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Promising Biomarkers of Environmental Enteric Dysfunction: A Prospective Cohort study in Pakistani Children. Sci Rep 2018; 8:2966. [PMID: 29445110 PMCID: PMC5813024 DOI: 10.1038/s41598-018-21319-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 01/22/2018] [Indexed: 12/13/2022] Open
Abstract
Environmental Enteric Dysfunction (EED), a syndrome characterized by chronic gut inflammation, contributes towards stunting and poor response to enteric vaccines in children in developing countries. In this study, we evaluated major putative biomarkers of EED using growth faltering as its clinical proxy. Newborns (n = 380) were enrolled and followed till 18 months with monthly anthropometry. Biomarkers associated with gut and systemic inflammation were assessed at 6 and 9 months. Linear mixed effects model was used to determine the associations of these biomarkers with growth faltering between birth and 18 months. Fecal myeloperoxidase (neutrophil activation marker) at 6 months [β = −0.207, p = 0.005], and serum GLP 2 (enterocyte proliferation marker) at 6 and 9 months [6M: β = −0.271, p = 0.035; 9M: β = −0.267, p = 0.045] were associated with decreasing LAZ score. Ferritin at 6 and 9 months was associated with decreasing LAZ score [6M: β = −0.882, p < 0.0001; 9M: β = −0.714, p < 0.0001] and so was CRP [β = −0.451, p = 0.039] and AGP [β = −0.443, p = 0.012] at 9 months. Both gut specific and systemic biomarkers correlated negatively with IGF-1, but only weakly correlated, if at all with each other. We therefore conclude that EED may be contributing directly towards growth faltering, and this pathway is not entirely through the pathway of systemic inflammation.
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Prendergast AJ, Humphrey JH, Mutasa K, Majo FD, Rukobo S, Govha M, Mbuya MNN, Moulton LH, Stoltzfus RJ. Assessment of Environmental Enteric Dysfunction in the SHINE Trial: Methods and Challenges. Clin Infect Dis 2016; 61 Suppl 7:S726-32. [PMID: 26602300 PMCID: PMC4657593 DOI: 10.1093/cid/civ848] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Environmental enteric dysfunction (EED) is a virtually ubiquitous, but poorly defined, disorder of the small intestine among people living in conditions of poverty, which begins early in infancy and persists. EED is characterized by altered gut structure and function, leading to reduced absorptive surface area and impaired intestinal barrier function. It is hypothesized that recurrent exposure to fecal pathogens and changes in the composition of the intestinal microbiota initiate this process, which leads to a self-perpetuating cycle of pathology. We view EED as a primary gut disorder that drives chronic systemic inflammation, leading to growth hormone resistance and impaired linear growth. There is currently no accepted case definition or gold-standard biomarker of EED, making field studies challenging. The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in Zimbabwe is evaluating the independent and combined effects of a package of infant feeding and/or water, sanitation, and hygiene interventions on stunting and anemia. SHINE therefore provides an opportunity to longitudinally evaluate EED in a well-characterized cohort of infants, using a panel of biomarkers along the hypothesized causal pathway. Our aims are to describe the evolution of EED during infancy, ascertain its contribution to stunting, and investigate the impact of the randomized interventions on the EED pathway. In this article, we describe current concepts of EED, challenges in defining the condition, and our approach to evaluating EED in the SHINE trial.
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Affiliation(s)
- Andrew J Prendergast
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe Blizard Institute, Queen Mary University of London, United Kingdom Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Jean H Humphrey
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Kuda Mutasa
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
| | - Florence D Majo
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
| | - Sandra Rukobo
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
| | - Margaret Govha
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
| | - Mduduzi N N Mbuya
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland Division of Nutritional Sciences, Cornell University, Ithaca, New York
| | - Lawrence H Moulton
- Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
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Abstract
Diarrheal diseases are a major cause of childhood death in resource-poor countries, killing approximately 760,000 children younger than 5 years each year. Although deaths due to diarrhea have declined dramatically, high rates of stunting and malnutrition have persisted. Environmental enteric dysfunction (EED) is a subclinical condition caused by constant fecal-oral contamination with resultant intestinal inflammation and villous blunting. These histological changes were first described in the 1960s, but the clinical effect of EED is only just being recognized in the context of failure of nutritional interventions and oral vaccines in resource-poor countries. We review the existing literature regarding the underlying causes of and potential interventions for EED in children, highlighting the epidemiology, clinical and histologic classification of the entity, and discussing novel biomarkers and possible therapies. Future research priorities are also discussed.
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Fujishiro M, Nozawa K, Kawasaki M, Yamaguchi A, Iwabuchi K, Yanagida M, Suzuki F, Miyazawa K, Fukui H, Kaneko K, Ogawa H, Takamori K, Takasaki Y, Sekigawa I. Regenerating gene (REG) 1 alpha promotes pannus progression in patients with rheumatoid arthritis. Mod Rheumatol 2014. [DOI: 10.3109/s10165-011-0564-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Peterson KM, Buss J, Easley R, Yang Z, Korpe PS, Niu F, Ma JZ, Olortegui MP, Haque R, Kosek MN, Petri WA. REG1B as a predictor of childhood stunting in Bangladesh and Peru. Am J Clin Nutr 2013; 97:1129-33. [PMID: 23553156 PMCID: PMC3628379 DOI: 10.3945/ajcn.112.048306] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Undernutrition remains a significant problem worldwide, with environmental enteropathy implicated as a contributing factor. An understanding of the pathogenesis and identification of children at risk are critical to the design of more-effective interventions. OBJECTIVE The stool regenerating gene 1β (REG1B) protein, which is a putative measure of intestinal injury and repair, was tested as a noninvasive biomarker of future childhood stunting. DESIGN A total of 222 children from Bangladesh and 97 children from Peru, who were from impoverished communities, were followed from birth through 24 mo of age with anthropometric measures obtained every 3 mo. Stool REG1B protein concentrations were obtained by using an REG1B polyclonal-polyclonal ELISA at 3 mo of age. We tested for the ability of REG1B to forecast future anthropometric shortfalls, independent of known predictors of undernutrition of family income and baseline height and weight. RESULTS In the Bangladesh cohort of 222 children, higher REG1B concentrations at month 3 were significantly and independently associated with a growth shortfall in a linear regression analysis at months 9, 12, 18, 21, and 24 and, in the Peru cohort, at months 12, 15, 18, 21, and 24. With the use of a mixed model for repeated measurements, higher stool REG1B concentrations at 3 mo were also independently predictive of a lower future length-for-age z score through 24 mo of age (Bangladesh P = 0.006; Peru P = 0.058). CONCLUSION The ability of fecal REG1B to predict growth shortfall in independent cohorts of impoverished children from the developing world offers promise as a malnutrition biomarker and supports a role for environmental enteropathy in the pathogenesis of growth shortfall.
