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Gastric Digestive Function Gastrointestinal Functions, edited by Edgard E. Delvin and Michael J. Lentze. Nestle Nutrition Workshop Series. Pediatric Program, Vol. 46. Nestec Ltd.. Vevey/Lippincott Williams & Wilkins. Philadelphia © 2001. Gastric Digestive Function Daniel Menard and Jean-Rene Basque Department of Anatomy and Cell Biology, Faculty of Medicine, University of Sherbrooke, Quebec, Canada The gastric epithelium not only has a protective barrier function (against hydro- chloric acid, peptidases, Helicobacter pylori, and so on) and a primary role in epithe- lial restitution (ulcer healing), but it also has specific digestive functions. The gastric mucosa is responsible for the secretion of luminal compounds such as mucus, hydro- chloric acid, pepsinogen, and lipase. One of the main purposes of gastric secretion is the digestion of dietary proteins. This involves the release of different pepsinogens (Pgl-5) by the fundic and antral gastric glands (1). These inactive proenzymes are synthesized and packaged into secretory granules of surface or glandular epithelial cells. Under acidic conditions, these secreted proenzymes are autocatalytically cleaved to generate their active form—pepsins (pepsin, prochymosin, progastricsin)—which are representative members of a group of proteolytic enzymes classified as aspartic proteases (2). In humans, pepsinogen 5 (Pg5), which is specifically synthesized and secreted by zymogenic chief cells, plays a primary role in the initiation of protein digestion and the proteolysis of collagen (the protein component of meat). Although pepsinogen has been a subject of research since the 19th century (3), knowledge acquired over the last decade on the functions of the human stomach has expanded to include a significant role in fat digestion (4). In contrast to pepsin, the presence of a true gastric lipase has been the subject of a long controversy (4). In 1988, it was clearly established in humans that no lingual lipase exists, but instead a true lipase of gastric origin (5). This human gastric lipase (HGL) consists of a 379-amino acid polypeptide with a molecular weight of 49 kd. The characteristics of HGL (e.g., optimal acid pH) resistance to the acidic environment and to gastric protease action, and the ability to function in the absence of bile salts or cofactors, are advantageous in gastric lypolysis (6,7). Accumulating evidence supports that gastric digestion of triglycerides in normal physiologic situations is a prerequisite for efficient intestinal lipolysis, as free fatty acids and monoglycerides resulting from gastric lipolysis enhance subsequent hydrolysis of triglycerides by pancreatic lipase (8-10). Furthermore, the importance of gastric lipolysis increases in the con- text of perinatal physiology and pathologic conditions where secretion of gastric 147 148 GASTRIC DIGESTIVE FUNCTION lipase could compensate, to some extent, for the depressed pancreatic activity. As HGL may have a special compensatory function in premature and newborn infants, it is important, therefore, to establish its ontogenesis and cellular localization and to understand the regulatory mechanisms controlling its synthesis and secretion. MORPHOGENESIS OF HUMAN GASTRIC MUCOSA The development of human gastric glands takes place very early during life (10-12 weeks of gestation) as opposed to rodent gastric glands, which mature strikingly during the last few days of gestation (11,12). At 8 to 10 weeks of gestation, human gastric epithelium is stratified and accumulation of glycogen occurs in the undifferen- tiated cells of the stratified epithelium (Fig. 1). At 11 to 12 weeks, the glandular pits are formed and the first differentiated epithelial cells, the parietal cells, appear. These cells are mainly located at the base of the developing glands and are already immunoreactive to intrinsic factor (13). From 11 weeks onward, the surface epithelial cells differentiate into mucous columnar cells, and the gastric glands develop further with the appearance of endocrine cells, mucous neck cells, and chief cells. Although the gastric glands will continue to grow during gestation, the thickness of the mucosa, as well as of the entire stomach wall in the newborn infant, is much less than in adults. Therefore, by 15 to 17 weeks of gestation, the fetal gastric glands are representative of the adult gastric glands and show all the morphologic compartments (foveolus, isthmus, neck, and base) in which cell lineages with different phenotypes exist. i' B FIG. 1. Development of human gastric mucosa. (A) At 10 to 12 weeks of gestation, accumula- tion of glycogen is seen in undifferentiated cells of the stratified epithelium. Glandular buds begin to form (arrows) (x 160). (B) At 17 to 20 weeks, as gastric glands develop, the surface columnar epithelium displays basal nuclei and accumulation of mucus in the apical cytoplasm. Parietal cells can be seen at the base region of gastric glands (arrows) (x 100). GASTRIC DIGESTIVE FUNCTION 149 The proliferation pool responsible for the continuous renewal of all gastric epithe- lial