The gastrointestinal mucosa is very sensitive, and gastrointestinal surgery always destroy the intestinal mechanical barrier. At the same time, the gastrointestinal muscle layer is filled with macrophages, many of which are released when stimulated,further promoting the release of cell factors, prostaglandins and other factors. Therefore, when mucosal injuries occur, they can cause local and systemic inflammatory responses and even sepsis, resulting in postoperative gastrointestinal dysfunction.
In recent years, an increasing number of scholars have proposed that the intestinal tract plays an important role in the development of sepsis. Some scholars have proposed that the intestinal tract is not only the first organ involved in sepsis but also the "initiating organ" of sepsis. Approximately 30% of sepsis patients who die of multiple organ dysfunction syndrome (MODS) do not clinically exhibit a primary infection focus, but bacteria similar to intestinal bacteria can be found in their blood cultures[22-25].
The intestinal tract is often involved earlier and recovers later in the disease course. The study found that abdominal distension, intra-abdominal pressure and the time to recovery of intestinal function were significantly delayed in patients with sepsis. The mechanism of injury might be that the gastrointestinal mucosa and villi are rich in blood flow, sensitive to ischaemia and hypoxia, and vulnerable to damage under hypoperfusion. When sepsis occurs, the circulatory blood volume decreases, and the intestinal blood flow decreases significantly. When the systemic circulatory blood volume decreases by 10%, gastrointestinal blood perfusion decreases by nearly half. Long-term hypoperfusion can cause intestinal mucosal cell oedema, villous degeneration and necrosis, damage or even loss of tight junctions between cells, and increased intestinal permeability. If not controlled in time, this condition will eventually result in MODS[1, 2, 21]. Therefore, controlling inflammatory reactions, maintaining intestinal function, protecting the intestinal barrier integrity and avoiding intestinal bacteria and endotoxin release into the blood are the key points for preventing MODS.
Recent studies have found that the “cholinergic anti-inflammatory pathway” (CAP) is a neuroimmune regulatory pathway with obvious anti-inflammatory effects. The CAP is composed mainly of the vagus nerve, α7nAChR and muscarinic receptors，it′s play different anti-inflammatory roles. Activation of the CAP can effectively reduce the release of TNF-α, IL-6, IL-1β and other inflammatory factors and can significantly inhibit the inflammatory reaction caused by various local and systemic causes[28, 29]. α7nAChR is an important target in the CAP, and it has been a popular research topic in recent years.
Compared with other nicotinic acetylcholine receptors, α7nAChR can be activated rapidly by agonists. The permeability of these receptors to calcium ions increases when activated and can allow for the inflow of calcium ions without causing the depolarization of cell membranes. Therefore, α7nAChR can participate in the regulation of calcium-related events conveniently and quickly. Research have shown that the CAP mainly plays a role through α7nAchR. Directional knockout of the α7nAChR gene or vagotomy can reduce the activity of the CAP and aggravate the inflammatory reaction in various inflammatory model animals. A preliminary study based on clinical sepsis patients showed that high expression of α7nAChR in peripheral blood mononuclear cells was associated with reduced inflammatory status and improved prognosis.
DEX is a new type of α2-adrenergic receptor agonist that can simultaneously act on the central and peripheral nervous systems, regulate autonomic nervous activity, and produce dose-dependent sedative, hypnotic and anti-anxiety effects. At the same time, DEX can reduce the incidence of delirium in patients , and it was widely used in the sedative treatment of critically ill patients [26, 32-34]. Our study found that, compared to MID, DEX had no significant effect on blood pressure at the depth of shallow sedation, At the same time, DEX can also shorten the length of ICU stay.
Several animal experiments on acute inflammation have shown that DEX significantly inhibits the over-release of TNF-α, IL-1β, IL-6 and other inflammatory factors. Clinical studies have also found that DEX use in general anaesthesia can significantly reduce the levels of plasma inflammatory factors in perioperative patients. Especially in patients with severe sepsis caused by intestinal obstruction, DEX treatment can not only reduce the release of inflammatory factors but also reduce the increased intra-abdominal pressure of sepsis patients[14, 15]. Our study found that the borborygmus resumption time (BRT) in the DEX group was significantly shorter than that in the control group. At the same time, our study found that the level of TNF-α in the DEX group was significantly lower, showing that the clinical sedative dose of DEX could produce an obvious anti-inflammatory effect and block the cascade reaction of inflammation.
Many studies have shown that DEX exerts its anti-inflammatory effects by activating the CAP of the vagus nerve and the α-2 adrenergic receptor, and its activation of the CAP is achieved mainly by activating α7nAChR.. In our study, we found that DEX increased the expression of α7nAChR in peripheral blood mononuclear cells.
When the gut was damaged, IFN-γ, TNF-α and IL-1β inflammatory factors, through the CAP, activate myosin light streptokinase within intestinal epithelial cells, resulting in myosin light chain phosphorylation, promoting a variety of proteins (such as adhesion molecule-1, occludin, and claudin) in the closely connected intestinal epithelial cells, thereby inducing functional changes and eventually damaging the integrity of tight junctions[36, 37]. Therefore, the key to maintaining intestinal barrier function is inhibiting the inflammatory response. The serum D-Lac level are often used as important reference indicators for evaluating intestinal barrier function. Our study showed that the level of D-Lac decreased significantly in the DEX group, indicating that DEX could significantly improve intestinal permeability in patients undergoing gastrointestinal surgery. At the same time, combined with the increased expression of α7nAChR in peripheral blood mononuclear cells, it can be inferred that mechanism might be related to the activation of α7nAChR, increased CAP activity and inhibition of the intestinal inflammatory response