The Adherent Gastric Mucous Layer Is Composed of Alternating Layers of MUC5AC and MUC6 Mucin Proteins

Mucin-type glycoproteins are the major structural proteins in gastric mucus. Stomach mucin proteins include MUC5AC, synthesized by surface foveolar or pit cells, and MUC6, synthesized by neck and gland cells. The aim of this study was to determine the spatial distribution of these mucin proteins within the extracellular mucous coat. Double-labeling immunoflourescence/confocal microscopy was used in histologically normal surgical resection specimens. Intralumenal mucin within antral glands consisted entirely of MUC6 protein. Intralumenal mucin within the gland isthmus region consisted of an irregular mixture of MUC5AC and MUC6. The mucous layer on the gastric surface consisted primarily of MUC5AC extending in layered sheets with MUC6 protein layered in between. The laminated appearance of the surface mucus was present in both H. pylori-infected and noninfected specimens. These data indicate that MUC5AC and MUC6 proteins remain segregated within the mucous gel in a laminated linear arrangement. The physical stratification of mucin proteins may confer increased strength to the mucous layer or represent independent and redundant protection.     

Expression of gastric mucin in the stomachs of two patients with Menetrier's disease: an immunohistochemical study

Menetrier's disease is a rare gastric condition characterized by marked proliferation of the mucosa and variable mucus secretion and achlorhydria. We report, for the first time, minor variations in MUC1-7 distribution in the mucosa of two stomachs from patients with Menetrier's disease, when compared with a normal stomach. All stomachs stained positively for MUC4, 5AC and 6 and showed no or little staining with MUC2 and 3. Thus, Menetrier's disease is characterized by an excess quantity of mucus secretion, but differs little from normal stomachs with regards to the types of mucin produced. The mucins, MUC1-7, are found with variable distribution in different body tissues; MUC4, MUC5AC and MUC6 are typically found in gastric mucosa.     

A role for 12R-lipoxygenase in MUC5AC expression by respiratory epithelial cells

Eicosanoids are metabolites of arachidonic acid produced by cyclooxygenases (COXs) or lipoxygenases (LOXs). They mediate inflammation and mucus secretion in chronic pulmonary inflammatory diseases. The gel-forming mucin MUC5AC is over-expressed in the airways of patients with these diseases. MUC5AC expression is mediated by an extracellular signal-regulated kinase (ERK)/Sp1 dependent mechanism. Our aim was to study the role of eicosanoids and their signalling pathways in MUC5AC expression. Inhibitors of 12-LOX, but not those of COX, 5-LOX or 15-LOX, reduce MUC5AC expression induced by phorbol myristate acetate (PMA) in the bronchial epithelial cell line NCI-H292. These inhibitors also abrogate the production of whole mucus by cell monolayers. Two forms of 12-LOX (R and S) exist in mammals. Using siRNAs we show that 12R-LOX but not 12S-LOX is involved in MUC5AC expression induced by PMA, lipopolysaccharide or transforming growth factor-α. 12R-LOX also participates in MUC2 and MUC5B expression, although to a lesser extent than for MUC5AC. Contrarily, 12R-LOX silencing does not modify interleukin-8 production. 12-LOX inhibitors reduce ERK activation and Sp1 translocation induced by PMA. Moreover, the 12R-LOX product 12(R)-hydroxyeicosatetraenoic acid, induces MUC5AC expression, ERK activation and Sp1 translocation. 12R-LOX is involved in MUC5AC expression. This occurs via ERK- and Sp1-signalling pathways.     

