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Gastroenterology Feb 2022The mucosa of the body of the stomach (ie, the gastric corpus) uses 2 overlapping, depth-dependent mechanisms to respond to injury. Superficial injury heals via surface... (Review)
Review
The mucosa of the body of the stomach (ie, the gastric corpus) uses 2 overlapping, depth-dependent mechanisms to respond to injury. Superficial injury heals via surface cells with histopathologic changes like foveolar hyperplasia. Deeper, usually chronic, injury/inflammation, most frequently induced by the carcinogenic bacteria Helicobacter pylori, elicits glandular histopathologic alterations, initially manifesting as pyloric (also known as pseudopyloric) metaplasia. In this pyloric metaplasia, corpus glands become antrum (pylorus)-like with loss of acid-secreting parietal cells (atrophic gastritis), expansion of foveolar cells, and reprogramming of digestive enzyme-secreting chief cells into deep antral gland-like mucous cells. After acute parietal cell loss, chief cells can reprogram through an orderly stepwise progression (paligenosis) initiated by interleukin-13-secreting innate lymphoid cells (ILC2s). First, massive lysosomal activation helps mitigate reactive oxygen species and remove damaged organelles. Second, mucus and wound-healing proteins (eg, TFF2) and other transcriptional alterations are induced, at which point the reprogrammed chief cells are recognized as mucus-secreting spasmolytic polypeptide-expressing metaplasia cells. In chronic severe injury, glands with pyloric metaplasia can harbor both actively proliferating spasmolytic polypeptide-expressing metaplasia cells and eventually intestine-like cells. Gastric glands with such lineage confusion (mixed incomplete intestinal metaplasia and proliferative spasmolytic polypeptide-expressing metaplasia) may be at particular risk for progression to dysplasia and cancer. A pyloric-like pattern of metaplasia after injury also occurs in other gastrointestinal organs including esophagus, pancreas, and intestines, and the paligenosis program itself seems broadly conserved across tissues and species. Here we discuss aspects of metaplasia in stomach, incorporating data derived from animal models and work on human cells and tissues in correlation with diagnostic and clinical implications.
Topics: Animals; Cell Plasticity; Cellular Reprogramming; Gastric Mucosa; Helicobacter Infections; Humans; Hyperplasia; Metaplasia; Parietal Cells, Gastric; Regeneration; Stomach
PubMed: 34728185
DOI: 10.1053/j.gastro.2021.10.036 -
American Journal of Physiology. Cell... Dec 2020Spasmolytic polypeptide/trefoil factor 2 (TFF2)-expressing metaplasia (SPEM) is a mucous-secreting reparative lineage that emerges at the ulcer margin in response to... (Review)
Review
Spasmolytic polypeptide/trefoil factor 2 (TFF2)-expressing metaplasia (SPEM) is a mucous-secreting reparative lineage that emerges at the ulcer margin in response to gastric injury. Under conditions of chronic inflammation with parietal cell loss, SPEM has been found to emerge and evolve into neoplasia. Cluster-of-differentiation gene 44 (CD44) is known to coordinate normal and metaplastic epithelial cell proliferation. In particular, CD44 variant isoform 9 (CD44v9) associates with the cystine-glutamate transporter xCT, stabilizes the protein, and provides defense against reactive oxygen species (ROS). xCT stabilization by CD44v9 leads to defense against ROS by cystine uptake, glutathione (GSH) synthesis, and maintenance of the redox balance within the intracellular environment. Furthermore, p38 signaling is a known downstream ROS target, leading to diminished cell proliferation and migration, two vital processes of gastric epithelial repair. CD44v9 emerges during repair of the gastric epithelium after injury, where it is coexpressed with other markers of SPEM. The regulatory mechanisms for the emergence of CD44v9 and the role of CD44v9 during the process of gastric epithelial regeneration are largely unknown. Inflammation and M2 macrophage infiltration have recently been demonstrated to play key roles in the induction of SPEM after injury. The following review proposes new insights into the functional role of metaplasia in the process of gastric regeneration in response to ulceration. Our insights are extrapolated from documented studies reporting oxyntic atrophy and SPEM development and our current unpublished findings using the acetic acid-induced gastric injury model.
