Inhibition of gastric mucosal regeneration by tyrphostin: evaluation of the role of epidermal growth factor receptor tyrosine kinase.
Although induction of mucosal cell proliferation is a crucial event in gastric mucosal regeneration after injury, intracellular regulatory processes have not been fully elucidated. We hypothesize that tyrosine kinases (Tyr-k)--specifically the enzyme associated with epidermal growth factor receptor (EGF-R)--play an important role in mucosal regeneration. Utilizing tyrphostin--a Tyr-k inhibitor with a greater specificity for EGF-R Tyr-k than for other Tyr-ks--we have examined the role of EGF-R Tyr-k in gastric mucosal regeneration after injury. Gastric mucosal injury in 3-to 4-month-old rats was induced by orogastric administration of 2 mol/L NaCl, whereas the control animals received an equivalent volume of water. The animals were killed 24 hours later. During this 24-hour experimental period (reparative phase), one of the groups was also injected (IP) with tyrphostin-51 (0.65 mg/kg in 30% dimethyl sulfoxide), whereas the control group received the vehicle. In the absence of tyrphostin, the gastric mucosa showed signs of extensive regeneration, whereas in its presence the degree of regeneration was greatly attenuated. These changes were accompanied by parallel alterations in the number of proliferating cell nuclear antigen-immunoreactive cells and the Tyr-k activity of EGF-R. In water-fed control animals, tyrphostin also caused a significant 30% reduction in proliferating cell nuclear antigen-immunoreactive cells. In these animals, the Tyr-k activity of EGF-R was also decreased by 30%. At 24 hours after injury, EGF-R mRNA levels were increased 36-fold over the water-fed controls, and this increase was not significantly affected by tyrphostin. Our current data suggest that activation of EGF-R is an important event in mucosal regeneration.
Majumdar
A P
AP
VA Medical Center, Detroit, MI 48201, USA.
Fligiel
S E
SE
Jaszewski
R
R
Tureaud
J
J
Dutta
S
S
Chelluderai
B
B
D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D008297:Male; D009092:Mucous Membrane / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines; D051381:Rats; D011916:Rats, Inbred F344; D012038:Regeneration / Q000187:drug effects*; D013270:Stomach / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D020032:Tyrphostins
D001597:Benzylidene Compounds; D009570:Nitriles; D018809:Proliferating Cell Nuclear Antigen; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D004815:Epidermal Growth Factor; D011505:Protein-Tyrosine Kinases