Abstract
Dexmedetomidine (Dex), a highly selective α2-adrenergic receptor agonist, has been shown to attenuate systemic inflammatory response induced by lipopolysaccharide (LPS). The protective effects of Dex may reportedly be due to the activation of the α7 nicotinic acetylcholine receptor (α7nAChR)-dependent cholinergic anti-inflammatory pathway. Spleen has been shown to play a pivotal role in the neural cholinergic anti-inflammatory pathway. However, little is known about the specific function of spleen in the protective effects of Dex against sepsis. To investigate the role of spleen in the treatment of Dex against sepsis, we studied the effects of preemptive administration of Dex to septic mice on the NF-κB p65 activation and downstream pro-inflammatory cytokine expression in the spleen. Our results provided evidence that Dex treatment attenuated LPS-activated NF-κB p65 activation, as well as the production of tumor necrosis factor-α, interleukin-6, and interleukin-1β at the level of both mRNA and protein in spleen. Consequently, serum concentrations of these cytokines decreased. Conversely, preemptive injection of α-bungarotoxin, a selective α7nAChR antagonist, reversed these effects of Dex. Our findings indicated that spleen played a critical role in the protective effects of Dex against sepsis and provided further insight into the anti-inflammatory mechanisms of Dex.
Highlights
Sepsis is a condition characterized by uncontrolled infection and affects many organs, with an attendant high mortality rate (Angus et al 2001)
No significant differences were found between α-Bgt + LPS and LPS groups in terms of the serum levels of tumor necrosis factor-α (TNF-α), IL-6, and IL-1β
Effects of Dex and α‐Bgt on TNF‐α, IL‐6, and IL‐1β levels in spleen tissues As shown in Figs. 2 and 3, we found that pretreatment with Dex efficiently suppressed the LPS-induced increase in TNF-α, IL-6, and IL-1β in spleen tissues
Summary
Sepsis is a condition characterized by uncontrolled infection and affects many organs, with an attendant high mortality rate (Angus et al 2001). The onset and perpetuation of sepsis involve the up-regulation of NF-κB (Müller et al 1993) and a complex network of cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) (Beutler and Cerami 1989; Durum et al 1985; Hofer et al 2009; Wong and Clark 1988). The unbalanced overproduction of these mediators provokes overwhelming inflammation responses and eventual lethal multiple-organ failure. Earlier research has shown that Dex can regulate systemic inflammatory response by decreasing the synthesis of proinflammation cytokines, such as TNF-α, IL-6, and IL-1β (Hofer et al 2009; Taniguchi et al 2008).
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