[Lactate induces gastric mucosal injury by promoting M1 polarization of macrophages via the cardio-gastric axis].

OBJECTIVES

To investigate the role of lactate in myocardial ischemia-reperfusion (MIR)-induced gastric mucosal injury.

METHODS

Thirty C57BL/6J mice were randomized into sham-operated group, MIR (45 min ischemia and 2 h reperfusion) group, and MIR+LDHAI group, and gastric mucosal injury was assessed using macroscopic scoring and HE staining; serum lactate and cTnT levels were measured using ELISA. Metabolomics analysis was conducted to identify the differential serum metabolites between the sham-operated and MIR mice. In the cell experiment, human gastric mucosal cells (GES-1) were indirectly co-cultured with THP-1 cell-derived macrophages polarized to the M1 phenotype by lactate and/or lipopolysaccharide (LPS) stimulation. In both the gastric mucosa tissues of the mice and the co-cultured GES-1 cells, the protein expression levels of CD68, iNOS, Arg-1, COX-1, and COX-2 were detected using Western blotting and immunofluo-rescence staining.

RESULTS

Compared to sham operation, MIR induced concurrent injury in both the heart and stomach of the mice and caused elevation of iNOS protein levels and reduction of Arg-1 protein expression in the gastric mucosa, where increased overlapping fluorescent areas were detected after MIR using fluorescent double-labeling for CD68 and iNOS. Serum metabolomics analysis revealed a significant increase in circulating lactate levels after MIR. In GES-1 cells, indirect co-culture with M1 macrophages induced obvious cell injury, decreased COX-1 expression, and increased cellular COX-2 protein expression. Western blotting and immunofluorescence staining confirmed that 15 mmol/L lactate significantly increased iNOS and decreased Arg-1 expression in THP-1-derived macrophages. Indirect co-culture of GES-1 cells with M1 macrophages induced by lactate or LPS resulted in obvious GES-1 cell injury. In the mouse models of MIR, inhibition of lactic acid production effectively alleviated MIR-induced gastric mucosal injury.

CONCLUSIONS

Lactate-induced M1 macrophage polarization mediates MIR-related gastric mucosal injury in mice via the heart-gastric axis, an effect reversible by LDHA inhibition.