Pharmacological effects of epidermal growth factor (EGF) with focus on the urinary and gastrointestinal tracts.

Abstract

Epidermal growth factor (EGF) belongs to a family of growth factor ligands and receptors. At present, five ligands have been recognized which as EGF exert their effects via binding to the same EGF receptor. The family has three other receptors erbB2, erbB3, and erbB4, which have their own ligands (the heregulins). The system is ubiquitously distributed in mammals, and has important roles in normal development, and in regenerative and neoplastic growth. Mouse and human EGF were discovered in 1962 and 1975 by Stanley Cohen and Harry Gregory, respectively, due to EGFs potent systemic effects. EGF accelerated eyelid opening in newborn mice and inhibited gastric acid secretion in humans. Already in the late thirties, a factor in human urine was recognized which prevented or accelerated healing of experimental damage in the gastrointestinal tract. This factor appeared to be EGF. Around 1980, an effect of commercial interest was described-EGF caused shedding of the fleece in sheep. In line with the original observations, several studies have examined effects of EGF on developmental processes. Amongst other effects, EGF accelerates lung and intestinal maturation before birth and in newborn mammals. Due to the possible use of EGF in the wool industry, it was mandatory to know more about EGF. Amongst other effects in mature sheep and other animals are haemodynamic changes, changes in electrolyte homeostasis, and endocrinological changes. In relation to experimental damage, the therapeutic potential of systemic EGF has been demonstrated in all parts of the gastrointestinal tract, in the kidneys, in the liver and in the trachea. EGF has even been tried in humans in gastric ulcer healing and in necrotising enterocolitis. Studies on prolonged treatment with EGF have first recently appeared. We described effects of 4-5 weeks of treatment in Goettingen minipigs and in rats, and two other groups described effects in monkeys and in rats. In summary, species differences were observed. The species of higher order were most sensitive to treatment with EGF. EGF did not consistently change the total body weight despite EGF consistently reduced circulating levels of insulin-like growth factor I (IGF-I) in Goettingen minipigs as well as in rats. Low circulating levels of IGF-I are usually associated with retarded growth. This review mostly focuses on the organs which appeared to be most sensitive to EGF, the urinary and gastrointestinal tracts including the liver and the pancreas. The histopathological changes consisted mainly of epithelial proliferations in the gastrointestinal, urinary and respiratory tracts. These findings match the knowledge obtained from animals overexpressing the EGF agonist, transforming growth factor alpha (TGF alpha), and the mice with a knock out of the gene encoding for the EGF receptor. EGF receptor hyperstimulation (TGF alpha overexpression) in the context of the whole animal leads to epithelial proliferations whereas hypostimulation (EGF receptor knock out) leads to epithelial immaturities. In the minipigs, the epithelia of the oesophagus, ducts of the pancreas, and the urothelium were hyperplastic, the latter two epithelia with accumulation of glycoconjugates. In the rats, the epithelial hyperplasias in these tissues and in the small and large intestines were without glycoconjugate accumulations. In rats, the mucosal proliferations in the intestines resulted in increased mucosal surface area. Mesenchymal growth effects were also noted. In the ureters of the minipigs, smooth muscle cell hyperplasia and hypertrophia were found. The heart of the minipigs was also enlarged, an interesting finding regarding interactions between the different parts of the EGF system, as knock out mice of the receptors erbB2 and erbB4 die due to maldevelopments in the heart. Measurements in blood and serum also revealed consistent changes. (ABSTRACT TRUNCATED)