LCHS/CS±BB. BB was achieved with propranolol (10mg/kg) daily until the day of sacrifice. Hemoglobin (Hgb), plasma EPO, plasma hepcidin, bone marrow cellularity and bone marrow erythroid colony growth were assessed. RNA was isolated to measure transferrin, TFR-1 and ferroportin expression. Data is presented as mean±SD; *p<0.05 vs. untreated counterpart by t-test. Results The addition of CS to LCHS leads to persistent anemia on post-trauma day 7, while the addition of BB improved Hgb levels (LCHS/CS: 10.6±0.8 vs. LCHS/CS+BB: 13.9±0.4* g/dL). Daily BB use following LCHS/CS improved BM cellularity, CFU-GEMM, BFU-E and CFU-E colony growth. LCHS/CS+BB significantly reduced plasma EPO levels and increased plasma hepcidin levels on day 7. The addition of CS to LCHS resulted in decreased liver ferroportin expression as well as decreased bone marrow transferrin and TFR-1 expression, thus, blocking iron supply to erythroid cells. However, daily BB after LCHS/CS improved expression of all iron regulators. Conclusions Daily propranolol administration following LCHS/CS restored bone marrow function and improved anemia after severe trauma. In addition, iron regulators are significantly reduced following LCHS/CS, which may contribute to iron restriction after injury. However, daily propranolol administration after LCHS/CS improved iron homeostasis. Level of Evidence Level II, therapeutic study

Discrete β-adrenergic mechanisms regulate early and late erythropoiesis in erythropoietin-resistant anemia

“…In a separate sequential study, the authors observed an increase in Hgb levels with propranolol. (46). The latter model varies with a superimposed chronic stress to the hemorrhagic shock where the bone marrow cellularity was altered.…”

Impact of Injury Severity on the Inflammatory State and Severe Anemia

“…[8][9][10] In preclinical rodent studies of blunt trauma, hemorrhagic shock and chronic stress, postinjury hypercatecholaminemia is associated with a suppression of bone marrow erythroid progenitor growth, reduced erythroid commitment, an abnormal EPO response, prolonged mobilization of hematopoietic progenitor cells, and dysregulation of iron homeostasis. 11,12 Norepinephrine, a key modulator of hematopoietic progenitor mobilization and an inhibitor of bone marrow erythroid cell growth, also directly stimulates IL-6 release, and several of our prior studies have implicated these cytokines directly in the development of persistent injury-associated anemia. 13,14 Tumor necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6) are both proinflammatory cytokines that influence hematopoiesis and have altered expression following severe trauma.…”

“…19,20 Dysfunctional erythropoiesis in a rodent trauma model can be ameliorated with chemical sympathectomy using either propranolol or clonidine, suggesting that a reduction of hypercatecholaminemia improves erythropoiesis. [11][12][13][21][22][23][24][25][26] Prior research has evaluated the postinjury inflammatory state in severely injured trauma patients and demonstrated their erythropoietic dysfunction and iron dysregulation. 27 To validate our preclinical findings and to expand upon our prior study of the postinjury inflammatory state in humans, the purpose of this study was to evaluate additional severely injured trauma patients and determine if there is a relationship between the ISS in trauma patients, and the degree of neuroendocrine activation and systemic inflammation that is related with persistent injury-associated anemia as well as to further characterize the bone marrow response to injury.…”

Effect of Beta-Blockade on the Expression of Regulatory MicroRNA after Severe Trauma and Chronic Stress

“…42 These miR findings correlate with our previous studies demonstrating significant erythroid growth suppression after LCHS/CS and improvement in inflammation and erythropoiesis with the use of propranolol after LCHS/CS. 3,13,14,43 Also, bone marrow miR-130b expression was suppressed in the LCHS/CS group compared with LCHSþBB and naïve rodents. Previous studies have demonstrated that miR-130b downregulation played a role in prostate and pancreatic cancer, likely through its targeting of STAT3.…”

“…[9][10][11][12] In addition, both human and rodent studies have demonstrated that a reduction in hypercatecholaminemia and inflammation with propranolol or clonidine can mitigate this persistent injury-associated anemia and improve bone marrow erythropoietic function. 3,[13][14][15] Therefore, continuing to focus on potential targets of inflammatory processes would provide novel treatment strategies for the treatment of erythropoietic dysfunction after trauma.…”