Prior Ablation of the Splanchnic Sympathetic Nerves Increases Plasma Inflammatory Cytokine Levels and Suppresses Bacteremia in Response to Systemically Administered E. coli in Sheep

Abstract

The splanchnic sympathetic nerves exert a powerful anti‐inflammatory action in response to systemic administration of lipopolysaccharide in rats (Martelli et al. J. Physiol. 592: 1677–1686, 2014). However, it is not known how this endogenous anti‐inflammatory influence of the splanchnic nerve affects the body’s ability to fight infection. The aim of this study was to determine if and how the endogenous reflex activation of the splanchnic anti‐inflammatory pathway affects blood cytokine levels and the disease course of bacteremia after intravenous infusion of live E. coli into a conscious large animal (sheep). One month prior to infection, the greater splanchnic nerve was cut bilaterally (SplancX, n = 8) or sham surgery (Sham, n = 7) performed in anesthetized sheep (isoflurane/O2). After 1 month, these conscious sheep were infused with live E. coli (2.8 × 109 CFU in 30 min) into a jugular vein. Blood samples were obtained at 1.5, 3, 6, 24 and 48 h after bacterial injection. As expected, i.v. infusion of E. coli caused systemic bacteremia with high blood counts of E. coli [3.02 ± 0.64 Log10(CFU/ml + 1), mean ± sem] in 5 of 7 sham sheep. By contrast, no significant bacteremia was observed in any of the 8 SplancX sheep (0.18 ± 0.18 Log10[CFU/ml + 1], p < 0.01, c.f. Sham sheep). Plasma levels of tumour necrosis factor‐α peaked after 1.5 h, and were significantly greater in SplancX vs Sham sheep (2.4 ± 0.6 vs 1.5 ± 0.2 ng/ml, p < 0.05) at this time. Plasma levels of another pro‐inflammatory cytokine, interleukin‐6, peaked at 6h and were higher in SplancX vs Sham sheep (7.4 ± 0.6 vs 2.4 ± 0.6 ng/ml, p < 0.01). Although plasma levels of the anti‐inflammatory cytokine interleukin‐10 increased in both groups, they were lower in SplancX vs Sham sheep from 1.5 h to 24 h (2.9 ± 0.4 vs 6.7 ± 1.1 ng/ml at 24 h, p < 0.01). All plasma cytokine levels measured had returned to baseline by 48 h. Plasma cortisol levels were higher (p<0.01) in SplancX sheep only at 6 h (298 ± 29 vs 138 ± 37 ng/ml), while the fever was less (p < 0.05) in SplancX at 6 h (40.3 ± 0.3 vs 40.8 ± 0.3°C). The greater pro‐inflammatory response in splanchnic denervated animals most likely contributes to their enhanced ability to clear bacteremia. The present findings demonstrate the powerful consequences of neural control of inflammation in the context of an acute systemic infection.Support or Funding InformationSupported by the National Heart Foundation of Australia