Topics: Acetic Acid; Animals; Gastric Mucosa; Humans; Metaplasia; Regeneration; Stomach
PubMed: 32755448
DOI: 10.1152/ajpcell.00415.2019 -
Physiological Reviews Apr 2014Reactive oxygen species (ROS) are generated as by-products of normal cellular metabolic activities. Superoxide dismutase, glutathione peroxidase, and catalase are the... (Review)
Review
Reactive oxygen species (ROS) are generated as by-products of normal cellular metabolic activities. Superoxide dismutase, glutathione peroxidase, and catalase are the enzymes involved in protecting cells from the damaging effects of ROS. ROS are produced in response to ultraviolet radiation, cigarette smoking, alcohol, nonsteroidal anti-inflammatory drugs, ischemia-reperfusion injury, chronic infections, and inflammatory disorders. Disruption of normal cellular homeostasis by redox signaling may result in cardiovascular, neurodegenerative diseases and cancer. ROS are produced within the gastrointestinal (GI) tract, but their roles in pathophysiology and disease pathogenesis have not been well studied. Despite the protective barrier provided by the mucosa, ingested materials and microbial pathogens can induce oxidative injury and GI inflammatory responses involving the epithelium and immune/inflammatory cells. The pathogenesis of various GI diseases including peptic ulcers, gastrointestinal cancers, and inflammatory bowel disease is in part due to oxidative stress. Unraveling the signaling events initiated at the cellular level by oxidative free radicals as well as the physiological responses to such stress is important to better understand disease pathogenesis and to develop new therapies to manage a variety of conditions for which current therapies are not always sufficient.
Topics: Animals; Antioxidants; Gastric Mucosa; Gastrointestinal Diseases; Homeostasis; Humans; Intestinal Mucosa; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Signal Transduction
PubMed: 24692350
DOI: 10.1152/physrev.00040.2012 -
World Journal of Gastroenterology Mar 2011Helicobacter pylori (H. pylori) has co-evolved with humans to be transmitted from person to person and to colonize the stomach persistently. A well-choreographed... (Review)
Review
Helicobacter pylori (H. pylori) has co-evolved with humans to be transmitted from person to person and to colonize the stomach persistently. A well-choreographed equilibrium between the bacterial effectors and host responses permits microbial persistence and health of the host, but confers a risk for serious diseases including gastric cancer. During its long coexistence with humans, H. pylori has developed complex strategies to limit the degree and extent of gastric mucosal damage and inflammation, as well as immune effector activity. The present editorial thus aims to introduce and comment on major advances in the rapidly developing area of H. pylori/human gastric mucosa interaction (and its pathological sequelae), which is the result of millennia of co-evolution of, and thus of reciprocal knowledge between, the pathogen and its human host.
Topics: Antigens, Bacterial; Bacterial Proteins; Biological Evolution; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Host-Pathogen Interactions; Humans; Signal Transduction; Stomach Neoplasms; Virulence; Virulence Factors
PubMed: 21472096
DOI: 10.3748/wjg.v17.i11.1383 -
Gastroenterology Aug 2021The homeostasis of the gastrointestinal epithelium relies on cell regeneration and differentiation into distinct lineages organized inside glands and crypts....
BACKGROUND & AIMS
The homeostasis of the gastrointestinal epithelium relies on cell regeneration and differentiation into distinct lineages organized inside glands and crypts. Regeneration depends on Wnt/β-catenin pathway activation, but to understand homeostasis and its dysregulation in disease, we need to identify the signaling microenvironment governing cell differentiation. By using gastric glands as a model, we have identified the signals inducing differentiation of surface mucus-, zymogen-, and gastric acid-producing cells.