Inhibition of gastric mucin synthesis by Helicobacter pylori

BACKGROUND & AIMS: Mucins are high-molecular-weight glycoproteins that protect the gastric epithelium. Previous data suggested that gastric surface-type mucin is decreased in Helicobacter pylori-infected patients and restored after eradication of the infection. Our aim was to determine the effect of H. pylori on mucin synthesis in cultured gastric epithelial cells. METHODS: Mucin synthesis was measured by labeling with [(3)H]glucosamine and size-exclusion chromatography. Expression of MUC5AC and MUC1 mucin protein antigens was quantitated by Western blot analysis. RESULTS: Mucin synthesis was inhibited more than 80% when KATO III cells were incubated with H. pylori, with no effect on mucin secretion or degradation. Inhibition was rapid (4 hours), partially reversible, dependent on concentration of bacteria, and associated with the insoluble membrane fraction. H. pylori decreased levels of MUC5AC and MUC1 mucins. MUC1 inhibition was half-maximal by 4 hours and partially reversed by 24 hours, but the decrease in MUC5AC was less rapid and not reversible within 24 hours. CONCLUSIONS: H. pylori inhibits total mucin synthesis in vitro and decreases the expression of MUC5AC and MUC1. A decrease in gastric mucin synthesis in vivo may disrupt the protective surface mucin layer.     

白细胞介素-13对人支气管上皮细胞SPDEF表达的影响及SPDEF在哮喘气道黏液高分泌中的作用

目的探讨白细胞介素(IL)-13对人支气管上皮细胞SPDEF表达的影响及SPDEF在哮喘气道黏液高分泌中的作用。方法将人原代支气管上皮细胞(NHBE细胞)分为对照组、IL-13组及IL-13+SPDEF siRNA组。培养28天后,收集NHBE细胞并提取总RNA,采用实时荧光定量聚合酶链反应检测NHBE细胞SPDEF、粘蛋白MUC5AC及MUC5B mRNA的表达水平,流式细胞术检测MUC5AC阳性细胞数量和免疫荧光强度,免疫荧光染色检测粘蛋白MUC5AC和MUC5B的表达水平。结果IL-13组NHBE细胞SPDEF和MUC5AC mRNA的表达水平、MUC5AC阳性细胞数量和免疫荧光强度均明显高于对照组(P<0.001),而MUC5B mRNA的表达水平明显低于对照组(P<0.05);IL-13+SPDEF siRNA组NHBE细胞SPDEF和MUC5AC mRNA的表达水平、MUC5AC阳性细胞数量和免疫荧光强度均明显低于IL-13组(P<0.001);IL-13+SPDEF siRNA组MUC5B mRNA的表达水平明显低于对照组(P<0.05)。IL-13组NHBE细胞MUC5AC的表达水平明显高于对照组和IL-13+SPDEF siRNA组,而MUC5B的表达水平低于对照组。结论IL-13可能通过诱导人支气管上皮细胞SPDEF上调,促进气道粘蛋白MUC5AC的高表达,引起哮喘气道黏液高分泌。     

LPS-induced mucin expression in human sinus mucosa can be attenuated by hCLCA inhibitors

BACKGROUND: hCLCA1 is a member of the calcium-activated chloride channel family and is associated with disease-inducible mucus expression. Niflumic acid (NFA) and a closely related chemical structure are reported inhibitors of calcium-activated chloride channels and endotoxin-inducible mucus expression in the mouse. Therefore, we tested the hypothesis that hCLCA1 may be involved in lipopolysaccharide (LPS) induced mucin up-regulation in human airways. We also investigated the effect of NFA and MSI-2216 on LPS-induced mucin up-regulation. MATERIALS AND METHODS: Explanted human airways and the muco-epidermoid cell line Calu-3 were stimulated with LPS. Different concentrations of NFA or MSI-2216 were added to LPS-stimulated airway mucosa and Calu-3 cells. Expression of hCLCA1 and MUC5AC mRNA and protein was quantified in human airways using real-time PCR and PAS staining. In addition, immunohistochemistry was performed for quantification of inflammatory cells (lymphocytes, monocytes, eosinophils, and neutrophils) in the submucosa of the airways. Expression of hCLCA1 protein in Calu-3 cells was analysed by FACS. RESULTS: LPS significantly induced hCLCA1 and MUC5AC mRNA and protein expression in human airway mucosa (P < 0.05). NFA and MSI-2216 significantly decreased LPS-induced mucus expression in explanted airway mucosa in a dose-dependent manner (P < 0.05). In Calu-3 cells, LPS significantly increased hCLCA1 surface expression whereas intracellular expression was significantly decreased (P < 0.05). In Calu-3 cells, NFA and MSI-2216 also significantly reduced MUC5AC mRNA expression (P < 0.05). CONCLUSIONS: These data suggest that hCLCA1 may play a role in LPS-induced mucin expression in human airway mucosa. Calcium-activated chloride channel inhibitors significantly decreased LPS-induced mucus expression both ex vivo and in vitro . Therefore, blocking of hCLCA1 may offer a therapeutic approach to reduce bacterial-induced mucus hypersecretion.     