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HU HAOLIN, ZHANG QI, KONG BO, SHI XIN. Expression of pancreatic regenerating gene in lung and intestinal tissue correlates with the severity of disease in rats with acute necrotizing pancreatitis. Mol Med Rep 2012; 7:503-8. [DOI: 10.3892/mmr.2012.1187] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2012] [Accepted: 10/31/2012] [Indexed: 11/05/2022] Open
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Fujishiro M, Nozawa K, Kawasaki M, Yamaguchi A, Iwabuchi K, Yanagida M, Suzuki F, Miyazawa K, Fukui H, Kaneko K, Ogawa H, Takamori K, Takasaki Y, Sekigawa I. Regenerating gene (REG) 1 alpha promotes pannus progression in patients with rheumatoid arthritis. Mod Rheumatol 2011; 22:228-37. [PMID: 22203215 DOI: 10.1007/s10165-011-0564-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2010] [Accepted: 06/30/2011] [Indexed: 11/26/2022]
Abstract
INTRODUCTION A protein analysis using mass spectrometry revealed the existence of serum proteins with significant quantitative changes after the administration of infliximab. Among these proteins, regenerating gene (REG) 1α appears to be related to the pathogenesis of rheumatoid arthritis (RA). Therefore, the present study was conducted to examine the mechanism of REG1α in RA disease progression. METHODS Serum samples were collected from RA patients and normal healthy controls. REG1α expression was evaluated by ELISA, RT-PCR, and indirect immunofluorescence microscopy. The functions of REG1α on synovial fibroblasts with regard to apoptosis, receptor activator of NF-κB ligand (RANKL) expression, and cellar proliferation were evaluated using siRNA to inhibit the intrinsic REG1α mRNA expression. RESULTS The serum concentrations of REG1α in RA patients were higher than in normal healthy controls. The high expression of REG1α was also observed in the synovial tissue of RA patients compared to those of osteoarthropathy patients. In addition, tumor necrosis factor-α (TNF-α) upregulated REG1α expression in the synovial fibroblasts cell line (MH7A). Inhibition of REG1α expression suppressed the induction of RANKL expression by TNF-α. Furthermore, exogenous recombinant REG1α protein inhibited apoptosis and promoted cell proliferation in MH7A cells. These effects were abolished in the REG1α-siRNA MH7A cells. CONCLUSION The present data suggest that TNF-α induces aberrant REG1α expression and that REG1α plays an important role in aberrant cell proliferation and RANKL expression of synovial fibroblasts, ultimately resulting in pannus formation. Restoration of normal physiological REG1α expression may contribute to disease amelioration.
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Affiliation(s)
- Maki Fujishiro
- Institute for Environment and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan,
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The expression of REG 1A and REG 1B is increased during acute amebic colitis. Parasitol Int 2011; 60:296-300. [PMID: 21586335 DOI: 10.1016/j.parint.2011.04.005] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2011] [Revised: 04/26/2011] [Accepted: 04/29/2011] [Indexed: 01/31/2023]
Abstract
Entamoeba histolytica, a protozoan parasite, is an important cause of diarrhea and colitis in the developing world. Amebic colitis is characterized by ulceration of the intestinal mucosa. We performed microarray analysis of intestinal biopsies during acute and convalescent amebiasis in order to identify genes potentially involved in tissue injury or repair. Colonic biopsy samples were obtained from 8 patients during acute E. histolytica colitis and again 60 days after recovery. Gene expression in the biopsies was evaluated using microarray, and confirmed by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). REG 1A and REG 1B were the most up-regulated of all genes in the human intestine in acute versus convalescent E. histolytica disease: as determined by microarray, the levels of induction were 7.4-fold and 10.7 fold for REG 1A and B; p=0.003 and p=0.006 respectively. Increased expression of REG 1A and REG 1B protein in the colonic crypt epithelial cells during acute amebiasis was similarly observed by immunohistochemistry. Because REG 1 protein is anti-apoptotic and pro-proliferative, and since E. histolytica induces apoptosis of the intestinal epithelium as part of its disease process, we next tested if REG 1 might be protective during amebiasis by preventing parasite-induced apoptosis. Intestinal epithelial cells from REG 1-/- mice were found to be more susceptible to spontaneous, and parasite-induced, apoptosis in vitro (p=0.03). We concluded that REG 1A and REG 1B were upregulated during amebiasis and may function to protect the intestinal epithelium from parasite-induced apoptosis.
