Inhibition of GKN2 Attenuates Acute Gastric Lesions Through the NLRP3 Inflammasome.

Abstract

Objective: Acute gastric lesions are commonly seen in critically ill patients in the intensive care unit and can result in significant upper gastrointestinal bleeding. However, the signaling mechanisms that regulate this severe disease are still unclear. In this study, we explored the involvement of gastrokine 2 (GKN2) in the development of acute gastric lesions in mice. Approach: We measured the degree of injury using the water immersion restraint stress mouse model. Inflammatory cells and factors were analyzed after gastric lesion induction. The luciferase reporter assay was used to detect the transcription activity of nuclear receptor subfamily 3 group C member 1 (NR3C1) in regulation of GKN2. We also detected the downstream pathway of GKN2 in gastric lesions. Results: The results showed that GKN2 could aggravate stress-induced gastric lesions and gastric mucosal cell death. Moreover, the gastric lesion promoted by GKN2 was gastric acid independent. GKN2 could recruit neutrophils and promote the release of inflammatory factors to contribute to inflammation. NR3C1, activated by cortisol under stress, could act as a transcription factor to upregulate the expression of GKN2. Innovation: This study elucidates the process of gastric lesion at a molecular level and explores the possible contender biomarkers for diagnosis and drug targets in wound healing of gastric lesions. Conclusion: In conclusion, GKN2, which was upregulated by cortisol, aggravated the gastric lesion through activation of the inflammasome and inflammatory reaction.