Abstract
Remimazolam is a new benzodiazepine of sedative drugs with an ultra-short-acting anesthetic effect, commonly used for critically ill patients (especially septic patients) in intensive care units (ICUs). Although some anesthetics have been reported to show certain anti-inflammatory effects, the role of remimazolam in inflammation is still remained unknown. Here, we studied the effects of remimazolam on macrophage in response to LPS both in vivo and in vitro. Interestingly, compared with LPS treatment group, remimazolam remarkably improved survival rate of endotoxemia mice and decreased the release of LPS-induced inflammatory mediators (such as TNF-α, IL-6, and IL-1β). We further found that remimazolam not only inhibited the activation of MAPK signal pathway at 15 min after LPS treatment but also disturbed Rab5a related TLR4 expression at cell surface in response to LPS at a later time. Such evidence suggests that remimazolam might be beneficial to septic patients who are suffering from uncontrolled inflammatory responses.
Highlights
Sepsis is a severe inflammatory response to infection and remains the primary cause of morbidity and mortality in intensive care unit (ICU) patients worldwide (Drewry et al, 2017)
LPS/TLR4 endocytosis mediated by clathrin by Rab5a promotes the transport of more TLR4 stored in the Golgi apparatus to the cell membrane, amplifying inflammatory signaling and exacerbating the inflammatory response and cell death (Tang et al, 2020)
In vitro, we found that remimazolam disturb LPS-induced macrophages overactivation process, including inflammatory signal transduction and the cell surface translocation of TLR4, not via PBR
Summary
Sepsis is a severe inflammatory response to infection and remains the primary cause of morbidity and mortality in intensive care unit (ICU) patients worldwide (Drewry et al, 2017). Sepsis usually triggers cell dysfunction and subsequent organ failure, leading to death Inflammatory factors such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 (IL-1) act as key regulators of the immune response and play a critical role in the complex pathophysiological mechanisms of sepsis (Parameswaran and Patial, 2010; Schulte et al, 2013). Excessive release of these inflammatory cytokines can lead to dysfunction of the immune system and, damage to multiple tissues (Schulte et al, 2013). LPS/TLR4 endocytosis mediated by clathrin by Rab5a promotes the transport of more TLR4 stored in the Golgi apparatus to the cell membrane, amplifying inflammatory signaling and exacerbating the inflammatory response and cell death (Tang et al, 2020)
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