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Imaoka H, Ishihara S, Kazumori H, Kadowaki Y, Aziz MM, Rahman FB, Ose T, Fukuhara H, Takasawa S, Kinoshita Y. Exacerbation of indomethacin-induced small intestinal injuries in Reg I-knockout mice. Am J Physiol Gastrointest Liver Physiol 2010; 299:G311-9. [PMID: 20508157 DOI: 10.1152/ajpgi.00469.2009] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Nonsteroidal anti-inflammatory drug (NSAID)-induced small intestinal injuries are serious clinical events and a successful therapeutic strategy is difficult. Regenerating gene (Reg) I protein functions as a regulator of cell proliferation and maintains intercellular integrity in the small intestine. The aim of this study was to evaluate the role of Reg I in NSAID-induced small intestinal injuries. First, to examine the effect of Reg I deficiency on such injuries, indomethacin, a widely used NSAID, was injected subcutaneously into 10-wk-old male Reg I-knockout (Reg I(-/-)) and wild-type (Reg I(+/+)) mice twice with an interval of 24 h, after which the mice were euthanized. Small intestinal injuries were assessed by gross findings, histopathology, and contents of IL-1beta and MPO in the experimental tissues. Next, we investigated the therapeutic potential of Reg I in indomethacin-induced small intestinal injuries. Recombinant Reg I protein (rReg I) was administered to 10-wk-old male ICR mice, then indomethacin was administered 6 h using the same protocol as noted above, after which small intestinal injuries were assessed after euthanasia. Our results showed that Reg I(-/-) mice had a greater number of severe small intestinal lesions after indomethacin administration. Histological examinations of the small intestines from those mice revealed deep ulcers with prominent inflammatory cell infiltration, whereas the mucosal content of proinflammatory agents was also significantly increased. In addition, rReg I administration inhibited indomethacin-induced small intestinal injuries in ICR mice. In conclusion, Reg I may be useful as a therapeutic agent in NSAID-induced small intestinal injuries.
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Affiliation(s)
- Hiroshi Imaoka
- Dept. of Gastroenterology and Hepatology, Shimane Univ., Izumo, Japan.
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Peterson AJ, Nguyen N, Okamoto H, Giraud AS, van Driel IR, Judd LM. Loss of RegI in conjunction with gastrin deficiency in mice facilitates efficient gastric ulcer healing but is dispensable for hyperplasia and tumourigenesis. ACTA ACUST UNITED AC 2009; 160:9-18. [PMID: 19969026 DOI: 10.1016/j.regpep.2009.12.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2009] [Revised: 11/10/2009] [Accepted: 12/02/2009] [Indexed: 01/08/2023]
Abstract
RegI (Regenerating islet derived-1) was originally characterized as a growth factor involved in pancreatic islet cell regeneration. It is also considered a gastrointestinal mitogen as its expression is increased during pathologies involving aberrant cell proliferation that can lead to neoplasia. However, the absolute requirement for RegI to directly stimulate gastric mucosal cell proliferation in vivo requires further investigation. We used RegI-deficient mice to determine the requirement for RegI in normal gastric mucosal development, wound healing, hyperplasia and tumourigenesis. We found that epithelial repair of acetic acid ulcers in compound mutant RegI/gastrin-deficient mice was significantly reduced compared to wild type, RegI-deficient or gastrin-deficient mice. In contrast, RegI was dispensable for normal gastric mucosal development, hyperplasia in HKbeta-deficient mice and tumourigenesis in gp130(F/F) mice. Although RegI was not required for proliferation in these pathological models, expression of multiple Reg family members were increased during gp130(F/F) tumourigenesis. Interestingly, loss of RegI in gp130(F/F) mice resulted in decreased expression of other Reg family members. Our results indicate that RegI and gastrin may synergistically regulate gastric mucosal proliferation during certain pathological settings like wound healing while gastric epithelial proliferation in other pathologies may require coordinated expression of multiple Reg genes.
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Affiliation(s)
- Anthony J Peterson
- GRIP Lab (Gastrointestinal Research, Inflammation & Pathology), Murdoch Children's Research Institute, Parkville 3052, Australia
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Kimura T, Fukui H, Sekikawa A, Yamagishi H, Ichikawa K, Tomita S, Fujii S, Imura J, Kawamata H, Chiba T, Imai Y, Fujimori T. Involvement of REG Ialpha protein in the regeneration of ductal epithelial cells in the minor salivary glands of patients with Sjögren's syndrome. Clin Exp Immunol 2008; 155:16-20. [PMID: 19016805 DOI: 10.1111/j.1365-2249.2008.03806.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
The regenerating gene (Reg) was originally isolated from regenerating rat pancreatic islets and revealed recently to constitute a multi-gene family in humans. REG Ialpha protein is known to be overexpressed not only in various human inflammatory diseases but also in various experimental models of inflammation in animal tissues. However, its involvement in pathophysiology of the minor salivary gland (MSG) is not clear. We investigated REG Ialpha expression in the MSG of patients with primary Sjögren's syndrome (SS) and assessed its role in ductal epithelial cell proliferation in such tissues. Lip biopsy specimens were obtained from 40 patients with primary SS and examined using immunohistochemistry for REG Ialpha protein, Ki67 and single-strand DNA (ssDNA). The relationships among clinicopathological factors and expression of REG Ialpha protein, Ki67 and ssDNA in the MSG were then analysed. REG Ialpha protein was expressed rarely in ductal epithelial cells of the normal MSG but was apparently overexpressed in those of patients with SS. The labelling indices for both Ki67 and ssDNA in the ductal cells of the MSGs were significantly higher in SS patients than in controls. Moreover, these labelling indices were significantly higher in REG Ialpha-positive than in negative SS patients. REG Ialpha protein may play a role in the regeneration of ductal epithelial cells in the MSGs of patients with SS.
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Affiliation(s)
- T Kimura
- Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, Mibu, Shimotsuga, Tochigi, Japan
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Hu HL, Shi X, Zhang Q, Kong B. Correlation between reg I expression and intestinal mucosal lesion of acute necrotizing pancreatitis in rats. Shijie Huaren Xiaohua Zazhi 2008; 16:1985-1989. [DOI: 10.11569/wcjd.v16.i18.1985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate gene expression of reg I in intestinal tissues in rats with acute necrotizing pancreatitis (ANP) and to determine correlation between reg Ⅰ gene expression and intestinal mucosal lesion.