Entamoeba histolytica cysteine proteases cleave the MUC2 mucin in its C-terminal domain and dissolve the protective colonic mucus gel

In order for the protozoan parasite Entamoeba histolytica (E.h.) to cause invasive intestinal and extraintestinal infection, which leads to significant morbidity and mortality, it must disrupt the protective mucus layer by a previously unknown mechanism. We hypothesized that cysteine proteases secreted from the amoeba disrupt the mucin polymeric network, thereby overcoming the protective mucus barrier. The MUC2 mucin is the major structural component of the colonic mucus gel. Heavily O-glycosylated and protease-resistant mucin domains characterize gel-forming mucins. Their N- and C-terminal cysteine-rich domains are involved in mucin polymerization, and these domains are likely to be targeted by proteases because they are less glycosylated, thereby exposing their peptide chains. By treating recombinant cysteine-rich domains of MUC2 with proteases from E.h. trophozoites, we showed that the C-terminal domain was specifically targeted at two sites by cysteine proteases, whereas the N-terminal domain was resistant to proteolysis. The major cleavage site is predicted to depolymerize the MUC2 polymers, thereby disrupting the protective mucus gel. The ability of the cysteine proteases to dissolve mucus gels was confirmed by treating mucins from a MUC2-producing cell line with amoeba proteases. These findings suggest a major role for E.h. cysteine proteases in overcoming the protective mucus barrier in the pathogenesis of invasive amoebiasis. In this report, we identify a specific cleavage mechanism used by an enteric pathogen to disrupt the polymeric nature of the mucin gel.     

Overexpressing mouse model demonstrates the protective role of Muc5ac in the lungs

MUC5AC, a major gel-forming mucin expressed in the lungs, is secreted at increased rates in response to infectious agents, implying that mucins exert a protective role against inhaled pathogens. However, epidemiological and pathological studies suggest that excessive mucin secretion causes airways obstruction and inflammation. To determine whether increased MUC5AC secretion alone produces airway obstruction and/or inflammation, we generated a mouse model overexpressing Muc5ac mRNA ∼20-fold in the lungs, using the rCCSP promoter. The Muc5ac cDNA was cloned from mouse lungs and tagged internally with GFP. Bronchoalveolar lavage fluid (BALF) analysis demonstrated an approximate 18-fold increase in Muc5ac protein, which formed high-molecular-weight polymers. Histopathological studies and cell counts revealed no airway mucus obstruction or inflammation in the lungs of Muc5ac-transgenic (Muc5ac-Tg) mice. Mucus clearance was preserved, implying that the excess Muc5ac secretion produced an “expanded” rather than more concentrated mucus layer, a prediction confirmed by electron microscopy. To test whether the larger mucus barrier conferred increased protection against pathogens, Muc5ac-Tg animals were challenged with PR8/H1N1 influenza viruses and showed significant decreases in infection and neutrophilic responses. Plaque assay experiments demonstrated that Muc5ac-Tg BALF and purified Muc5ac reduced infection, likely via binding to α2,3-linked sialic acids, consistent with influenza protection in vivo. In conclusion, the normal mucus transport and absence of a pulmonary phenotype in Muc5ac-Tg mice suggests that mucin hypersecretion alone is not sufficient to trigger luminal mucus plugging or airways inflammation/goblet cell hyperplasia. In contrast, increased Muc5ac secretion appears to exhibit a protective role against influenza infection.     

