Aging diminishes gastric mucosal regeneration: relationship to tyrosine kinases

Abstract

Background: Increased incidence of gastric ulcer observed in the aged could be partly attributed to increased susceptibility of the mucosa to various damaging agents together with impediment of the repair process. The present investigation was undertaken to compare the rate of mucosal regeneration and the role of tyrosine kinases in regulation of this process between young (4-month-old) and aged (24-month-old) rats during the first 24 hours after injury.

Experimental design: Groups of young and aged rats were given intragastrically with either 2 M NaCl (1.5 ml/130 gm body weight), or an equivalent volume of water and killed 1, 6, and 24 hours later. Each animal was injected intraperitoneally with 5-bromo-2'-deoxyuridine (BrdU; 50 mg/kg) 1 hour before killing to assess proliferative activity by immunocytochemistry. The stomach (oxyntic gland area) was also evaluated by light microscopy for the extent of injury and subsequent regeneration, and mucosa assayed for ornithine decarboxylase and tyrosine kinase (Tyr-k) activity and tyrosine phosphorylation of membrane proteins.

Results: Although 2 M NaCl caused extensive damage to the gastric mucosa in both young and aged rats, as evidenced by the total loss of the surface epithelium at 1 hour postinjury, the degree of regeneration was faster in young animals. In young rats, gastric epithelium showed signs of regeneration at 6 hours postinjury and was essentially complete by 24 hours. In contrast, in aged rats, only intermittent surface cells were seen 24 hours after injury. In both age groups, injury resulted in stimulation of mucosal proliferative activity. However, whereas ornithine decarboxylase activity in both age groups was maximally stimulated (350% in young versus 80% in aged) at 6 hours after injury, the number of BrdU-positive cells in young rats increased steadily with time after injury. In contrast, aged rats showed a biphasic pattern in that the number of BrdU-positive cells/gland remained decreased for up to 6 hours, whereafter a steep rise occurred. At 24 hours after injury, the number of BrdU-positive cells/gastric gland in aged rats were found to be higher than in young rats (6 +/- 1.5 cells/gland in young rats versus 9 +/- 2.1 cells/gland in aged rats). The pattern of Tyr-k activity in young and aged rats after injury was found to be quite different from that observed for proliferative activity. In young rats, mucosal Tyr-k activity increased by about 60% at 1 hour after injury, then decreased slightly over the next 5 hours and increased again revealing a 120% rise at 24 hours postinjury. This was associated with a concomitant change in tyrosine phosphorylation of six membrane proteins with molecular weight (in kilodalton) of 30, 35, 50, 55, 60 and 70. In contrast, in aged rats, Tyr-k activity was increased only marginally (about 20%) during the first 6 hours, but at 24 hours postinjury it was found to be 70% above the control. In aged rats, injury produced no significant stimulation in tyrosine phosphorylation of gastric mucosal membrane proteins.

Conclusions: We conclude that aging is associated with the diminished regenerative capacity of the gastric mucosa. This could partly be attributed to diminished activation of mucosal Tyr-k and decreased tyrosine phosphorylation of certain membrane proteins.