Role of insulin-like growth factor-I in esophageal mucosal healing processes.
The current study examines the stimulation of healing processes and signal transduction that is mediated by insulin-like growth factor-I (IGF-I) in an ex vivo esophageal explant model when using tyrphostin inhibition of receptor tyrosine kinase. The explant model provides a 3-dimensional cellular environment of multiple interacting cells isolated from the neural and vascular supply. Tyrphostins previously characterized for their interactions with epithelial growth factor (EGF) receptor-associated protein tyrosine kinases were tested for their potential effects on IGF-I growth-promoting activity. Explants of rabbit esophagus were incubated in media with or without IGF-I. Tyrphostins 1, 23, 25, 46, 47, 51, and 63 were added. We assessed DNA synthesis by tritiated thymidine incorporation. Outgrowth from the edge of the primary mucosa of the explant was evaluated on histologic sections, and cell proliferation was confirmed with immunohistology. IGF-I increased the incorporation of tritiated thymidine by 50% to 100%. Tyrphostins 23 and 47 eliminated IGF-I-induced proliferation in a dose-dependent manner. Tyrphostins 25, 46, and 51--along with negative controls tyrphostin 1 and tyrphostin 63--were ineffective, inasmuch as IGF-I-stimulated growth remained unchanged in their presence. Proliferative activity demonstrated by PCNA staining was confined to new mucosa. Two of 5 tyrphostins originally developed as EGF receptor protein tyrosine kinase inhibitors were effective in inhibiting the actions of exogenous IGF-I. We conclude that IGF-I stimulation may play an important role in repair processes in the esophagus and that this stimulation can be inhibited by using specific tyrphostins.
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
M T
MT
Tchorzewski
F G
FG
Qureshi
M D
MD
Duncan
K L
KL
Duncan
N
N
Saini
J W
JW
Harmon
D000818:Animals; D002396:Catechols / Q000494:pharmacology; D002455:Cell Division; D046508:Culture Techniques; D004247:DNA / Q000096:biosynthesis; D004935:Esophageal Diseases / Q000473:pathology*; D004947:Esophagus / Q000737:chemistry / Q000473:pathology*; D006131:Growth Inhibitors / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology* / Q000502:physiology; D008297:Male; D009092:Mucous Membrane / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011817:Rabbits; D012038:Regeneration; D015398:Signal Transduction; D020032:Tyrphostins
D002396:Catechols; D006131:Growth Inhibitors; D009570:Nitriles; D018809:Proliferating Cell Nuclear Antigen; D020032:Tyrphostins; C060152:tyrphostin 47; D007334:Insulin-Like Growth Factor I; D004247:DNA; C060641:tyrphostin A23