Remimazolam attenuates traumatic brain injury-induced acute lung injury by suppressing pulmonary epithelial pyroptosis

Background and objectives: TBI-induced acute lung injury (TBI-ALI), with an incidence rate of 22-25%, represents a critical determinant of secondary mortality. Remimazolam is a novel sedative that has shown potential for anti-inflammatory effects. However, whether remimazolam ameliorates TBI-ALI remains unclear.

Methods: We established a controlled cortical impact (CCI) mouse model of TBI and combined ATF3 knockdown with remimazolam administration to assess lung injury. Subsequently, we employed WB and mRNA-seq techniques to investigate the potential molecular mechanisms of remimazolam’s effect on ALI. Finally, we conducted in vivo and in vitro experiments to validate our findings on these mechanisms.

Results: Remimazolam significantly mitigated TBI-ALI. Western blot and mRNA sequencing (mRNA-seq) analyses demonstrated that remimazolam inhibited post-TBI upregulation of activating transcription factor 3 (ATF3) and activation of the NOD-like receptor signaling pathway. In vitro experiments revealed that remimazolam reduced pyroptosis activation in mouse alveolar epithelial cells (MLE-12) by suppressing ATF3 expression, concurrently attenuating degradation of junctional proteins (ZO-1/E-cadherin). In vivo studies confirmed that remimazolam inhibited pulmonary epithelial pyroptosis and preserved blood-air barrier (BAB) integrity post-TBI, ultimately alleviating ALI progression.

Conclusion: Remimazolam mitigates TBI-ALI by suppressing post-traumatic ATF3 upregulation, thereby reducing NLRP3 inflammasome activation. This attenuates alveolar epithelial pyroptosis, preserves junctional protein integrity and BAB function, and ultimately ameliorates pulmonary pathology. These findings position remimazolam as a key therapeutic agent for neurotrauma-induced secondary organ dysfunction.