Alamo Ines G, Kannan Kolenkode B, Bible Letitia E, Loftus Tyler J, Ramos Harry, Efron Philip A, Mohr Alicia M
From the Department of Surgery and Center for Sepsis and Critical Illness Research (I.G.A., K.B.K., L.E.B., T.J.L., H.R., P.A.E., A.M.M.), University of Florida, Gainesville, Florida.
J Trauma Acute Care Surg. 2017 Apr;82(4):714-721. doi: 10.1097/TA.0000000000001374.
After severe trauma, patients develop a norepinephrine-mediated persistent, injury-associated anemia. This anemia is associated with suppression of bone marrow (BM) 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), is 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 nonselective β blocker, restores BM function and improves iron homeostasis.
Male Sprague-Dawley rats were subjected to LCHS ± BB and LCHS/CS ± BB. BB was achieved with propranolol (10 mg/kg) daily until the day of sacrifice. Hemoglobin, plasma EPO, plasma hepcidin, BM cellularity and BM erythroid colony growth were assessed. RNA was isolated to measure transferrin, TFR-1 and ferroportin expression. Data are presented as mean ± SD; *p < 0.05 versus untreated counterpart by t test.
The addition of CS to LCHS leads to persistent anemia on posttrauma day 7, while the addition of BB improved hemoglobin levels (LCHS/CS: 10.6 ± 0.8 vs. LCHS/CS + BB: 13.9 ± 0.4* g/dL). Daily BB use after LCHS/CS improved BM cellularity, colony-forming units granulocyte, erythrocyte, monocyte megakaryocyte, burst-forming unit erythroid and colony-forming unit erythroid cell 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 BM transferrin and TFR-1 expression, thus, blocking iron supply to erythroid cells. However, daily BB after LCHS/CS improved expression of all iron regulators.
Daily propranolol administration after LCHS/CS restored BM function and improved anemia after severe trauma. In addition, iron regulators are significantly reduced after LCHS/CS, which may contribute to iron restriction after injury. However, daily propranolol administration after LCHS/CS improved iron homeostasis.
严重创伤后，患者会出现去甲肾上腺素介导的持续性、与损伤相关的贫血。这种贫血与骨髓红系集落生长受抑制、铁水平降低以及促红细胞生成素（EPO）水平升高有关，而EPO水平升高不足以促进有效的红细胞生成。去甲肾上腺素对铁调节因子，如铁转运蛋白、转铁蛋白和转铁蛋白受体-1（TFR-1）的影响尚不清楚。我们使用一种临床相关的啮齿动物模型，即肺挫伤（LC）、失血性休克（HS）和慢性应激（CS）模型，假设每日使用普萘洛尔（一种非选择性β受体阻滞剂）可恢复骨髓功能并改善铁稳态。
将雄性Sprague-Dawley大鼠分为LCHS ± BB组和LCHS/CS ± BB组。每日用普萘洛尔（10 mg/kg）给药直至处死日以实现使用BB。评估血红蛋白、血浆EPO、血浆铁调素、骨髓细胞密度和骨髓红系集落生长。分离RNA以测量转铁蛋白、TFR-1和铁转运蛋白的表达。数据以平均值±标准差表示；通过t检验，*p < 0.05表示与未处理的对应组相比。
在LCHS基础上加用CS会导致创伤后第7天出现持续性贫血，而加用BB可提高血红蛋白水平（LCHS/CS组：10.6 ± 0.8 vs. LCHS/CS + BB组：13.9 ± 0.4* g/dL）。LCHS/CS后每日使用BB可改善骨髓细胞密度、粒系、红系、单核系、巨核系集落形成单位、红系爆式集落形成单位和红系集落形成单位细胞集落生长。LCHS/CS + BB组在第7天显著降低血浆EPO水平并升高血浆铁调素水平。在LCHS基础上加用CS导致肝脏铁转运蛋白表达降低以及骨髓转铁蛋白和TFR-1表达降低，从而阻断向红系细胞的铁供应。然而，LCHS/CS后每日使用BB可改善所有铁调节因子的表达。
LCHS/CS后每日给予普萘洛尔可恢复骨髓功能并改善严重创伤后的贫血。此外，LCHS/CS后铁调节因子显著降低，这可能导致损伤后的铁限制。然而，LCHS/CS后每日给予普萘洛尔可改善铁稳态。