Prognostic Significance of Mucin Expression in Gastric Carcinoma

In patients with gastric carcinomas, the role of the alteration of mucin expression in overall survival has been a matter of some speculation, but few studies have been reported. The aim of our study was to determine the relationship between MUC1, MUC2, and MUC5AC expression and patient survival, with a secondary aim designed to investigate the alteration of MUC expression within various clinicopathologic parameters. Forty-four specimens from gastric carcinoma patients were immunohistochemically evaluated using the monoclonal antibodies for MUC1 (EMA, clone E29), MUC2 (CCP58), and MUC5AC (human gastric mucin, clone 45M1). MUC1 expression increased in gastric carcinoma. MUC1 positivity was determined to be statistically significant, with poor clinicopathological parameters and decreased long-term survival. MUC5AC expression decreased in gastric carcinoma. In addition, patients with MUC5AC-positive tumors also had poor clinicopathological parameters and showed shorter survival than those with MUC5AC-negative tumors. MUC2 expression was not significantly associated with patient survival. We confirmed that the expression of mucins is associated with characteristics of differentiation in gastric carcinoma. Poor patient outcomes were seen in gastric carcinomas with MUC1 mucin expression and MUC5AC positivity.     

A confirmatory report for the close interaction of Helicobacter pylori with gastric epithelial MUC5AC expression

BACKGROUND: Helicobacter pylori (H. pylori) infection is associated with the development of gastritis and peptic ulcer and is presumed to be a risk factor for low-grade B-cell lymphoma and gastric cancer. H. pylori also causes critical alterations in gastric mucin structure. Our aim was to determine the effect of H. pylori on MUC1, MUC2, and MUC5AC expression. METHODS: Thirty H. pylori-positive and 15 H. pylori-negative antral gastric endoscopic biopsy specimens were evaluated for MUC1, MUC2, and MUC5AC expression with immunohistochemical staining. From the same specimens, we scrutinized the presence of H. pylori infection by hematoxylin and eosin and immunohistochemical staining. RESULTS: In H. pylori infected patients, the expression of MUC5AC was found to be localized to the cells in the superficial epithelium and upper parts of the gastric glands. The number of MUC5AC-expressing cells and the staining intensity of MUC5AC were shown to decrease in patients with H. pylori infection. Histopathology and immunostaining patterns of gastric mucins implied that H. pylori was physically associated with extracellular MUC5AC and MUC5AC-producing cells. H. pylori infection does not significantly affect staining intensity and patterns of MUC1 and MUC2 expressions. MUC1 was not found in dysplastic tissues or intestinal metaplasia areas. MUC5AC was expressed in dysplastic areas, but not in intestinal metaplasia. MUC2 was expressed in both dysplastic and intestinal metaplasia areas. CONCLUSION: H. pylori decreases the amount of MUC5AC expression. With reducing MUC5AC-producing cells and MUC5AC mucin, H. pylori may potentially cause significant alterations of the structure and function of gastric mucins. H. pylori-dependent inhibition of mucin synthesis deserves more investigations to clarify the role of H. pylori and gastric MUC5AC interaction.     

