Inhibitors of IFN Gene Stimulators (STING) Improve Intestinal Ischemia-Reperfusion Induced Acute Lung Injury by Activating AMPK Signal

Abstract

Background: Acute lung injury (ALI) caused by intestinal ischemia-reperfusion is a life-threatening disease. Interferon gene stimulator (STING) is a cytoplasmic DNA sensor, participating in the initiation of inflammatory response. This study aims to establish whether C-176 (STING inhibitor) improves the ALI under intestinal ischemia-reperfusion conditions.Methods: To induce ALI, 72 C57BL/6 mice male were subjected to intestinal ischemia-reperfusion for 90 min. Through intraperitoneal injection, C-176, a selective STING inhibitor was injected 30 minutes before surgical treatment; meanwhile, compound C, an antagonist of adenosine monophosphate-activated protein kinase (AMPK) was administered 30 min after surgery. Based on immunofluorescence and Western blot assays, post-ALI assessments included lung water content (TLW), bronchoalveolar lavage fluid (BALF) protein, H&E staining, Masson staining, pulmonary apoptosis (TUNEL, cleaved caspase-3), and pyroptosis (Gasdermin-D [GSDMD], cleaved caspase-1).Results: C-176 administration significantly attenuated intestinal ischemia-reperfusion-mediated ALI; this was reflected by exasperated TLW and BALF protein, aggravated lung injury score, elevated degree of pulmonary fibrosis, increased TUNEL- and GSDMD-positive cells, as well as upregulated phosphor-AMPK, cleaved caspase-3, and cleaved caspase-1 expression. Moreover, C-176 increased phosphor-AMPK under ALI conditions. Nonetheless, compound C partially reversed these beneficial effects.Conclusion: C-176, a selective STING inhibitor improves intestinal ischemia-reperfusion-mediated ALI, and its underlying mechanism may be associated with AMPK signal activation.