beta2 Adrenoreceptor blockade attenuates the hyperinflammatory response induced by traumatic injury

Surgery. 2009 Feb;145(2):235-42. doi: 10.1016/j.surg.2008.09.013.


Background: Major operative injury initiates immunologic changes that may result in a systemic inflammatory response, leading to organ dysfunction/sepsis. Catecholamines seem to be key mediators. The effects of beta(2) receptor blockade in vitro and in vivo before and after operative injury were studied to clarify their role.

Methods: In vitro studies were done in RAW 264.7 cells using epinephrine (50 micromol/L) with or without alpha(2)- and beta(2)-receptor blockade. Comparative gene expression analysis on the Toll-like receptor (TLR)-4 receptor signaling pathway was performed between RAW cells pretreated with epinephrine with subsequent lipopolysaccharide (LPS) stimulation versus LPS alone. Confirmatory studies were performed by real-time reverse transcription polymerase chain reaction (RT-PCR). Tumor necrosis factor (TNF)-alpha gene and protein expression were determined via real time RT-PCR and enzyme-linked immunosorbent assay, respectively. In vivo, Balb/C mice received no treatment nor injury (group I). Group II received operative injury and vehicle injection, group III received ICI 118,551 (beta(2)-receptor antagonist) 30 minutes before or in separate studies after operative injury. At 7 days, splenic macrophages were harvested and cytokine production was measured with or without LPS. In separate experiments, cecal ligation and puncture (CLP) was done 7 days after operation and survival determined.

Results: In vitro studies demonstrated that epinephrine pretreatment significantly increased TNF-alpha production with LPS stimulation (P < .05). beta(2)-Receptor blockade significantly attenuated (P < .05) LPS stimulated TNF-alpha production. MD-2, an essential coactivator of TLR-4 signaling, gene expression was significantly elevated when cells were pretreated with epinephrine before LPS exposure (P < .001). In vivo studies demonstrated a significant decrease (P < .05) in TNF-alpha and interleukin-6 production in the ICI 118,551 group. Similar findings were demonstrated measuring monocyte chemoattractant protein-1 and interferon-gamma cytokine levels (P < .05) versus no treatment. ICI 118,551 treatment 30 minutes before operation demonstrated a 31% reduction in mortality after CLP (P < .05).

Conclusion: This study demonstrates that beta(2)-receptor blockade reduces macrophage cytokine production and improves survival showing the critical importance of catecholamines to the immunologic response in surgery.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenergic beta-2 Receptor Antagonists*
  • Animals
  • Cell Line, Tumor
  • Epinephrine / administration & dosage
  • Epinephrine / metabolism*
  • Female
  • Hemorrhage / complications
  • Lipopolysaccharides
  • Lymphocyte Antigen 96 / metabolism
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Multiple Trauma / complications
  • Multiple Trauma / drug therapy
  • Multiple Trauma / immunology*
  • Propanolamines / therapeutic use*
  • Systemic Inflammatory Response Syndrome / etiology
  • Systemic Inflammatory Response Syndrome / immunology*
  • Systemic Inflammatory Response Syndrome / prevention & control
  • Tumor Necrosis Factor-alpha / metabolism
  • Up-Regulation


  • Adrenergic beta-2 Receptor Antagonists
  • Lipopolysaccharides
  • Ly96 protein, mouse
  • Lymphocyte Antigen 96
  • Propanolamines
  • Tumor Necrosis Factor-alpha
  • ICI 118551
  • Epinephrine