Assembly and organization of the N-terminal region of mucin MUC5AC: Indications for structural and functional distinction from MUC5B

Elevated levels of MUC5AC, one of the major gel-forming mucins in the lungs, are closely associated with chronic obstructive lung diseases such as chronic bronchitis and asthma. It is not known, however, how the structure and/or gel-making properties of MUC5AC contribute to innate lung defense in health and drive the formation of stagnant mucus in disease. To understand this, here we studied the biophysical properties and macromolecular assembly of MUC5AC compared to MUC5B. To study each native mucin, we used Calu3 monomucin cultures that produced MUC5AC or MUC5B. To understand the macromolecular assembly of MUC5AC through N-terminal oligomerization, we expressed a recombinant whole N-terminal domain (5ACNT). Scanning electron microscopy and atomic force microscopy imaging indicated that the two mucins formed distinct networks on epithelial and experimental surfaces; MUC5B formed linear, infrequently branched multimers, whereas MUC5AC formed tightly organized networks with a high degree of branching. Quartz crystal microbalance-dissipation monitoring experiments indicated that MUC5AC bound significantly more to hydrophobic surfaces and was stiffer and more viscoelastic as compared to MUC5B. Light scattering analysis determined that 5ACNT primarily forms disulfide-linked covalent dimers and higher-order oligomers (i.e., trimers and tetramers). Selective proteolytic digestion of the central glycosylated region of the full-length molecule confirmed that MUC5AC forms dimers and higher-order oligomers through its N terminus. Collectively, the distinct N-terminal organization of MUC5AC may explain the more adhesive and unique viscoelastic properties of branched, highly networked MUC5AC gels. These properties may generate insight into why/how MUC5AC forms a static, “tethered” mucus layer in chronic muco-obstructive lung diseases.

Gel-forming mucins are an essential component of the mucus layer that covers and protects epithelial surfaces from environmental insults. The mucin composition of mucus lining different mucosal surfaces depends on the functional requirements imposed on the epithelium. For instance, in the small intestine and colon, which harbor diverse microbiota, MUC2 is the mucin structurally adapted to form a “tight mucus layer” that provides a niche for the microbes and protects the underlying epithelia by preventing bacterial invasion (1). While in the stomach, MUC6 and MUC5AC together provide a barrier that protects the epithelium from the harsh effects of high luminal acidity (pH = 2 to 3) (2). The mouth, which is the major portal of food and microbes, is protected by saliva, and the dominant gel-forming mucin is MUC5B (3). The lungs, another major portal with exposure to the environment, are mainly protected during homeostasis by MUC5B with a lesser contribution by MUC5AC (4, 5). The distinct regions of the airways have different functional and innate protective requirements for homeostasis, and this necessitates the diverse expression patterns of both mucins throughout the respiratory system (6). MUC5B, secreted by cells in the submucosal glands and the surface epithelium (6), has been shown to be essential for lung innate defense (7). MUC5AC, secreted only by cells in the surface epithelium mainly in the larger airways (6), is generally produced in response to stresses such as cigarette smoke and allergens and is closely associated with muco-obstructive lung diseases, including chronic bronchitis (CB), chronic obstructive pulmonary disease (COPD) (4, 8), and asthma (9, 10). MUC5AC is also critical for defense against enteric parasites, some of which invade the lung (11).Both MUC5B and MUC5AC are large (2 to 100 MDa), polymeric glycoproteins with a high degree of sequence similarity and domain homology, particularly in their N- and carboxyl- terminal regions (12–15). Similar to MUC5B, the N-terminal region of MUC5AC contains von Willebrand factor–like domains (D1, D2, and D3) in addition to trypsin inhibitory–like (TIL) domains and unique regions. The N terminus is followed by a central, highly O-glycosylated mucin domain, which is interrupted by cysteine-rich (CysD) domains and a carboxyl-terminal region that mediates dimerization. In contrast to other gel-forming mucins, MUC5AC contains a putative leucine zipper (LZ) domain (16) at the end of the carboxyl-terminal end of the D1 domain of the N terminus, with no known function.The major gel-forming mucins (MUC2, MUC5AC, MUC5B, and MUC6) assemble intracellularly to form polymers, first via disulfide-linked dimerization between their carboxyl termini and then via disulfide-linked N-terminal multimerization. However, knowledge of multimerization is incomplete. The MUC5B N-terminal region is assembled exclusively as dimers (17). However, assembly of the MUC2 N-terminal region is more controversial, and it has been reported to assemble solely as trimers (18) or dimers (19). The N-terminal assembly of MUC5AC has not been investigated. It is thought that the unique structural organization of the different gel-forming mucins results in mucus gels optimized to meet the functional demands and provide proper protection to the diverse epithelial environments across the body.MUC5AC mucin production is modulated by both type 1 [e.g., in response to viral infections (20, 21) and cigarette smoke (22)] and type 2 [e.g., in response to allergens (9)] immune responses, associated with lung disease and, indeed, disproportionately increases as compared to MUC5B (4, 8, 9, 23, 24). How MUC5AC contributes to both innate defense of the lung and the pathogenesis of chronic obstructive lung diseases remains unclear. As a first step of understanding the structural, organizational, and functionally distinctive properties of MUC5AC mucin and how these properties may affect the mucus gel organization/properties as compared to the other major lung mucin, MUC5B, we investigated the nature of MUC5AC multimeric organization through its N-terminal domain using an expressed recombinant protein (5ACNT), with a focus on the unique LZ region at the carboxyl-terminal end of the D1 domain. To understand if the LZ region has an organizational role in the assembly of the N-terminal region of MUC5AC, we mutated the four leucine residues in the LZ region of 5ACNT.     

