Aquaporins in Glandular Secretion.

Exocrine and endocrine glands deliver their secretory product, respectively, at the surface of the target organs or within the bloodstream. The release of their products has been shown to rely on secretory mechanisms often involving aquaporins (AQPs). This chapter will provide insight into the role of AQPs in secretory glands located within the gastrointestinal tract, including salivary glands, gastric glands, duodenal Brunner's glands, liver, gallbladder, intestinal goblets cells, and pancreas, as well and in other parts of the body, including airway submucosal glands, lacrimal glands, mammary glands, and eccrine sweat glands. The involvement of AQPs in both physiological and pathophysiological conditions will also be highlighted.

Subcellular redistribution of AQP5 by vasoactive intestinal polypeptide in the Brunner's gland of the rat duodenum.

Aquaporin (AQP)5, an exocrine-type water channel, was detected in the rat duodenum by Western blot analysis, and was localized by immunohistochemistry in the secretory granule membranes as well as in the apical and lateral aspects of the plasma membrane of Brunner's gland cells. Incubation of duodenal slices with vasoactive intestinal polypeptide (VIP) in vitro significantly increased the amount of AQP5 in the apical membrane fraction in a dose- and time-dependent manner with the amount reaching a plateau at 100 nM VIP and becoming near maximal after a 30-s incubation. Protein kinase inhibitors, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7, 50 muM), and N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89; PKA-specific, 1 muM) blocked this increase, but PKC-specific inhibitor calphostin C did not, implying the involvement of PKA but not PKC in this cellular event. Intravenous injection with VIP (40 mug/kg body wt) provoked dilation of the lumen of the Brunner's gland at 2 and 7 min and increased the staining intensity of AQP5 in the apical and lateral membranes. AQP1 (both nonglycosylated and glycosylated forms) was also found to localize in the apical and basolateral membranes of cells of Brunner's gland. VIP, however, did not provoke any significant change in the AQP1 level in the apical membrane, as judged from the results of the above in vitro and in vivo experiments. These results suggest that VIP induced the exocytosis of granule contents and simultaneously caused translocation of AQP5 but not of AQP1 to the apical membrane in Brunner's gland cells.

Tumor de las glándulas de Brunner / Brunner's gland tumor

Las glándulas de Brunner son estructuras túbulo-acinares ubicadas en la submucosa del duodeno. Secretan factores de crecimiento epidérmicos y un fluido alcalino que protege el epitelio duodenal de los jugos gástricos. Su crecimiento excesivo normalmente no da síntomas o éstos son mínimos, sin embargo, en ocasiones puede llegar a ser causa de hemorragia digestiva e incluso de obstrucción intestinal. El diagnóstico de esta patología es por lo general un hallazgo durante procedimientos endoscópicos , aunque la imagenología puede ser de gran ayuda. Pese a que no se han reportado casos de transformación maligna, la literatura describe que su tratamiento puede ser la observación en casos de lesiones pequeñas que no producen síntomas y en quienes la biopsia es categórica del diagnóstico. Dichas lesiones pueden ser tributarias de tratamiento endoscópico, reservando la cirugía clásica para tumores muy grandes, en casos de duda diagnóstica, cuando existen complicaciones o por fracaso de la técnica endoscópica. El resultado de las intervenciones es generalmente excelente sin existir hasta el momento estudios que señalen una recurrencia de las lesiones.

Brunner's glands: a structural, histochemical and pathological profile.

Brunner's glands are unique to mammalian species and in eutherians are confined primarily to the submucosa of the proximal duodenum. In the majority of species examined, they begin at the gastrointestinal junction and extend for variable distances distally in the wall of the proximal small intestine. Ducts of individual glands empty either directly into the intestinal lumen or unite with overlying intestinal glands (crypts of Lieberkühn) dependent on the species. Secretory units of Brunner's glands consist of epithelial tubules that show frequent distal branchings. The secretory units, with the exception of those found in rabbits and horses, consist primarily of a mucin producing cell type. However, other cell types normally associated with the overlying intestinal epithelium may be encountered scattered within the secretory units reflecting the developmental origin of these glands. Secretion from Brunner's glands contributes to a layer of mucus that forms a slippery, viscoelastic gel that lubricates the mucosal lining of the proximal intestinal tract. The unique capacity of this mucus layer to protect delicate underlying epithelial surfaces is due primarily to the gel-forming properties of its glycoprotein molecules. Mucin glycoproteins produced by Brunner's glands consist primarily but not exclusively of O-linked oligosaccharides attached to the central protein core of the glycoprotein molecule. Human Brunner's glands produce class III mucin glycoproteins and are thought to be the product of mucin gene MUC6 which is assigned to chromosome 11 (11p15-11p15.5 chromosome region). In addition to mucin glycoproteins and a limited amount of bicarbonate, numerous additional factors (epidermal growth factor, trefoil peptides, bactericidal factors, proteinase inhibitors, and surface-active lipids) have been identified within the secretory product of Brunner's glands. These factors, incorporated into the mucus layer, guard against the degradation of this protective barrier and underlying mucosa by gastric acid, pancreatic enzymes, and other surface active agents associated with this region. Yet other factors produced by Brunner's glands function to provide active and passive immunological defense mechanisms, promote cellular proliferation and differentiation, as well as contribute factors that elevate the pH of luminal contents of this region by promoting secretion of the intestinal mucosa, pancreatic secretion and gall bladder contraction. Additional insights concerning the role of Brunner's glands in the mammalian gastrointestinal tract as well as their possible evolution in this class of vertebrates have been gained from a basic understanding of their pathobiology.

