title: Daily propranolol administration reduces persistent injury-associated anemia after severe trauma and chronic stress.
abstract: 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.
authors.affiliation: 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.
authors.forename: Ines G
authors.initials: IG
authors.lastname: Alamo
authors.forename: Kolenkode B
authors.initials: KB
authors.lastname: Kannan
authors.forename: Letitia E
authors.initials: LE
authors.lastname: Bible
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Loftus
authors.forename: Harry
authors.initials: H
authors.lastname: Ramos
authors.forename: Philip A
authors.initials: PA
authors.lastname: Efron
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Mohr
mesh_terms: D000740:Anemia / Q000503:physiopathology* / Q000517:prevention & control*; D000818:Animals; D001853:Bone Marrow / Q000503:physiopathology*; D003288:Contusions / Q000503:physiopathology*; D004195:Disease Models, Animal; D055370:Lung Injury / Q000503:physiopathology*; D008297:Male; D011433:Propranolol / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012149:Restraint, Physical; D012771:Shock, Hemorrhagic / Q000503:physiopathology*; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D011433:Propranolol