INDUCTION OF EGF-RECEPTOR TYROSINE KINASE DURING EARLY REPARATIVE PHASE OF GASTRIC-MUCOSA AND EFFECTS OF AGING

BACKGROUND: Although the gastric mucosa of adult healthy animals posse sses a remarkable capacity to promptly repair its mucosal architecture after an acute injury, aging attenuates this process. We hypothesize that certain tyrosine kinases (Tyr-k), specifically the enzyme associa ted with EGF-receptor (EGF-R), may play a role in this process. The pr esent investigation was undertaken to evaluate the role of this enzyme in the early reparative phase of the gastric mucosa in young and aged rats. EXPERIMENTAL DESIGN: In our initial effort to test the hypothes is, we examined the changes in both total and EGF-R-associated Tyr-k a ctivities in the gastric mucosa of young adult rats (4-months old) dur ing the first 60 minutes after hypertonic saline (2 M NaCl; 1.5 ml/130 g body weight)-induced injury. Because the maximal stimulation (90-10 0% over the controls) in both total and EGF-R-associated Tyr-k occurre d at 30 minutes after injury, we used this time point to perform the n ext experiment, in which groups of young and aged rats were given (int ragastically) 2 M NaCl or water. One of the young and aged groups of r ats was also injected (i.p.) with the Tyr-k inhibitor tyrphostin-51 (3 00 pg/kg body weight) 60 minutes before injury. The gastric mucosa was assayed for EGF-R Tyr-k activity and tyrosine phosphorylation and exp ression of EGF-R, phospholipase C (PLC) activity and relative concentr ation and tyrosine phosphorylation of PLC-(gamma 1), as well as transf orming growth factor-alpha (TGF-alpha) levels. RESULTS: Basal EGF-R Ty r-k activity and the extent of tyrosine phosphorylation of EGF-R, as w ell as PLC activity, were all found to be higher in the gastric mucosa of aged than in young rats. Although 30 minutes after injury, EGF-R T yr-k activity, tyrosine phosphorylation of EGF-R, and relative abundan ce of the receptor were all increased in the gastric mucosa of both yo ung and aged rats, the magnitude of stimulation of each of the paramet ers was found to be considerably lower in aged than in young rats, com pared with the corresponding basal levels. A similar phenomenon was al so observed for PLC activity and tyrosine phosphorylation of PLC-(gamm a 1). The relative concentration of mucosal PLC-(gamma 1) level was, h owever, not affected by injury in either young or aged rats. Tyrphosti n greatly attenuated the injury-induced increases in the above mention ed parameters in both young and aged rats. In young but not in aged ra ts, injury caused a significant increase in mucosal TGF-alpha levels. CONCLUSIONS: We conclude that (a) activation of EGF-R Tyr-k is an impo rtant event in the early reparative process of the gastric mucosa, and (b) local production of TGF-alpha may play an important role in regul ating the activation of EGF-R Tyr-k.