METHODS: Sprague-Dawley rats were randomly allocated into the control group (n = 40) and ANP group (n = 80). The rats in control group received laparotomy only. In ANP group, 30 g/L sodium taurocholate was injected under constant temperature into the pancreatic duct to develop the ANP model. Reverse transcriptase polymerase chain reaction (RT-PCR) was performed to detect reg Ⅰ mRNA level in pancreas and intestines. The pathologic changes of pancreas and intestines were observed, the permeability of intestinal mucosa was estimated. The measured parameters were evaluated to find whether correlation exited between reg Ⅰ mRNA expression level and pathological mucosal changes of ANP.
RESULTS: The intestinal pathological scores of ANP rats were significantly higher than that of control group at 12, 24, 36 h (1.8 ± 0.89 vs 0.2 ±0.42, 3.3 ± 1.17 vs 0.3 ± 0.48, 4.2 ± 0.95 vs 0.3 ± 0.48, all P < 0.01), postoperatively. The excretory rate of [99mTc]-DTPA in ANP rats were higher at 12, 24, 36 h, postoperatively, compared with control group (34.70% ± 4.03% vs 4.62% ± 1.17%, 54.63% ± 6.94% vs 6.14% ± 1.42%, 66.83% ± 7.56% vs 7.48% ± 0.92%, all P < 0.01). Reg Ⅰ mRNA was highly expressed in intestine in ANP rats compared with that in control group. Reg Ⅰ expression level was positively correlated with intestinal pathological scores(r = 0.6728, P < 0.01) and with intestinal permeability (r = 0.7092, P < 0.01).
CONCLUSION: Reg Ⅰ mRNA expression is up-regulated in intestinal tissues in ANP rats, and expression level of reg Ⅰ is positively correlated with severity of intestinal mucosal lesion caused by ANP.
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Fossmark R, Qvigstad G, Waldum HL. Gastric cancer: Animal studies on the risk of hypoacidity and hypergastrinemia. World J Gastroenterol 2008; 14:1646-51. [PMID: 18350594 PMCID: PMC2695903 DOI: 10.3748/wjg.14.1646] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gastric hypoacidity and hypergastrinaemia are seen in several conditions associated with an increased risk of gastric malignancy. Hypoacidity and hypergastrinaemia are closely related and their long-term effects are difficult to study separately in patients. Studies using animal models can provide valuable information about risk factors and mechanisms in gastric cancer development as the models allow a high degree of intervention when introducing or eliminating factors possibly affecting carcinogenesis. In this report, we briefly review findings from relevant animal studies on this topic. Animal models of gastric hypoacidity and hypergastrinaemia provide evidence hypergastrinaemia is a common causative factor in many otherwise diverse settings. In all species where sufficient hypoacidity and hypergastrinaemia have been induced, a proportion of the animals develop malignant lesions in the gastric oxyntic mucosa.
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Yoshino N, Ishihara S, Rumi MAK, Ortega-Cava CF, Yuki T, Kazumori H, Takazawa S, Okamoto H, Kadowaki Y, Kinoshita Y. Interleukin-8 regulates expression of Reg protein in Helicobacter pylori-infected gastric mucosa. Am J Gastroenterol 2005; 100:2157-66. [PMID: 16181363 DOI: 10.1111/j.1572-0241.2005.41915.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIM Chronic inflammation induced by Helicobacter pylori infection is closely associated with epithelial cell proliferation and apoptosis, which are related to cellular turnover in gastric mucosa. Reg protein is a regenerating gene product and a potent growth factor for gastric mucosal cells, however, little is known regarding its association with the pathogenesis of H. pylori infection. The aim of this study was to investigate Reg protein production and its regulation in H. pylori-associated gastritis. METHODS Gastric fundic biopsy samples were taken from patients with and without H. pylori infection. In vivo expression of Reg protein was examined by Western blotting and immunohistochemistry methods. The effects of interleukin (IL)-8 on Reg protein expression and transcriptional activation of the Reg gene in ECC10 cells were investigated by Western blotting and luciferase assays, respectively. RESULTS Reg expression was found localized in the deeper part of gastric fundic glands and clearly shown in chromogranin A-positive cells in the gastric corpus. Semiquantitative immunohistochemistry and Western blotting results for Reg expression were significantly associated with polymorphonuclear neutrophil activity and chronic inflammation of gastric mucosa. IL-8 production in the gastric mucosa was significantly augmented by H. pylori infection, while IL-8 dose-dependently stimulated Reg protein production and Reg promoter activity in vitro in cultured ECC10 cells. CONCLUSION The present study showed for the first time that Reg protein may be a potent stimulator of gastric epithelial cells in H. pylori-infected human gastric mucosa stimulated by IL-8. Further, our findings provide evidence of a novel link between Reg protein and H. pylori infection, which may help explain the molecular mechanisms underlying H. pylori-associated diseases, including gastric cancer.