METHODS
We generated mucosoid cultures from the human stomach and exposed them to different growth factors to obtain cells with features of differentiated foveolar, chief, and parietal cells. We localized the source of the growth factors in the tissue of origin.
RESULTS
We show that epidermal growth factor is the major fate determinant distinguishing the surface and inner part of human gastric glands. In combination with bone morphogenetic factor/Noggin signals, epidermal growth factor controls the differentiation of foveolar cells vs parietal or chief cells. We also show that epidermal growth factor is likely to underlie alteration of the gastric mucosa in the precancerous condition atrophic gastritis.
CONCLUSIONS
Use of our recently established mucosoid cultures in combination with analysis of the tissue of origin provided a robust strategy to understand differentiation and patterning of human tissue and allowed us to draw a new, detailed map of the signaling microenvironment in the human gastric glands.
Topics: Body Patterning; Bone Morphogenetic Protein 4; Carrier Proteins; Cell Differentiation; Cell Lineage; Cells, Cultured; Cellular Microenvironment; Chief Cells, Gastric; Epidermal Growth Factor; Epithelial Cells; Gastric Mucosa; Gastritis, Atrophic; Gene Expression Regulation, Developmental; Humans; Organoids; Parietal Cells, Gastric; Wnt Signaling Pathway
PubMed: 33957136
DOI: 10.1053/j.gastro.2021.04.062 -
Digestive Diseases (Basel, Switzerland) 2022
Topics: Humans; Gastric Mucosa; Helicobacter Infections
PubMed: 34942630
DOI: 10.1159/000521610 -
World Journal of Gastroenterology Apr 2014This review updates the current views on aging gastric mucosa and the mechanisms of its increased susceptibility to injury. Experimental and clinical studies indicate... (Review)
Review
This review updates the current views on aging gastric mucosa and the mechanisms of its increased susceptibility to injury. Experimental and clinical studies indicate that gastric mucosa of aging individuals-"aging gastropathy"-has prominent structural and functional abnormalities vs young gastric mucosa. Some of these abnormalities include a partial atrophy of gastric glands, impaired mucosal defense (reduced bicarbonate and prostaglandin generation, decreased sensory innervation), increased susceptibility to injury by a variety of damaging agents such as ethanol, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), impaired healing of injury and reduced therapeutic efficacy of ulcer-healing drugs. Detailed analysis of the above changes indicates that the following events occur in aging gastric mucosa: reduced mucosal blood flow and impaired oxygen delivery cause hypoxia, which leads to activation of the early growth response-1 (egr-1) transcription factor. Activation of egr-1, in turn, upregulates the dual specificity phosphatase, phosphatase and tensin homologue deleted on chromosome ten (PTEN) resulting in activation of pro-apoptotic caspase-3 and caspase-9 and reduced expression of the anti-apoptosis protein, survivin. The imbalance between pro- and anti-apoptosis mediators results in increased apoptosis and increased susceptibility to injury. This paradigm has human relevance since increased expression of PTEN and reduced expression of survivin were demonstrated in gastric mucosa of aging individuals. Other potential mechanisms operating in aging gastric mucosa include reduced telomerase activity, increase in replicative cellular senescence, and reduced expression of vascular endothelial growth factor and importin-α-a nuclear transport protein essential for transport of transcription factors to nucleus. Aging gastropathy is an important and clinically relevant issue because of: (1) an aging world population due to prolonged life span; (2) older patients have much greater risk of gastroduodenal ulcers and gastrointestinal complications (e.g., NSAIDs-induced gastric injury) than younger patients; and (3) increased susceptibility of aging gastric mucosa to injury can be potentially reduced or reversed pharmacologically.
