Abnormal gastric histology and decreased acid production in cholecystokinin-B/gastrin receptor-deficient mice
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Gastrin attenuates sepsis-induced myocardial dysfunction by down-regulation of TLR4 expression in macrophages
2023, Acta Pharmaceutica Sinica BMyocardial dysfunction is the most serious complication of sepsis. Sepsis-induced myocardial dysfunction (SMD) is often associated with gastrointestinal dysfunction, but its pathophysiological significance remains unclear. The present study found that patients with SMD had higher plasma gastrin concentrations than those without SMD. In mice, knockdown of the gastrin receptor, cholecystokinin B receptor (Cckbr), aggravated lipopolysaccharide (LPS)-induced cardiac dysfunction and increased inflammation in the heart, whereas the intravenous administration of gastrin ameliorated SMD and cardiac injury. Macrophage infiltration plays a significant role in SMD because depletion of macrophages by the intravenous injection of clodronate liposomes, 48 h prior to LPS administration, alleviated LPS-induced cardiac injury in Cckbr-deficient mice. The intravenous injection of bone marrow macrophages (BMMs) overexpressing Cckbr reduced LPS-induced myocardial dysfunction. Furthermore, gastrin treatment inhibited toll-like receptor 4 (TLR4) expression through the peroxisome proliferator-activated receptor α (PPAR-α) signaling pathway in BMMs. Thus, our findings provide insights into the mechanism of the protective role of gastrin/CCKBR in SMD, which could be used to develop new treatment modalities for SMD.
Unique membranous gastrin receptor expression of parietal cells and its distribution pattern in the gastric oxyntic mucosa and fundic gland polyps
2022, Human PathologyThe aim of this study was to clarify the correlation between gastrin receptor (GR) expression in the gastric oxyntic mucosa and fundic gland polyps (FGPs) and the histological and immunohistochemical findings of the mucosa as well as the history of proton pump inhibitor (PPI) administration. The unique membranous linear positivity of GR in parietal cells was reproducibly observed by immunohistochemistry, which was also validated by immunofluorescence. Further histological and immunohistochemical examination of 34 oxyntic mucosae and 43 FGPs revealed the following: 1) parietal cells (PCs) with membranous linear GR expression (mGR) were observed to be limited to the isthmus-neck region in the normal state; 2) appearance of PCs with mGR in the deep oxyntic gland regions was significantly related to the PPI medication history; 3) PCs with mGR were more frequently observed in the deep oxyntic gland regions when the oxyntic mucosa showed derangement of mucosal component cell compartmentalization revealed by MUC5AC and MUC6 immunohistochemistry, which was also significantly related to the PPI use; and 4) PCs with intense membranous linear positivity of GR were observed to be diffusely distributed in all of the cases of FGPs. In conclusion, the distribution of unique GR membranous linear expression in PCs of the oxyntic mucosa under PPI medication and FGPs could reflect the pathologic mucosal state characterized by derangement of the compartmentalization of mucosal component cells, which could be another basis for evaluating physiologic and/or pathophysiologic conditions of the gastric mucosa.
Cholecystokinin attenuates β-cell apoptosis in both mouse and human islets
2022, Translational ResearchLoss of functional pancreatic β-cell mass and increased β-cell apoptosis are fundamental to the pathophysiology of type 1 and type 2 diabetes. Pancreatic islet transplantation has the potential to cure type 1 diabetes but is often ineffective due to the death of the islet graft within the first few years after transplant. Therapeutic strategies to directly target pancreatic β-cell survival are needed to prevent and treat diabetes and to improve islet transplant outcomes. Reducing β-cell apoptosis is also a therapeutic strategy for type 2 diabetes. Cholecystokinin (CCK) is a peptide hormone typically produced in the gut after food intake, with positive effects on obesity and glucose metabolism in mouse models and human subjects. We have previously shown that pancreatic islets also produce CCK. The production of CCK within the islet promotes β-cell survival in rodent models of diabetes and aging. We demonstrate a direct effect of CCK to reduce cytokine-mediated apoptosis in a β-cell line and in isolated mouse islets in a receptor-dependent manner. However, whether CCK can protect human β-cells was previously unknown. Here, we report that CCK can also reduce cytokine-mediated apoptosis in isolated human islets and CCK treatment in vivo decreases β-cell apoptosis in human islets transplanted into the kidney capsule of diabetic NOD/SCID mice. Collectively, these data identify CCK as a novel therapy that can directly promote β-cell survival in human islets and has therapeutic potential to preserve β-cell mass in diabetes and as an adjunct therapy after transplant.