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Affiliation(s)
- Nagisa Yoshino
- Department of Gastroenterology and Hepatology, Shimane University, School of Medicine, Izumo, Japan
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Sekikawa A, Fukui H, Fujii S, Takeda J, Nanakin A, Hisatsune H, Seno H, Takasawa S, Okamoto H, Fujimori T, Chiba T. REG Ialpha protein may function as a trophic and/or anti-apoptotic factor in the development of gastric cancer. Gastroenterology 2005; 128:642-53. [PMID: 15765400 DOI: 10.1053/j.gastro.2004.12.045] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND & AIMS Although a significant amount of regenerating gene (REG) Ialpha protein is present not only in normal gastric mucosa but also in gastric cancer tissues, its pathophysiologic role in gastric cancer development remains unclear. We investigated REG Ialpha protein expression in early gastric cancers, and examined whether cytokines are responsible for REG Ialpha gene expression and whether REG Ialpha protein has a trophic and/or an antiapoptotic effect on gastric cancer cells. METHODS Early gastric cancer specimens were analyzed histologically using immunohistochemistry for REG Ialpha protein and proliferating cell nuclear antigen (PCNA). The effects of cytokines on REG Ialpha promoter activity and its messenger RNA (mRNA) expression in AGS (a kind of gastric cancer cell line) cells were examined by luciferase reporter assay and Northern blot analysis, respectively. Effects of REG Ialpha protein on cell growth and H2O2-induced apoptosis in AGS cells were examined by 3,-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphatase nick-end labeling (TUNEL) assays, respectively. RESULTS REG Ialpha-positive early gastric cancers showed a significantly higher PCNA labeling index and more severe inflammatory cell infiltration in adjacent gastric mucosa than the negative cancers. REG Ialpha gene expression and its promoter activity were enhanced by interferon (IFN)-gamma and interleukin (IL)-6. REG Ialpha protein promoted cell growth and cell resistance to H2O2-induced apoptosis in AGS cells. These effects were abolished by concomitant treatment with anti-REG Ialpha antibody. REG Ialpha protein enhanced Akt phosphorylation and Bcl-xL expression in AGS cells. CONCLUSIONS REG Ialpha gene is inducible by cytokine stimulation and its gene product may function as a mitogenic and/or an antiapoptotic factor in the development of early gastric cancer.
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Affiliation(s)
- Akira Sekikawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Ono M, Sato H, Kazumori H, Yuki M, Rumi MAK, Ortega-Cava CF, Ishihara Y, Ishihara S, Adachi K, Kinoshita Y. Effect of a gastrin/cholecystokinin B receptor antagonist, S-0509, on the omeprazole-induced proliferation of gastric mucosa in rats. ACTA ACUST UNITED AC 2003; 142:364-71. [PMID: 14713888 DOI: 10.1016/s0022-2143(03)00151-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Hypergastrinemia is known to cause hyperplasia of the gastric mucosa, especially in gastric enterochromaffinlike (ECL) cells. In some clinical conditions causing hypergastrinemia, such as long-term gastric-acid inhibition and gastric-mucosa atrophy, hyperplastic ECL cells may develop into gastric carcinoid tumors. A newly developed gastrin-receptor antagonist, S-0509, has been reported to block gastrin-induced stimulation of gastric-acid secretion. We therefore investigated whether S-0509 inhibits the omeprazole- and gastrin-stimulated hyperproliferation of gastric mucosa, especially of ECL cells. Daily administration of omeprazole and gastrin in male Sprague-Dawley rats induced marked hypergastrinemia and increased proliferation of gastric-mucosa cells. The numbers of ECL cells and of ECL cells producing messenger RNA for regenerating gene, a potent growth factor for gastric-mucosa cells, were also augmented by long-term administration of omeprazole and gastrin. Coadministration of S-0509 with omeprazole or gastrin almost completely inhibited the omeprazole- and gastrin-induced changes in gastric mucosa, including mucosal thickening and ECL hyperplasia. S-0509 did not induce gastric-mucosa atrophy, even when administered for as long as 4 weeks. In summary, we have found that a newly developed gastrin receptor antagonist, S-0509, inhibits omeprazole- and gastrin-induced mucosal hyperplasia, especially ECL-cell hyperplasia, in rats.
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Affiliation(s)
- Masahiro Ono
- The Department of Medicine II, Shimane Medical University School of Medicine, Izumo, Japan
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Fukui H, Franceschi F, Penland RL, Sakai T, Sepulveda AR, Fujimori T, Terano A, Chiba T, Genta RM. Effects of Helicobacter pylori infection on the link between regenerating gene expression and serum gastrin levels in Mongolian gerbils. J Transl Med 2003; 83:1777-86. [PMID: 14691296 DOI: 10.1097/01.lab.0000106501.56339.ce] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Although regenerating gene (Reg) protein is reported to have a trophic effect on gastric epithelial cells, its involvement in human gastric diseases is not clear. We have recently shown that both gastrin and gastric mucosal inflammation enhance Reg gene expression in the fundic mucosa in rats. This study was designed to clarify whether Reg protein is involved in Helicobacter pylori-induced gastritis and whether Reg gene expression is linked to serum gastrin levels in this condition. Mongolian gerbils were inoculated with an H. pylori strain isolated from a gastric cancer patient. Four weeks later, some of the gerbils with H. pylori infection were eradicated by lansoprazole, amoxicillin, and clarithromycin. The time courses of changes in Reg gene expression, serum gastrin levels, gastric acidity, and histopathologic factors were examined. Four weeks after H. pylori infection, gastritis started spreading to the fundic mucosa, and gastric acidity started reducing. Serum gastrin levels and Reg mRNA expression in the fundus were significantly increased 6 weeks after infection. Reg mRNA expression in the fundus correlated significantly with both serum gastrin levels and the severity of fundic mucosal inflammation. After H. pylori eradication, serum gastrin levels and fundic mucosal inflammation were normalized, and the increase in Reg mRNA expression was abolished. The Reg gene is associated with hypergastrinemia and fundic mucosal inflammation and may be involved in H. pylori-induced gastritis.
