Glucocorticoids alter the balance between pro- and anti-inflammatory mediators in the myocardium in a porcine model of brain death.
BACKGROUND
Cardiac dysfunction after brain death (BD) limits donors for cardiac transplantation. Glucocorticoids ameliorate brain death-induced donor heart dysfunction. We hypothesized that glucocorticoid therapy alleviates myocardial depression through altering the balance between pro- and anti-inflammatory mediators via the nuclear factor-kappaB (NF-kappaB)/inhibitor of kappaB-alpha (IkappaBalpha) pathway and/or by preserving beta-adrenergic receptor (betaAR) signaling in the heart.


METHODS
Crossbred pigs (25 to 35 kg) were randomly assigned to the following groups (n = 5/treatment): sham (Group 1); BD (Group 2); and BD with glucocorticoids (30 mg/kg methylprednisolone), either 2 hours before (Group 3) or 1 hour after BD (Group 4). Tumor necrosis factor-alpha (TNF-alpha) levels were measured in plasma at baseline and 1 hour and 6 hours after BD. Protein levels were measured in left ventricular homogenates procured 6 hours after BD.


RESULTS
Pro-inflammatory proteins (TNF-alpha) and interleukin-6 were lower in Group 3 and Group 4 compared with Group 2 at 6 hours after BD (p < 0.01). Intracellular adhesion molecule-1 was also lower in Group 4 compared with Group 2 (p = 0.001). Interleukin-10, an anti-inflammatory mediator, was lower in Group 4 than in Group 2 (p < 0.001), but not different between Groups 2 and 3. At 6 hours after BD, neither NF-kappaB activity nor basal adenylate cyclase activity differed between Groups 3 and 4 compared with Group 2.


CONCLUSIONS
Glucocorticoids maintained myocardial function and shifted the balance of pro- and anti-inflammatory mediators after BD. The mechanisms by which glucocorticoids preserve myocardial function, however, do not appear to involve the NF-kappaB pathway or betaAR signaling.
McLean
Kelly M
KM
Division of Cardiothoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA.
Duffy
Jodie Y
JY
Pandalai
Prakash K
PK
Lyons
Jefferson M
JM
Bulcao
Christian F
CF
Wagner
Connie J
CJ
Akhter
Shahab A
SA
Pearl
Jeffrey M
JM
D000818:Animals; D001926:Brain Death / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005938:Glucocorticoids / Q000494:pharmacology*; D006352:Heart Ventricles / Q000187:drug effects* / Q000473:pathology; D020672:I-kappa B Proteins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D005938:Glucocorticoids; D020672:I-kappa B Proteins; D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10