Higher proximal duodenal mucosal bicarbonate secretion is independent of Brunner's glands in rats and rabbits.

BACKGROUND & AIMS: Duodenal bicarbonate secretion is impaired in patients with duodenal ulcer. Before characterization of any cellular transport defect is possible, the origin of duodenal bicarbonate (epithelial cells and/or Brunner's glands) must be determined. The aim of this study was to determine the role of Brunner's glands in duodenal bicarbonate secretion. METHODS: Rats, which have Brunner's glands only in the proximal duodenum, and rabbits, which have Brunner's glands throughout the duodenum, were anesthetized. Basal and stimulated (with HCl, prostaglandin E2, and vasoactive intestinal polypeptide [VIP]) bicarbonate secretion was measured in three isolated intestinal segments: proximal duodenum, distal duodenum, and proximal jejunum. Mucosal surface area and Brunner's gland thickness was quantitated in each segment. RESULTS: Secretion rates in proximal and distal duodenum and proximal jejunum were significantly different. Normalized proximal-to-distal duodenal gradients in bicarbonate secretion were similar in the two species despite significantly different gradients of Brunner's gland thickness. In rabbits, gradients of bicarbonate secretion and Brunner's gland thickness were not correlated. In both species, HCl, prostaglandin E2, and VIP stimulated secretion in all three segments. If the agonists specifically stimulated Brunner's gland bicarbonate secretion, relationships between gradients of bicarbonate secretion and Brunner's gland thickness would have been anticipated. This was not observed. CONCLUSIONS: The higher rates of bicarbonate secretion in the proximal duodenum than in the distal duodenum and proximal jejunum are independent of Brunner's glands.

[Effects of surgical removal of the Brunner's region of the duodenum on nutrient digestibility in rats]. / Vliianie khirugicheskogo udaleniia brunnerovskogo otdela dvenadtsatiperstnoi kishki na usvoiaemost' pishchevykh veshchestv u krys.

In 1.5 months after surgical ablation of duodenum of Brunner's region the digestibility of proteins, carbohydrates, lipids and minerals was investigated in Wistar male rats. Estimation was based on the measurement of consumed and excreted nutrients. The rats with a bypass gastroduodenal anastomosis and sham-operated animals were used as a control. It was ascertained that Brunner's region of ablated rats showed a reduced proteins digestibility. Possible reasons for change established are being discussed. Participation of duodenal glands in digestion is suggested.

The role of Brunner's glands in the mucosal protection of the proximal part of duodenum.

In the course of a prospective study authors examined the role of the hyperplasia of Brunner's glands in the mucosal protection of proximal part of duodenum in patients with peptic ulcer, chronic pancreatitis and chronic renal insufficiency. Their method for this study was the histological examination of the endoscopic biopsy specimens. The hyperplasia of Brunner's glands occurs with significant frequency in all the three examined groups of patients, while we found it less frequently in the controls. Hyperplasia of Brunner's glands is one of the protective mechanisms of the organism, which serves the protection of the duodenal mucosa between the pyloric ring and the papilla of Vater, against the damaging effect of the hydrochloric acid.

Biological effects of epidermal growth factor, with emphasis on the gastrointestinal tract and liver: an update.