Aberrant expression of MUC5AC and MUC6 gastric mucins and sialyl Tn antigen in intraepithelial neoplasms of the pancreas

BACKGROUND & AIMS: It has recently been suggested that infiltrating adenocarcinoma of the pancreas arises from histologically well-defined precursor ductal lesions called pancreatic intraepithelial neoplasia (PanIN-1A, -1B, -2, and -3). This study examined alterations in the pattern and the level of expression of several mucin genes (MUC1, MUC2, MUC5AC, and MUC6) and mucin-associated tumor antigens (Nd2 and sialyl Tn) in these precursor lesions. METHODS: We examined 139 PanINs and 68 infiltrating ductal adenocarcinomas of the pancreas by using immunohistochemistry and in situ hybridization methods. RESULTS: Overexpression of MUC1, a pan-epithelial mucin, and MUC6, a pyloric-gland mucin, and de novo expression of MUC5AC, a gastric foveolar mucin, was observed in all stages of PanINs and invasive ductal adenocarcinoma. In contrast, the expression of mucin-associated carbohydrate antigen, sialyl Tn, was markedly increased only in PanlN-3 and invasive ductal adenocarcinoma. In addition, a decrease in the expression of these mucin-associated peptide and carbohydrate antigens was correlated with the degree of differentiation of the tumor. CONCLUSIONS: Expression of both gastric-foveolar and pyloric-gland mucin in PanINs is an early event, whereas sialyl Tn expression is a late event in the recently defined progression model of pancreatic carcinogenesis. This altered mucin gene expression provides new insight into the role of cell lineage-associated metaplasia in pancreatic carcinogenesis.     

Role of epithelial mucins during airway infection

Airway surface fluid contains two layers of mucins consisting mainly of 5 different mucin gene products. While the outer layer contains two gel-forming mucins (MUC5AC and MUC5B) that are tightly associated with various biologically active, defensive molecules, the inner layer contains three membrane-tethered mucins (MUC1, MUC4 and MUC16) shed from the apical cell surface. During airway infection, all of these mucins serve as a major protective barrier against pathogens. MUC1 mucin produced by virtually all the surface columnar epithelial cells in the respiratory tract as well as Type II pneumocytes in the alveoli plays an additional, perhaps more critical role during respiratory infection by controlling the resolution of inflammation that is essential to prevent the development of inflammatory lung disease.     