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Affiliation(s)
- Hirokazu Fukui
- Department of Pathology, Medicine, Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas, USA
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18
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Zhang YW, Ding LS, Lai MD. Reg gene family and human diseases. World J Gastroenterol 2003; 9:2635-2641. [PMID: 14669303 PMCID: PMC4612022 DOI: 10.3748/wjg.v9.i12.2635] [Citation(s) in RCA: 108] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2003] [Revised: 05/16/2003] [Accepted: 06/02/2003] [Indexed: 02/06/2023] Open
Abstract
Regenerating gene (Reg or REG) family, within the superfamily of C-type lectin, is mainly involved in the liver, pancreatic, gastric and intestinal cell proliferation or differentiation. Considerable attention has focused on Reg family and its structurally related molecules. Over the last 15 years, 17 members of the Reg family have been cloned and sequenced. They have been considered as members of a conserved protein family sharing structural and some functional properties being involved in injury, inflammation, diabetes and carcinogenesis. We previously identified Reg IV as a strong candidate for a gene that was highly expressed in colorectal adenoma when compared to normal mucosa based on suppression subtractive hybridization (SSH), reverse Northern blot, semi-quantitative reverse transcriptase PCR (RT-PCR) and Northern blot. In situ hybridization results further support that overexpression of Reg IV may be an early event in colorectal carcinogenesis. We suggest that detection of Reg IV overexpression might be useful in the early diagnosis of carcinomatous transformation of adenoma. This review summarizes the roles of Reg family in diseases in the literature as well as our recent results of Reg IV in colorectal cancer. The biological properties of Reg family and its possible roles in human diseases are discussed. We particularly focus on the roles of Reg family as sensitive reactants of tissue injury, prognostic indicators of tumor survival and early biomarkers of carcinogenesis. In addition to our current understanding of Reg gene functions, we postulate that there might be relationships between Reg family and microsatellite instability, apoptosis and cancer with a poor prognosis. Investigation of the correlation between tumor Reg expression and survival rate, and analysis of the Reg gene status in human malignancies, are required to elucidate the biologic consequences of Reg gene expression, the implications for Reg gene regulation of cell growth, tumorigenesis, and the progression of cancer. It needs to be further attested whether Reg gene family is applicable in early detection of cancer and whether Reg and Reg-related molecules can offer novel molecular targets for anticancer therapeutics. This has implications with regard to prognosis, such as in monitoring cancer initiation, progression and recurrence, as well as the design of chemotherapeutic drugs.
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Affiliation(s)
- Yu-Wei Zhang
- Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
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19
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Alderman BM, Ulaganathan M, Judd LM, Howlett M, Parker LM, Yeomans ND, Giraud AS. Insights into the mechanisms of gastric adaptation to aspirin-induced injury: a role for regenerating protein but not trefoil peptides. J Transl Med 2003; 83:1415-25. [PMID: 14563943 DOI: 10.1097/01.lab.0000092231.54761.cd] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
The phenomenon of reduced gastric mucosal injury despite repeated doses of a damaging agent is termed adaptation. Adaptation to nonsteroidal anti-inflammatory drug-induced injury has been clearly demonstrated in both humans and experimental animals; however, the precise mechanisms remain unclear. We hypothesized that mediators of adaptation might be the regenerating protein (RegI) and the trefoil peptides TFF1 and TFF2, because these proteins play pivotal roles in gastric mucosal protection and repair. The gene expression and the protein levels of these proteins were measured and compared in normal, aspirin-injured, and aspirin-adapted rat stomachs. TFF gene and protein expression levels were similar in all three groups, whereas RegI gene expression and protein levels in adapted stomach were increased. A time course analysis of RegI expression during the onset and offset of adaptation showed that mucosal RegI increased during the development of adaptation, was maintained during subsequent aspirin dosing, and returned to baseline levels once dosing had ceased and adaptation was lost-indicative of a causal role in the adaptation process. Colocalization of increased RegI with gastric epithelial areas showing increased proliferation also suggests that RegI may be an important mediator of the resolution of mucosal injury that is characteristic of gastric adaptation to aspirin.
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Affiliation(s)
- Barbara M Alderman
- University of Melbourne, Department of Medicine, Western Hospital, Footscray, Victoria, Australia
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20
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Peterson RL, Wang L, Albert L, Marchese E, Erickson J, Wong A, Mounts WM, Hayes L, Bouchard P, Keith J, Dorner AJ. Pharmacogenomic analysis of rhIL-11 treatment in the HLA-B27 rat model of inflammatory bowel disease. THE PHARMACOGENOMICS JOURNAL 2003; 2:383-99. [PMID: 12629504 DOI: 10.1038/sj.tpj.6500137] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2002] [Revised: 08/09/2002] [Accepted: 08/20/2002] [Indexed: 11/09/2022]
Abstract
Recombinant human interleukin-11 (rhIL-11) reduces the clinical signs and histological lesions of inflammatory bowel disease (IBD) in transgenic rats expressing the human major histocompatability complex (MHC) class I allele, HLA-B27. To elucidate the pharmacogenomic effects of rhIL-11 in this model, we examined the global gene expression pattern in inflamed colonic tissue before and following rhIL-11 treatment using oligonucleotide microarrays. In total, 175 disease-related genes were identified. Increased expression of genes involved in antigen presentation, cell death and inflammation, and decreased expression of metabolic genes was associated with disease. A total of 27 disease-related genes returned to normal expression levels following rhIL-11 treatment including the MHC class II gene RT1-DMbeta. rhIL-11 induced the expression of four intestinal epithelial growth factors. These gene expression patterns indicate that treatment of inflammatory bowel disease with rhIL-11 affects class II antigen processing and colonic epithelial cell proliferation and metabolism.
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Affiliation(s)
- R L Peterson
- Department of Molecular Medicine and Pharmacogenomics, 1 Burtt Road, Andover, MA, USA.
