Sepsis stimulates the sympathetic nervous system. The resultant elevation in plasma catecholamines, both norepinephrine and epinephrine (Epi), might be expected to alter the expression of inflammatory cytokines, which may directly or indirectly influence muscle protein balance. The purpose of this study was twofold: (1) determine whether Epi per se increases cytokine expression in skeletal muscle, and (2) determine whether β-adrenergic blockade alters the sepsis-induced expression of inflammatory cytokines and mediators of protein balance in skeletal muscle.Methods:
In the first study, rats were infused with Epi for 2 hour to increase the circulating Epi concentration to levels seen in septic animals. In the second study, sepsis was induced by cecal ligation and puncture and a nonspecific β-adrenergic blockade produced with a continuous infusion of propranolol (PP). Tissues were obtained 24 after induction of sepsis and analyzed for tumor necrosis factor (TNF)-α interleukin (IL)-1β, IL-6 mRNA and protein content. In addition, the tissue content of insulin-like growth factor (IGF)-I and various regulators of protein synthesis were assessed.Results:
Epi acutely increased TNF-α IL-6 and IL-1β mRNA content in muscle (3- to 40-fold). However, only the TNF-α and IL-6 protein content was increased in muscle by Epi. In the second study, β-adrenergic blockade with PP exacerbated the sepsis-induced increase in muscle IL-6 and TNF-α mRNA but did not alter the increment in IL-1β or HMGB1. Propranolol also accentuated the sepsis-induced increase in both IL-6 and TNF-α protein in muscle. The exaggerated muscle cytokine response in septic rats treated with PP was associated with a reduction in muscle IGF-I protein that was greater than detected in saline-infused septic rats. Finally, the combination of sepsis + PP also accentuated the sepsis-induced decrease in the phosphorylation of 4E-binding protein-1, ribosomal protein S6, and mTOR, which are key proteins controlling protein synthesis.Conclusions:
These results demonstrate that although Epi is capable of increasing tissue cytokines in naive rats, inhibition of the β-adrenergic effects of catecholamines exacerbates the sepsis-induced increase of selected inflammatory cytokines. This exaggerated tissue response is associated with alterations in muscle IGF-I protein and translation initiation, which would be expected to impair tissue protein synthesis.