cells is localized in the isthmus region. The epithelial cells leaving the prolifera- tive zone differentiate into mucous cells during their upward migration (foveolus and surface epithelium) and into mucous, endocrine, parietal, and chief cells during downward migration (neck and glandular epithelium). During gestation, the gastric stratified epithelium, which contains scattered proliferating cells, visualized by 3H- thymidine incorporation, is converted into an epithelium containing localized pro- genitor zones that resemble the patterns in adult gastric mucosa (11). The initial proliferation zone observed between 8 and 12 weeks is situated predominantly in the lower half of the early or pit glands. As the mucosa matures, the zone moves upward, establishing an adult location in the isthmus and neck of the glands. Thus, in the human gastric mucosa, the morphologic and proliferative compartments are already determined by 15 to 17 weeks of gestation. ONTOGENESIS OF DIGESTIVE FUNCTIONS Figure 2 illustrates the developmental profiles of HGL and Pg5 activities between 10 and 20 weeks of gestation, as well as the regional distribution of hydrolytic activities over the stomach. HGL activity is already present at low levels between 10 and 13 weeks of gestation and steadily increases up to 20 weeks (14). Pg5 activity is also present at 14 to 15 weeks, but does not significantly vary during the period studied. HGL activity is not evenly distributed throughout the stomach, being highest in the fundic area. Of note, HGL activity recorded in the fetal fundus at 20 weeks represents 30% of the mean lipase activity measured in the upper greater curvature in adult biopsy specimens (10). A clear, decreasing gradient is evident from the upper greater and lesser curvatures to the lower and lesser curvatures. As opposed to HGL, Pg5 activity does not show any particular distribution over the gastric regions, although a steady increase is observed in the antrum between 16 and 20 weeks of gestation (14). These data show that the adult regional distribution of HGL activity is already in place at 15 to 16 weeks' gestation, whereas that of Pg5 is not yet established. It is obvious that the adult distribution of Pg5 over the gastric regions will occur later during development and that the adult levels of hydrolytic activities will also be in place later on. Lee et al. (9) documented the developmental profile of preduodenal lipase activity in gastric aspirates from 350 premature infants who were at various gestational ages. They reported that lipolytic activity was lower in the younger infants (^26 weeks), increased to a peak at 30 to 32 weeks, and then declined to a lower level at term (>40 weeks). Specific HGL activity determined in gastric biopsies is high in infants and children, and no significant changes occur in the age range of 3 months to 26 years (15). However, HGL activity does decrease in people aged more than 60 years. Whether this develop- mental profile reflects variations of the secretory capacity of the gastric mucosa or variations in the synthesis of HGL remains to be established. 150 GASTRIC DIGESTIVE FUNCTION 40- -•- HGL -4 H»-PgS | 30- -3 i J / 2 mgp Q. j - 1 a 0- 10 12 14 16 18 20 Weeks of gestation B 120—1 —8 '« 90— —6 o .3 60— — 4 en 1 E 1 1 30- —2 HGL FIG. 2. Ontogeny (A) and tissue distribution (B) of human gastric digestive enzymes. (A) Human gastric lipase (HGL) and pepsin (Pg5) activities in gastric specimens between 10 and 20 weeks of gestation. (B) HGL and pepsin (Pg5) activities in the stomach of 20-week-old speci- mens. I, fundus; • upper greater curvature; • upper lesser curvature; ^, lower greater curvature; ^, lower lesser curvature; ^, antrum. (Adapted from Menard D, Monfils S, Tremblay E. Ontogeny of human gastric lipase and pepsin activities. Gastroenterology 1995; 108:1650-6.) GASTRIC DIGESTIVE FUNCTION 151 CELLULAR LOCALIZATION Pepsinogen is synthesized and secreted by the chief cells located at the base of gastric glands of all mammals including humans. On the other hand, gastric lipase shows differential distribution among species. Indeed, gastric lipase is absent in the rat, with all lipolytic activity reported in gastric lumen being mediated by the pres- ence of a lipase of lingual origin (4). In dog and cat models, the gastric lipase is associated with mucous-type cells of the pit compartment, whereas pepsinogen is present in chief cells located at the bottom of the fundic glands (6,16). In rabbit gastric biopsies, pepsinogen and lipase are located in a distinct zymogenic cell population in the cardiac area (17). In human gastric mucosa, HGL and Pg5 are always colocalized in chief cells of the fundic glands and never in mucous-type cells or in cells in the upper part of the gastric glands (18). These data illustrate a unique feature for the human adult gastric mucosa regarding the cellular distribution of Pg5 and HGL. The colocalization of both digestive en- zymes in human chief cells is already achieved as soon as these cells differentiate during the morphogenesis of the gastric mucosa.
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