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21
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Expression of the Regenerating Gene Family in Inflammatory Bowel Disease Mucosa: Reg Iα Upregulation, Processing, and Antiapoptotic Activity. J Investig Med 2002. [DOI: 10.1097/00042871-200211010-00026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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22
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Dieckgraefe BK, Crimmins DL, Landt V, Houchen C, Anant S, Porche-Sorbet R, Ladenson JH. Expression of the regenerating gene family in inflammatory bowel disease mucosa: Reg Ialpha upregulation, processing, and antiapoptotic activity. J Investig Med 2002; 50:421-34. [PMID: 12425429 DOI: 10.1136/jim-50-06-02] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND The pathophysiology of inflammatory bowel disease (IBD) reflects a balance between mucosal injury related to an ongoing inflammatory process and mucosal reparative mechanisms. Proreparative mucosal factors may offer new therapeutic paradigms. Transcriptional profiling can be applied to identify candidate gene products involved in colonic mucosal regeneration. METHODS Resection specimens from patients who underwent colonic resection for IBD or non-IBD indications were analyzed by performing Affymetrix GeneChip hybridization (Affymetrix, Inc., Santa Clara, Calif) and histopathologic scoring. Expression and physiologic processing of Reg Ialpha, the most highly expressed member of the regenerating (Reg) gene family, was further studied by performing specific immunohistochemistry, protein sequencing, and mass spectroscopy. RESULTS Foregut-derived tissues normally express human Reg proteins with minimal expression in the colon. In the setting of tissue injury associated with IBD, Reg Ialpha Reg Ibeta, and Reg III mRNA were highly expressed in colonic mucosa. Paired histopathologic scoring demonstrated that Reg expression was not related to the presence or the degree of mucosal inflammation. Studies of the Reg Ialpha protein revealed evidence of proteolytic cleavage at the N-terminus. In IBD, intact Reg Ialpha protein was expressed by the metaplastic Paneth granular cell population. Whereas Reg Ialpha cleaved at the N-terminus, it was also deposited throughout the lamina propria. Reg Ialpha treatment was shown to reduce epithelial apoptosis that occurred in response to treatment with hydrogen peroxide. CONCLUSION Ectopic expression, physiologic processing, and directed tissue deposition of Reg Ialpha are components of the colonic mucosal regenerative response in IBD. Reg Ialpha may serve to reduce epithelial apoptosis in inflammation.
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Affiliation(s)
- Brian K Dieckgraefe
- Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
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23
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Kazumori H, Ishihara S, Fukuda R, Kinoshita Y. Localization of Reg receptor in rat fundic mucosa. THE JOURNAL OF LABORATORY AND CLINICAL MEDICINE 2002; 139:101-8. [PMID: 11919548 DOI: 10.1067/mlc.2002.120796] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Reg protein has a trophic effect on gastric mucosal cells and pancreatic islets. Recently, the Reg receptor (Reg-R) has been cloned, and Reg-Reg-R interaction has been reported in the pancreas. The aim of this study was to investigate the localization of Reg-R in rat fundic mucosa. Gene expression of Reg-R was investigated with Northern blot analysis, laser capture microdissection coupled with reverse transcription-polymerase chain reaction, and in situ hybridization in the fundic mucosa, and the types of cells expressing this gene were determined. Reg-R mRNA expression was detected mainly in chief cells and parietal cells of the deep layers and faintly in surface epithelial cells and mucous neck cells of the proliferating zone. Our results suggest that regenerating protein may act not only as a regulator of gastric epithelial cell proliferation but also as a modifier of other multiple physiologic functions.
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Affiliation(s)
- Hideaki Kazumori
- Second Department of Internal Medicine, Shimane Medical UniversityIzumo, Japan
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24
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Hartupee JC, Zhang H, Bonaldo MF, Soares MB, Dieckgraefe BK. Isolation and characterization of a cDNA encoding a novel member of the human regenerating protein family: Reg IV. BIOCHIMICA ET BIOPHYSICA ACTA 2001; 1518:287-93. [PMID: 11311942 DOI: 10.1016/s0167-4781(00)00284-0] [Citation(s) in RCA: 132] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Human Reg and Reg-related genes constitute a multi-gene family belonging to the calcium (C-type) dependent lectin superfamily. Regenerating gene family members are expressed in the proximal gastrointestinal (GI) tract and ectopically at other sites in the setting of tissue injury. By high-throughput sequence analysis of a large inflammatory bowel disease library, two cDNAs have been isolated which encode a novel member of this multigene family. Based on primary sequence homology, tissue expression profiles, and shared exon-intron junction genomic organization, we assign this gene to the regenerating gene family. Specific protein structural differences suggest that the current three regenerating gene subtypes should be expanded to four. We demonstrate that Reg IV has a highly restricted tissue expression pattern, with prominent expression in the gastrointestinal tract. Reg IV mRNA expression is significantly up-regulated by mucosal injury from active Crohn's disease or ulcerative colitis.
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Affiliation(s)
- J C Hartupee
- Division of Gastroenterology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA
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25
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Kazumori H, Ishihara S, Hoshino E, Kawashima K, Moriyama N, Suetsugu H, Sato H, Adachi K, Fukuda R, Watanabe M, Takasawa S, Okamoto H, Fukui H, Chiba T, Kinoshita Y. Neutrophil chemoattractant 2 beta regulates expression of the Reg gene in injured gastric mucosa in rats. Gastroenterology 2000; 119:1610-1622. [PMID: 11113082 DOI: 10.1053/gast.2000.20262] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Regenerating (Reg) protein has a trophic effect on gastric mucosal cells. We have shown that Reg gene expression is increased in enterochromaffin-like (ECL) cells during the healing of damaged gastric mucosa around mucosal erosion. This study was designed to explore the stimulants of Reg expression during the healing of gastric mucosal damage. METHODS Time course changes of the expression of genes for various proinflammatory cytokines and Reg were investigated after induction of gastric mucosal lesions in rats. The direct effect of proinflammatory cytokines on Reg gene expression and Reg protein production were investigated in vitro using counterflow elutriation-enriched rat ECL cells. CXC receptor 2 (CXCR-2) expression was investigated in ECL cells by reverse-transcription polymerase chain reaction. Reg gene expression was also investigated in rats treated by the neutralizing antibody of cytokine-induced neutrophil chemoattractant (CINC-2 beta). RESULTS During healing, the gene expression of several proinflammatory cytokines and Reg was markedly augmented. Among the proinflammatory cytokines, CINC-2 beta is the only cytokine in which augmented expression preceded the increase of Reg gene expression. In rats treated with CINC-2 beta neutralizing antibody, the augmentation of Reg gene expression was significantly inhibited. When ECL cells were incubated with these proinflammatory cytokines, CINC-2 beta dose-dependently increased Reg messenger RNA and Reg protein in ECL cells. CXCR-2 was identified in isolated ECL cells. CONCLUSIONS CINC-2 beta, expressed in damaged gastric mucosa, stimulates the production of Reg protein in ECL cells via CXCR-2 and may be involved in the accelerated healing of injured gastric mucosa.
