Calcitonin and the C cells: role models for the neuroendocrine system.
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Biomedical subjects
Publications and source records attributed to A G Pearse.
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The distribution of peptide hormone-like immunostaining in the gastrointestinal tract of 11 teleost species was investigated by immunofluorescence. Cells immunoreactive for somatostatin were found in the glandular epithelium of the stomach of four species and in the epithelium of the pyloric appendage of one species. The mid-gut epithelium contained cells reactive with antibodies to glucagon (three species), gastrin (five species), pancreatic polypeptide (five species), and substance P (two species). Cells immunoreactive for met-enkephalin were found in the epithelium of both the mid-gut and the stomach of six species. In six species in which the endocrine pancreas was investigated, insulin-, glucagon-, and somatostatin-like immunoreactivity was observed. Pancreatic polypeptide was definitely localised by immunostaining in cells of the endocrine pancreas of only one out of three species examined. Vasocative intestinal polypeptide-, neurotensin-, bombesin-, and enkephalin-like immunoreactivity was identified in the gastrointestinal nerve fibres in various species. In view of the considerable species variation found, caution should be exercised in generalising about the peptides present in the gastrointestinal tract of fish.
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The distribution of a bombesin-like immunoreactive peptide in the avian gastro-intestinal tract was analysed by combined radioimmunoassay and immunocytochemistry. Radioimmunoassay of tissue extracts showed that the largest quantities of bombesin-like immunoreactivity were present in the proventriculus (64.5 +/- 6.0 pmol/g) with smaller but still considerable amounts in the gizzard (40.0 +/- 6.0 pmol/g). Immunocytochemically the extractable bombesin-like immunoreactivity was localised in numerous endocrine cells. These, in the proventriculus, were found mainly in the deeper layers of the mucosa. Further study of these cells by the semi-thin/thin technique revealed the presence of characteristic secretory granules. The functional name BN is proposed for this cell type.
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Indirect immunofluorescence studies using antisera to synthetic somatostatin, human calcitonin and substance P indicate, in the neural complex of the sea-squirt, Ciona intestinalis L., that these polypeptides are present in large perikarya situated at the periphery of the cerebral ganglion as well as in some smaller perikarya in the medulla. In the medullary and transitional zone, there are nerve fibres that cross-react positively with anti-calcitonin and anti-substance P.
We have been able to demonstrate 5-hydroxytryptamine in the enterochromaffin cells of the mammalian gastrointestinal tract, using a highly specific antiserum. Conventional histochemical techniques for identifying amines as cell markers can thus be replaced by more reliable and sensitive immunocytochemical methods. This has been facilitated by the use of p-benzoquinone as fixative which has been shown to preserve the localization and antigenicity of amines, as well as peptides.
The diffuse neuroendocrine system is constituted by the cells, now more than 40 in number, of the central and peripheral divisions of the amine precursor uptake and decarboxylation (APUD) series. At one time presumed to be derived from a common "neural" ancestor, all are now deemed to be "neuroendocrine-programmed," arising either in the embryonic epiblast itself or in one of its principal descendants. The APUD cells produce more than 35 physiologically active peptides and a small number of equally active amines. Within the last 3 years, 17 of these peptides have been identified jointly in endocrine cells and in neuronal cell bodies or processes. Sharing in this way a neural and an endocrine location and site of production, they are called the "common peptides." The diffuse neuroendocrine system is to be regarded as a third division of the nervous system, whose products suppress, amplify, or modulate the activities of the other two divisions. The relationship of its products to the cells and processes of these two divisions is currently the object of intensive inquiry.
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Application of the semithin-thin section technique indicates that the previously proposed identification of the ultrastructurally-defined K cell with the immunocytochemically-defined GIP cell is essentially correct. The K cell is established as a distinct entity and the way is open for an explanation of its role in the physiology and pathology of the gastroenteropancreatic system.
Somatostatin- and gastrin-like immunoreactivity has been found by immunofluorescence in cells of the stomach and intestinal epithelia of Ciona intestinalis L. The cells containing the peptide immunoreactive to mammalian anti-gastrin can be restained with Grimelius' technique for argyrophilia.
Evidence was obtained by the use of alternate semithin-thin serial secretions for light and electron microsocpy that the I cell is the source of CCK PZ. The antibodies used were raised to a synthetic fragment of the mid part (9-20) of the (1-33) CCK-PZ molecule, and were thus free from any contamination with cross-reacting subpopulations of antibodies that might bind to gastrin.
Urogastrone has been localised by immunostaining to granules of the cells of human duodenal (Brunner's) glands and their ducts and of acinar cells in the human submandibular gland. The immunoreactive peptide is present in large quantities in duodenal glands and their secretory ducts. Urogastrone or human epidermal growth factor promotes cellular proliferation in vivo as well as in vitro and inhibits gastric acid secretion and may, therefore, be one of the duodenal factors inhibiting gastric activity. Thus it may have an important regulatory and protective function for the intestinal mucosa and may possibly become a useful therapeutic agent.
Estimates of the G cell population were made in 24 resected human pyloric antra from counts of cells in multiple samples and from measurements of antral size. Measurements had been made previously in 20 subjects of acid output (basal and after pentagastrin) and in 10 subjects of plasma gastrin (basal and after insulin + bicarbonate). G cells were most dense near the pylorus, but their circumferential distribution was even. The G cell populations ranged from 8 to 15 (mean 10) million in four control patients and from 3 to 43 (mean 18) million in 15 patients with duodenal ulcer. Those with recurrent ulcer after vagotomy had either a low G cell count and incomplete vagotomy, or a high G cell count and apparently complete denervation. Two patients with hypergastrinaemia and duodenal ulcer had moderate (29 X 10(6)) or marked (56 X 10(6)) excesses of G cells. 'G cell hyperplasia' may represent the extreme end of the normal range of G cell numbers in the antrum, and can be assessed by semi-quantitative grading of G cell hyperplasia in antral biopsies. There were significant direct correlations between antral area and G cell density, between peak acid output and G cell population, and between basal plasma gastrin and G cell density (but not population). We suggest that, in patients with duodenal ulcer, acid and gastrin secretion are interrelated and that both are related to the masses of parietal cells and of G cells.
Two types of enterochromaffin cells can be demonstrated in the human duodenal mucosa by means of the Masson-Fontana reaction for argentaffinity applied to ultrathin sections. The 22-amino acid peptide motilin has now been localized exclusively to the duodenal type of enterochromaffin cell by immunoelectron microscopy. This cell occurs predominantly in the duodenum and upper jejunum. It is concluded that at least two types of enterochromaffin cells exist in the human gut mucosa and that they produce at least one biogenic amine as well as two peptides. Therefore they could provide a useful model for studies of the interrelationship of storage and release of amines and peptides.
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