Life with the pancreas: A personal experience
2020, Advances in Medical SciencesThis review article has primary objective to summarize pancreatic research which has been done in our laboratory since 1965, the first year of the author's registration in the Ph.D. program at the University of Sherbrooke (Canada). It covers the following major topics of pancreatic physiology: controls of pancreatic adaptation to diet, control of pancreatic enzyme secretion, control of pancreatic enzyme synthesis, control of pancreatic growth, intracellular events stimulated during pancreatic growth, pancreas regeneration after pancreatitis and pancreatectomy, the pancreatic cholecystokinin receptor types 1 and 2, growth control and cell signaling in pancreatic cancer cells and finally, cystic fibrosis.
Hypergastrinemia Expands Gastric ECL Cells Through CCK2R<sup>+</sup> Progenitor Cells via ERK Activation
2020, Cellular and Molecular Gastroenterology and HepatologyEnterochromaffin-like (ECL) cells in the stomach express gastrin/cholecystokinin 2 receptor CCK2R and are known to expand under hypergastrinemia, but whether this results from expansion of existing ECL cells or increased production from progenitors has not been clarified.
We used mice with green fluorescent protein fluorescent reporter expression in ECL cells (histidine decarboxylase [Hdc]-green fluorescent protein), as well as Cck2r- and Hdc-driven Tamoxifen inducible recombinase Cre (Cck2r-CreERT2, Hdc-CreERT2) mice combined with Rosa26Sor-tdTomato (R26-tdTomato) mice, and studied their expression and cell fate in the gastric corpus by using models of hypergastrinemia (gastrin infusion, omeprazole treatment).
Hdc-GFP marked the majority of ECL cells, located in the lower third of the gastric glands. Hypergastrinemia led to expansion of ECL cells that was not restricted to the gland base, and promoted cellular proliferation (Ki67) in the gastric isthmus but not in basal ECL cells. Cck2r-CreERT2 mice marked most ECL cells, as well as scattered cell types located higher up in the glands, whose number was increased during hypergastrinemia. Cck2r-CreERT2+ isthmus progenitors, but not Hdc+ mature ECL cells, were the source of ECL cell hyperplasia during hypergastrinemia and could grow as 3-dimensional spheroids in vitro. Moreover, gastrin treatment in vitro promoted sphere formation from sorted Cck2r+Hdc- cells, and increased chromogranin A and phosphorylated- extracellular signal-regulated kinase expression in CCK2R-derived organoids. Gastrin activates extracellular signal-regulated kinase pathways in vivo and in vitro, and treatment with the Mitogen-activated protein kinase kinase 1 inhibitor U0126 blocked hypergastrinemia-mediated changes, including CCK2R-derived ECL cell hyperplasia in vivo as well as sphere formation and chromogranin A expression in vitro.
We show here that hypergastrinemia induces ECL cell hyperplasia that is derived primarily from CCK2R+ progenitors in the corpus. Gastrin-dependent function of CCK2R+ progenitors is regulated by the extracellular signal-regulated kinase pathway.
The application of transgenic and gene knockout mice in the study of gastric precancerous lesions
2018, Pathology Research and PracticeGastric intestinal metaplasia is a precursor for gastric dysplasia, which is in turn, a risk factor for gastric adenocarcinoma. Gastric metaplasia and dysplasia are known as gastric precancerous lesions (GPLs), which are essential stages in the progression from normal gastric mucosa to gastric cancer (GC) or gastric adenocarcinoma. Genetically-engineered mice have become essential tools in various aspects of GC research, including mechanistic studies and drug discovery. Studies in mouse models have contributed significantly to our understanding of the pathogenesis and molecular mechanisms underlying GPLs and GC. With the development and improvement of gene transfer technology, investigators have created a variety of transgenic and gene knockout mouse models for GPLs, such as H/K-ATPase transgenic and knockout mutant mice and gastrin gene knockout mice. Combined with Helicobacter infection, and treatment with chemical carcinogens, these mice develop GPLs or GC and thus provide models for studying the molecular biology of GC, which may lead to the discovery and development of novel drugs. In this review, we discuss recent progress in the use of genetically-engineered mouse models for GPL research, with particular emphasis on the importance of examining the gastric mucosa at the histological level to investigate morphological changes of GPL and GC and associated protein and gene expression.