title: Chronic restraint stress after injury and shock is associated with persistent anemia despite prolonged elevation in erythropoietin levels.
abstract: BACKGROUND
  Following severe traumatic injury, critically ill patients have a prolonged hypercatacholamine state that is associated with bone marrow (BM) dysfunction and persistent anemia. However, current animal models of injury and shock result in a transient anemia. Daily restraint stress (chronic stress [CS]) has been shown to increase catecholamines. We hypothesize that adding CS following injury or injury and shock in rats will prolong the hypercatecholaminemia and prolong the initial anemia, despite elevated erythropoietin (EPO) levels.
  
  
  METHODS
  Male Sprague-Dawley rats (n = 6-8 per group) underwent lung contusion (LC) or combined LC/hemorrhagic shock (LCHS) followed by 6 days of CS. CS consisted of a 2-hour restraint period interrupted with repositioning and alarms every 30 minutes. At 7 days, urine was assessed for norepinephrine (NE) levels, blood for EPO and hemoglobin (Hgb), and BM for erythroid progenitor growth.
  
  
  RESULTS
  Animals undergoing LC or combined LCHS predictably recovered by Day 7; urine NE, EPO, and Hgb levels were normal. The addition of CS to LC and LCHS models was associated with a significant elevation in NE on Day 6. The addition of CS to LC led to a persistent 20% to 25% decrease in the growth of BM hematopoietic progenitor cells. These findings were further exaggerated when CS was added following LCHS, resulting in a 20%q to 40% reduction in BM erythroid progenitor colony growth and a 20% decrease in Hgb when compared with LCHS alone.
  
  
  CONCLUSIONS
  Exposing injured animals to CS results in prolonged elevation of NE and EPO, which is associated with worsening BM erythroid function and persistent anemia. Chronic restraint stress following injury and shock provides a clinically relevant model to further evaluate persistent injury-associated anemia seen in critically ill trauma patients. Furthermore, alleviating CS after severe injury is a potential therapeutic target to improve BM dysfunction and anemia.
authors.affiliation: From the Division of Trauma (L.E.B., L.V.P., A.V.G., Z.C.S.), Department of Surgery, Rutgers-New Jersey Medical School, Newark, New Jersey; and Division of Acute Care Surgery (K.B.K., A.M.M.), Department of Surgery, University of Florida, Gainesville, Florida.
authors.forename: Letitia E
authors.initials: LE
authors.lastname: Bible
authors.forename: Latha V
authors.initials: LV
authors.lastname: Pasupuleti
authors.forename: Amy V
authors.initials: AV
authors.lastname: Gore
authors.forename: Ziad C
authors.initials: ZC
authors.lastname: Sifri
authors.forename: Kolenkode B
authors.initials: KB
authors.lastname: Kannan
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Mohr
mesh_terms: D000740:Anemia / Q000503:physiopathology*; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D015672:Erythroid Precursor Cells / Q000378:metabolism; D004921:Erythropoietin / Q000097:blood*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D055370:Lung Injury / Q000150:complications / Q000503:physiopathology; D008297:Male; D009638:Norepinephrine / Q000652:urine; D017207:Rats, Sprague-Dawley; D012149:Restraint, Physical; D012771:Shock, Hemorrhagic / Q000150:complications / Q000503:physiopathology; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D004921:Erythropoietin; D009638:Norepinephrine