Insulin-like growth factor-I reduces stress-induced gastric mucosal injury by inhibiting neutrophil activation in...

We previously reported that activated neutrophils are critically involved in the development of stress-induced gastric mucosal injury in mice. Caspase activation plays an important role in the pathogenesis of tissue injury by activating neutrophils through an increase in the expression of endothelial monocyte-activating polypeptide-II (EMAP-II), a chemoattractant for neutrophils. Since insulin-like growth factor-I (IGF-I) inhibits caspase activation, it is possible that IGF-I reduces gastric mucosal injury by inhibiting neutrophil activation. In the present study, we examined this possibility in mice subjected to water-immersion restraint stress (WIR).

Mice were intraperitoneally administered with IGF-I or vehicle before being subjected to WIR. Gastric mucosal injury, gastric myeloperoxidase (MPO) activity, the immunofluorescence intensity of MPO, caspase-3 activity, number of apoptotic cells, EMAP-II expression and activation of Akt and glycogen synthase kinase-3beta (GSK-3beta) in gastric mucosa were determined in mice subjected to WIR. Neutropenia was induced by administration of methotrexate (MTX).

Administration of IGF-I at dosages higher than 200 microg/kg significantly reduced gastric mucosal injury and inhibited increases in gastric MPO activities after 8h of WIR. Administration of MTX also reduced the gastric mucosal injury as well as inhibiting increases in both gastric mucosal MPO activities and circulating neutrophil number. IGF-I (500 microg/kg) inhibited the increases in both gastric MPO activity and the immunofluorescence intensity of MPO observed in the gastric mucosa, but had no effect on the increase in circulating neutrophil number after 8h of WIR. It also markedly blunted WIR-induced increases in caspase-3 activities and the number of apoptotic cells in the gastric mucosa after 8h of WIR. Gastric expression of EMAP-II was markedly increased at 8h after starting WIR and this increase was inhibited by IGF-I administration. Administration of IGF-I enhanced WIR-induced phosphorylation of Akt and GSK-3beta in the gastric mucosa.

These observations indicate that IGF-I reduces stress-induced gastric mucosal injury by inhibiting gastric accumulation of neutrophils through inhibition of caspase-3-mediated EMAP-II activation. Furthermore, IGF-I might inhibit caspase-3 activation through Akt/GSK-3beta signaling.