Glutamine and transforming growth factor-alpha stimulate extracellular regulated kinases and enhance recovery of villous surface area in porcine ischemic-injured intestine

Background. Epidermal growth factor (EGF) signals enterocyte proliferation via extracellular regulated kinases (ERKs). Because glutamine is required f or EGF-stimulated proliferations and stimulates ERKs in intestinal cell cul ture, we hypothesized that glutamine and the EGF-related peptide transformi ng growth factor-alpha (TGF-alpha) would synergistically enhance repair ass ociated with stimulation of ERKs. Methods. Thiry-Vella loops were created in juvenile pigs. One half of the l oop was subjected to 2 hours of ischemia, and the other half served as cont rol. Loops were infused daily with ringer's solution containing 140 mmol/L glucose, 140 mmol/L glutamine, 140 mmol/L glucose plus 60 mu g/L TGF-alpha, or 140 mmol/L glutamine plus 60 mu g/L TGF-alpha. Results. After 2 hours of ischemia, complete villous epithelial sloughing w as present. By 18 hours, villous epithelium had fully restituted, but villi remained stunted until 144 hours after injury. Glutamine + TGF-alpha trigg ered sustained increases in ERK activity compared with glucose-treated tiss ues (maximal at 18 hours), whereas glutamine alone or glucose + TGF-alpha c aused only transient elevations in ERK activity. By 72 hours, villous surfa ce area had increased to normal values with glutamine plus TGF-alpha treatm ent, whereas villi remained stunted with glucose alone, glutamine alone, or glucose plus TGF-alpha. Conclusions. Glutamine plus TGF-alpha treatment restored mucosal architectu re within 72 hours of severe ischemic injury associated with sustained elev ations in ERK activity.