Adrenergic modulation of survival and cellular immune functions during polymicrobial sepsis.
OBJECTIVE
An immunomodulatory effect of epinephrine has been reported that is supposed to be mediated via beta-adrenergic receptors. The effect of epinephrine and/or beta-adrenergic blockade on cellular immune functions during systemic inflammation has not yet been investigated.


METHODS
Male NMRI mice were treated with either an infusion of epinephrine (0.05 mg/kg/h i.p.), administration of the nonselective beta-adrenoceptor antagonist propranolol (0.5 mg/kg s.c.), or a combination of epinephrine and propranolol after induction of a polymicrobial sepsis by cecal ligation and puncture. Forty-eight hours thereafter survival and cellular immune functions (splenocyte proliferation, splenocyte apoptosis and cytokine release, distribution of leukocyte subsets) were determined.


RESULTS
Infusion of epinephrine did not affect lethality of septic mice but induced alterations of splenocyte apoptosis, splenocyte proliferation and IL-2 release and was associated with profound changes of circulating immune cell subpopulations. Treatment with propranolol augmented the epinephrine-induced increase of splenocyte apoptosis, did not affect the decrease of splenocyte proliferation and IL-2 release, augmented the release of IL-6 and antagonized the mobilization of natural killer cells observed in epinephrine-treated animals. Furthermore, these immunologic alterations were accompanied by a significant increase of sepsis-induced mortality. Coadministration of propranolol and epinephrine augmented the propranolol-induced changes of splenocyte apoptosis and IL-6 release and was associated with the highest mortality of septic mice.


CONCLUSIONS
Epinephrine infusion modulated cellular immune functions during systemic inflammation without an impact on survival. A pharmacologic beta-adrenergic blockade partly augmented the epinephrine-induced immune alterations and was associated with a pronounced increase of mortality. This effect was further augmented by a combination of epinephrine infusion and beta-adrenergic blockade. These data indicate that adrenergic mechanisms modulate cellular immune functions and survival during sepsis, with these effects being mediated via alpha- and beta-adrenergic pathways.
Oberbeck
Reiner
R
Department of Trauma Surgery, University Hospital of Essen, Essen, Germany. reineroberbeck@hotmail.com
Schmitz
Daniel
D
Wilsenack
Klaus
K
Schüler
Marc
M
Pehle
Birthe
B
Schedlowski
Manfred
M
Exton
Michael S
MS
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000187:drug effects / Q000276:immunology; D004357:Drug Synergism; D004837:Epinephrine / Q000097:blood / Q000276:immunology* / Q000494:pharmacology; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D015213:Neuroimmunomodulation / Q000276:immunology*; D009638:Norepinephrine / Q000097:blood / Q000276:immunology; D011433:Propranolol / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000276:immunology*; D018805:Sepsis / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D015996:Survival Rate; D013564:Sympathetic Nervous System / Q000276:immunology*
D000319:Adrenergic beta-Antagonists; D016207:Cytokines; D011943:Receptors, Adrenergic, beta; D011433:Propranolol; D009638:Norepinephrine; D004837:Epinephrine