Epidermal growth factor (EGF) is a 6,000 Da polypeptide hormone produced by glands of the gastrointestinal tract, namely the salivary and Brunner's glands. It is found in a wide variety of external secretions as well as in blood and amniotic fluid. In fetal and neonatal life, EGF appears to play an important role in the development of the oral cavity, lungs, gastrointestinal tract and eyelids. Its presence in cells of the central nervous system suggests that it also plays a role in modulating the development of this system. In adult animals, the function of EGF is much less well understood. In rodents, it apparently modulates acid secretion from parietal cells in the stomach, and it undoubtedly plays an important role in wound healing, either through its localization within skin or by the licking of wounds with EGF-containing saliva. Considerable evidence now suggests that it may be one of the key factors in initiating liver regeneration after partial hepatectomy or chemical injury. The liver appears to be the principal organ which regulates the circulating level of EGF. In fact, EGF is cleared so efficiently by the liver that only the peripheral cells of the lobule (zone 1) sequester EGF, and little remains in the circulation for cells in the more distal zones (zones 2 and 3). In the liver, EGF normally binds to a plasma membrane receptor and is internalized within the liver cell, where the vast majority of EGF and its receptor are destroyed in lysosomes. A small but consistent quantity of EGF enters the bile intact. In the regenerating liver, however, the lysosomal pathway appears to be shut down, and the EGF is diverted to hepatocyte nuclei prior to the initiation of DNA synthesis. Nuclear EGF is found free as well as bound to a high-molecular-weight protein which has many characteristics identical to the plasma membrane EGF receptor. The plasma membrane receptor is a large transmembrane glycoprotein of 170,000 Da containing four domains: an extracellular EGF-binding portion, a hydrophobic membrane-spanning segment, a proximal cytoplasmic domain which binds ATP and protein substrates containing tyrosine for phosphorylation and a terminal cytoplasmic portion with 3 tyrosines which undergo autophosphorylation after EGF binding.(ABSTRACT TRUNCATED AT 400 WORDS)

Autoradiographic study on healing process of cysteamine-induced duodenal ulcer in rat. Possible importance of Brunner's glands in ulcer healing.

The healing process of cysteamine-induced duodenal ulcer was studied by [3H]thymidine autoradiography. After the development of ulcer in the duodenum, cell proliferation was markedly activated not only in the crypts but also in the Brunner's glands near the ulcer. In the initial stages of ulcer healing, they both contributed to form the surface covering regenerating epithelium. Granulation tissue also proliferated at the base of the ulcer. In later stages of ulcer healing, new crypts were formed in the floor of the ulcer. New villi regenerated from these crypts and Brunner's glands regenerated by proliferation in situ. The ulcer base then was completely covered with new villi and granulation tissue was replaced by dense fibrous connective tissue. The present study suggested that the Brunner's glands, together with the crypts of Lieberkühn, play an important role in the healing process of cysteamine-induced duodenal ulcer.

The effect of surgical ablation of Brunner's glands on the proximal duodenal mucosa.

Neither macroscopic nor microscopic lesions were observed in the gastrointestinal mucosa following the surgical removal of Brunner's glands. This observation leaves some doubt concerning the traditional view that Brunner's glands function primarily in the protection of the proximal duodenal mucosa from acid-pepsin entering from the stomach.

Gastroduodenal defence mechanisms.

In the healthy stomach and duodenum aggressive factors such as luminal acid and pepsin are balanced by defence and repair processes. In recent years components of the mucosal defences which have been identified include the layer of mucus gel adherent to the surface of these mucosae, surface epithelial alkali secretion, mucosal blood flow and the supply of bicarbonate to the surface epithelium as well as the processes involved in rapid mucosal repair. Secretion of alkali maintains the pH within the mucus gel on the epithelial cell surface at neutrality, in spite of luminal pHs as low as 1.5 to 2.0. Alkali secretion is stimulated up to ten-fold by luminal acid. This response is mediated by endogenous production of prostaglandins, humoral factors and, possibly, by nervous mechanisms. Impairment of the response results in mucosal ulceration. The mucus layer (approximately 200 micron deep in man) provides an unstirred zone at the mucosal surface in which diffusing is delayed, allowing time for secreted HCO-3 to neutralize acid diffusing toward the mucosa. In addition mucus is impermeable to pepsin. During secretion of H+ ions, HCO-3 is produced, and secreted by the surface epithelium. Stimulation of acid secretion increases the ability of gastric mucosa to resist acid and pepsin, presumably by providing more HCO-3. Parenteral HCO-3 (but not other buffer species) provides similar protection to both the gastric and duodenal mucosae. The remarkably rapid reconstitution of the surface epithelium, within 30 minutes after acute superficial damage, is clearly an important 'defence' mechanism. Studies of the control of these defence and repair mechanisms should provide a greater understanding of common gastroduodenal diseases.