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Affiliation(s)
- H Kazumori
- Second Department of Internal Medicine, Shimane Medical University, Izumo, Japan
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26
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Abstract
Gastrin has a potent trophic effect on gastric fundic mucosa. When serum concentrations of gastrin are elevated, proliferation of both the progenitor cells in the glandular neck zone and enterochromaffin-like (ECL) cells in the bottom of the glands is stimulated. Because ECL cells have gastrin receptors, their proliferation is directly stimulated by gastrin. However, because the proliferation of progenitor cells cannot be directly stimulated (so far there has been no gastrin receptor demonstrated on these proliferating cells), some indirect mechanisms must be involved. Enterochromaffin-like and parietal cells are only two types of cells that have demonstrated a strong gene expression of the gastrin receptor. Furthermore, they secrete several growth factors, such as Reg protein, heparin-binding epidermal growth factor-like growth factor (HB-EGF) and amphiregulin (AR). Reg protein production by ECL cells, as well as HB-EGF and AR production by parietal cells, is stimulated by gastrin and these growth factors are potent trophic agents of progenitor cells in the neck zone of the gastric fundic mucosa. Accordingly, gastrin may stimulate the proliferation of gastric mucosal cells indirectly via these growth factors in addition to its direct trophic effect on ECL cells.
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Affiliation(s)
- Y Kinoshita
- Department of Medicine II, Shimane Medical University, Izumo, Japan.
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27
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Abstract
Research performed in the laboratory and the clinic over the past several years has added to our understanding of the mechanisms that are operative in protecting the epithelial lining of the stomach and duodenum from injury and ulceration, most frequently caused by necrotic agents in the lumen. The defensive mechanism of the gastroduodenal mucosa comprises a series of physical, chemical, biologic, and immunologic barriers or mechanisms that act in concert to either prevent or limit cellular injury or transformation. The field of gastroduodenal defense can be subdivided into the following four areas: extracellular mucus barrier properties; membrane and ion transport properties; cellular factors promoting growth and restitution; and vascular, neural, and inflammatory factors ensuring optimal tissue perfusion and immune responsiveness, respectively. In addition, a great deal can be learned about gastroduodenal defense by studying the effects of ulcerogenic factors and conditions on the defensive mechanisms described here and specifically how they may be compromised by nonsteroidal anti-inflammatory drugs and Helicobacter pylori infection. This review presents interesting and noteworthy findings impacting on these properties contributing to gastroduodenal defense since the prior review article on this subject appearing in this journal.
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Affiliation(s)
- L M Lichtenberger
- Department of Integrative Biology, Pharmacology and Physiology, The University of Texas Medical School at Houston, Houston, Texas 77030, USA
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28
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Fukui H, Kinoshita Y, Maekawa T, Okada A, Waki S, Hassan S, Okamoto H, Chiba T. Regenerating gene protein may mediate gastric mucosal proliferation induced by hypergastrinemia in rats. Gastroenterology 1998; 115:1483-93. [PMID: 9834276 DOI: 10.1016/s0016-5085(98)70027-7] [Citation(s) in RCA: 141] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND & AIMS Regenerating gene (Reg) has been isolated from rat regenerating pancreatic islets, and Reg protein is mitogenic to islet cells. We have recently shown that Reg gene and Reg protein are expressed in gastric enterochromaffin-like (ECL) cells. This study aimed to clarify whether gastrin enhances Reg protein production in ECL cells and whether Reg protein is mitogenic to gastric mucosal cells. METHODS Reg gene expression in response to acute and chronic hypergastrinemia was investigated in rats. Immunohistochemical studies, Northern blotting, and in situ hybridization were performed to investigate the expression of Reg protein and Reg gene. The direct effect of gastrin on Reg gene expression was investigated using isolated ECL cells, and the trophic effect of Reg protein on cultured gastric epithelial cells was assessed by [3H]thymidine uptake. RESULTS Both chronic hypergastrinemia and short-term gastrin administration stimulated Reg gene expression and Reg protein production in fundic mucosa. Reg gene expression was also augmented in isolated ECL cells after incubation with rat gastrin. Reg protein was mitogenic to cultured rat gastric epithelial cells. CONCLUSIONS Gastrin stimulates the production of Reg protein in gastric ECL cells, which may be involved in the gastrin-induced gastric mucosal cell growth.
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Affiliation(s)
- H Fukui
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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29
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Waki S, Kinoshita Y, Wang HY, Asahara M, Matsushima Y, Hassan MS, Okada A, Maekawa T, Fukui H, Kawanami C, Kishi K, Chiba T. Effect of aging on gastrin receptor gene expression in rat stomach. Peptides 1998; 19:225-9. [PMID: 9493853 DOI: 10.1016/s0196-9781(97)00373-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Gastrin is a pivotal humoral factor which regulates gastric acid secretion through its receptors. There is no report, however, concerning the age-related changes of gastrin receptor gene expression in the stomach. Northern blot analysis and in situ hybridization were performed to clarify the changes of gastrin receptor expression during the aging. In situ hybridization clarified that gastrin receptor mRNA was expressed mainly in enterochromaffin-like (ECL) cells in adult rat gastric mucosa. With aging, gastrin receptor gene expression in the stomach increased with the concomitant increase in histidine decarboxylase mRNA. Since histidine decarboxylase is a marker of gastric ECL cells, the augmented gastrin receptor mRNA in aged rats may be caused by the increased ECL cells in gastric mucosa during the aging.
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Affiliation(s)
- S Waki
- Department of Medicine, Kobe University School of Medicine, Japan
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