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.