Sevoflurane Attenuates Acute Lung Injury Following Intestinal Ischemia-Reperfusion via Targeting NLRP3 Inflammasome

Abstract

Acute lung injury (ALI) is a major contributor to the high morbidity and mortality associated with intestinal ischemia-reperfusion (II/R). Despite its severity, current clinical management of ALI remains limited to supportive care without addressing the cause of the disease, underscoring the urgent need to investigate the underlying mechanism and develop targeted therapies. In this study, we employed both in vitro and in vivo models to explore ALI in the setting of II/R. Our findings demonstrated that II/R-induced systemic inflammation activates nucleotide-binding oligomerization (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in lung endothelium, leading to the release of pro-inflammatory cytokine interleukin-1β (IL-1β) and pyroptotic cell death. This cascade ultimately damages lung vasculature and exacerbates ALI. Importantly, we revealed that sevoflurane, a commonly used anesthetic, can inhibit NLRP3 inflammation under II/R condition and provide protection against ALI. Mechanistically, sevoflurane downregulates NLRP3 expression via deactivating inhibitor of nuclear factor kappa-B kinase (IKK)/nuclear factor kappa-B kinase (NF-κB) signaling pathway, and simultaneously inhibits NLRP3 activation through protein kinase A (PKA)-mediated mechanism. These findings offered novel insights into the pathogenesis of II/R-induced ALI and highlighted the therapeutic potential of sevoflurane. Given sevoflurane's established clinical use, our results could have immediate implications for patient care in II/R situations.