Exploring the Mechanism on the Medullary Visceral Zone Inhibiting the Cholinergic Anti-inflammatory Pathway Induced by Sepsis

Abstract

Inflammatory storm is an important pathological mechanism of multiple organ dysfunction, and it is associated with most deaths in septic patients, deserving to be studied. Recent findings have confirmed that the Medullary Visceral Zone (MVZ) regulates inflammation and immunity through the cholinergic anti-inflammatory pathway (CAP), but how sepsis affects the MVZ and leads to uncontrolled inflammation remain unclear. The current study reported that sepsis induced MVZ to inhibit CAP which underlies the inflammation storm. Our studies have shown that the rat models of sepsis prepared by cecal ligation and puncture had a higher inflammatory level, higher mortality, and higher Murine Sepsis Score. In septic rats, some indicators of heart rate variability (HRV) such as SDNN, HF band, RMSSD, SD1, and SD2 significantly reduced. In MVZ of septic rats, many cholinergic and catecholaminergic neurons showed apoptotic, with low expressions of tyrosine hydroxylase and choline acetyltransferase. The α7nAChR agonist GTS-21 can improve these pathologies, while the α7nAChR antagonist MLA is the opposite. Our study demonstrates for the first time that cholinergic and catecholaminergic neurons in MVZ went through significant apoptosis and inactiveness in sepsis, which contributes to the inhibition of CAP and acceleration of the inflammation storm in early sepsis. Intervening with CAP has a significant effect on the activity and apoptosis of MVZ neurons while altering systemic inflammation and immunity; in addition, for the first time, we confirmed that some indicators of HRV such as SDNN, HF band, RMSSD, SD1, and SD2 can reflect the activity of CAP, but the CAP interference had little effect on these indicators.

Sepsis-induced inflammatory demyelination in medullary visceral zone and cholinergic anti-inflammatory pathway: Insights from a Rat's model study

“…After 3 days, rats were euthanized under anesthesia with inhalation of isoflurane [ 17 ] to collect the medulla oblongata for reverse transcription-polymerase chain reaction (RT-PCR), TdT mediated dUTP nick end labeling (TUNEL), and Fluorescent immunolabeling analysis. Though these results have been reported in our previous study [ 12 ], it is necessary to remind it again.…”

“…As reported in previous study [ 12 , 17 ], after 7 days of adaptive feeding the formal experiment begins, 3 days after the relevant intervention, the rats’ blood and brain tissue were harvested for detection. The first experiment carry out such analysis as short-term HRV, TdT mediated dUTP Nick End Labeling (TUNEL), Immunofluorescence and Quantitative Reverse Transcription-Polymerase Chain Reaction (RT-PCR).…”

“…In previous studies [ 12 ], researchers have identified specific HRV parameters to evaluate the activity of CAP on inflammation and immune regulation. These parameters include frequency domain parameters such as high frequency (HF), time domain parameters such as standard deviation of all NN intervals (SDNN), the root mean square successive difference (RMSSD), and non-linear parameters such as width of a scatterplot of the deviations of successive pairs of RR intervals (SD1) and length of a scatterplot of the deviations of successive pairs of RR intervals (SD2).…”

The Regulation Effect of α7nAChRs and M1AChRs on Inflammation and Immunity in Sepsis

“…Our preliminary experiments confirmed that activation of α 7nAChRs significantly improved MVZ neuroinflammation and apoptosis [ 61 , 62 ]: in sepsis, intraperitoneally administered GTS-21, a specific agonist for α 7nAChRs, significantly reduced the apoptosis of the cholinergic and catecholaminergic neurons in MVZ in septic rats, accompanied by the elevated expression of tyrosine hydroxylase (TH) and choline acetyltransferase (CHAT), which significantly reversed the inhibition of CAP and the inflammatory storm, while intraperitoneally administered MLA, a specific antagonist for α 7nAChRs, does the opposite. Therefore, activation of α 7nAChRs not only directly inhibits the overactive systemic inflammation and immunity but also resumes the inflammatory and dysfunctional MVZ, thereby restoring CAP's regulation of inflammation.…”

“…In MVZ, neuroinflammation has a comprehensive influence on nerves architecture, synaptic plasticity, and nerve function. Studies show that cholinergic and catecholaminergic neurons in MVZ went through significant apoptosis and inactiveness, which contributes to the inhibition of CAP and the acceleration of the inflammatory storm in early sepsis [ 61 , 62 ]. Neuroinflammation facilitates reactive glial cells in the brain, releasing cytokines and damage-associated molecular patterns (DAMPs), which promote cell adhesion, migration, proliferation, and angiogenesis [ 86 ].…”