Topics: Age Factors; Aging; Animals; Gastric Mucosa; Gastrointestinal Agents; Humans; Risk Factors; Signal Transduction; Stomach Diseases; Treatment Outcome
PubMed: 24782600
DOI: 10.3748/wjg.v20.i16.4467 -
Medical Gas Research 2019Gastrointestinal disease is a major global threat to public health. In the past few decades, numerous studies have focuses on the application of small molecule gases in... (Review)
Review
Gastrointestinal disease is a major global threat to public health. In the past few decades, numerous studies have focuses on the application of small molecule gases in the disease treatment. Increasing evidence has shown that hydrogen sulfide (HS) has anti-inflammatory and anti-oxidative effects, and can regulate gastric mucosal blood flow in the gastric mucosa. After gastric mucosa damage, the level of HS in the stomach decreases. Administration of HS can protect and repair the damaged gastric mucosa. Therefore, HS is a new target for the repair and treatment of gastric mucosa damage. In this review, we introduce the roles of HS in the treatment of gastric mucosa damage and provide the potential strategies for further clinical treatment.
Topics: Animals; Anti-Inflammatory Agents; Carbon Monoxide; Gastric Mucosa; Humans; Hydrogen Sulfide; Nitric Oxide; Reactive Oxygen Species; Regional Blood Flow
PubMed: 31249257
DOI: 10.4103/2045-9912.260650 -
Biomedicine & Pharmacotherapy =... Mar 2022Ankyrin repeat domain 22 (ANKRD22) is a nuclear-encoded mitochondrial membrane protein that is highly expressed in normal gastric mucosal epithelial cells and activated... (Review)
Review
Ankyrin repeat domain 22 (ANKRD22) is a nuclear-encoded mitochondrial membrane protein that is highly expressed in normal gastric mucosal epithelial cells and activated macrophages. As a regulator of mitochondrial Ca, ANKRD22 could help repair damaged gastric mucosa by promoting the mobilization of LGR5 gastric epithelial cells via the upregulation of Wnt/β-catenin pathway activity in a mouse model. Furthermore, the inhibition of ANKRD22 alleviated the macrophage activation-mediated inflammatory response by reducing the phosphorylation of nuclear factor of activated T cells (NFAT). ANKRD22 plays a significant role in the repair of gastric mucosal damage and may become an ideal novel target for the treatment of gastric mucosal injury. However, there is no systematic introduction to ANKRD22 targeting. Therefore, we wrote this review to elaborate the functional mechanism of ANKRD22 in gastric mucosal injury and to analyze its potential application value in clinical therapy.
Topics: Animals; Biomarkers; Calcium Channels; Down-Regulation; Epithelial Cells; Gastric Mucosa; Inflammation Mediators; Membrane Proteins; Mice; Receptors, G-Protein-Coupled; Stem Cells; Wnt Signaling Pathway
PubMed: 35051858
DOI: 10.1016/j.biopha.2022.112649 -
World Journal of Gastroenterology Feb 2022Early gastric cancer (EGC) is an invasive carcinoma involving only the stomach mucosa or submucosa, independently of lymph node status. EGC represents over 50% of cases...
Early gastric cancer (EGC) is an invasive carcinoma involving only the stomach mucosa or submucosa, independently of lymph node status. EGC represents over 50% of cases in Japan and in South Korea, whereas it accounts only for approximately 20% of all newly diagnosed gastric cancers in Western countries. The main classification systems of EGC are the Vienna histopathologic classification and the Paris endoscopic classification of polypoid and non-polypoid lesions. A careful endoscopic assessment is fundamental to establish the best treatment of EGC. Generally, EGCs are curable if the lesion is completely removed by endoscopic resection or surgery. Some types of EGC can be resected endoscopically; for others the most appropriate treatment is surgical resection and D2 lymphadenectomy, especially in Western countries. The favorable oncological prognosis, the extended lymphadenectomy and the reconstruction of the intestinal continuity that excludes the duodenum make the prophylactic cholecystectomy mandatory to avoid the onset of biliary complications.
Topics: Early Detection of Cancer; Gastric Mucosa; Gastroscopy; Humans; Lymph Node Excision; Stomach Neoplasms
PubMed: 35317273
DOI: 10.3748/wjg.v28.i7.693