Mucin gene expression in human embryonic and fetal intestine

Background—The intestinal epithelium is coveredby a continuous layer of mucus which is secreted by well differentiatedepithelial cells. Disregulation of the expression of mucins has beenreported to have possible implications in the neoplastic process which affects intestinal mucosae. It is well known that preneoplastic andneoplastic tissues can express fetal phenotypic characteristics.
Aims—To assess whether the expression of mucingenes in the intestinal tract is linked to the stage of cellulardifferentiation and tissue development, by studying the expression ofsix mucin genes in human fetal small intestine and colon, and alsoadult tissues.
Methods—In situ hybridisation was used to studymRNA expression of MUC2, MUC3, MUC4, MUC5B, MUC5AC, and MUC6 in 32 human embryos and fetuses (6.5-27 weeks gestation). Normal adultmucosae were used as controls.
Results—Three mucin genes, MUC2, MUC4, andMUC5AC, were differently expressed in fetal intestine compared withexpression in normal adults.
Conclusion—These differences in mucin geneexpression suggest a possible regulatory role for these products inintestinal epithelial cell differentiation.

Keywords:mucin genes; mucins; intestine; differentiation; human fetus

     

Mucin core protein expression by colorectal mucinous carcinomas with or without mucus hyperplasia

Background In the categorization of colorectal mucinous carcinomas, much attention has been paid to the amount of extracellular mucin, but little to that of intracellular mucin. Perhaps this factor would be useful in further categorization.Methods We estimated the amount of intracellular mucin morphologically, and classified colorectal tumors (tubular adenomas, mucinous carcinomas, and nonmucinous carcinomas) into two categories each, those with and without intracellular mucus hyperplasia. From preliminary results, we chose a range of 50% or more for the ratio of intracellular mucus to the total area of tumor cells for our definition of such hyperplasia. Then, mucin expression in the different categories was examined immunochemically with antibodies to the mucin core proteins MUC1, MUC2, MUC5AC, and MUC6.Results MUC1 expression was found in none of the 40 adenomas, 8 (17%) of the 48 mucinous carcinomas (with little difference in those with and without mucus hyperplasia), and 4 (16%) of the 25 nonmucinous carcinomas. MUC2 was found in all mucinous carcinomas. MUC5AC was found in 18 (86%) of the 21 mucinous carcinomas with mucus hyperplasia and 18 (90%) of the 20 adenomas with mucus hyperplasia, but in only 9 (33%) of the 27 mucinous carcinomas without mucus hyperplasia, 5 (20%) of the 25 nonmucinous carcinomas, and 2 (10%) of the 20 adenomas without mucus hyperplasia.Conclusions Mucinous carcinomas with and without mucus hyperplasia may arise from adenomas with and without mucus hyperplasia, respectively. The amount of intracellular mucin may be a morphologic reflection of the origin of colorectal mucinous carcinomas.     

Mucin gene expression in intestinal epithelial cells in Crohn's disease

BACKGROUND: Crohn's disease (CD) is a chronic relapsing inflammatory bowel disease of unknown origin. It is characterised by chronic mucosal ulcerations which affect any part of the intestine but most commonly are found in the ileum and proximal colon. AIMS: Studies were undertaken to provide information regarding cell specific expression of mucin genes in the ileum of patients with CD. PATIENTS AND METHODS: Expression of mucin genes was analysed in the ileal mucosa of patients with CD and controls by in situ hybridisation and immunohistochemistry. RESULTS: In healthy ileal mucosa, patients with CD showed a pattern identical to normal controls with main expression of MUC2 and MUC3, lesser expression of MUC1 and MUC4, and no expression of MUC5AC, MUC5B, MUC6, or MUC7. In the involved mucosa, the pattern was somewhat comparable although heterogeneous to that observed in healthy ileal mucosa. Importantly, a particular mucin gene expression pattern was observed in ileal mucosa close to the ulcer margins in ulcer associated cell lineage, with the appearance of MUC5AC and MUC6 mRNAs and peptides, which are normally restricted to the stomach (MUC5AC and MUC6) and duodenum (MUC6), and disappearance of MUC2. CONCLUSIONS: Our results suggest that gel forming mucins (more particularly MUC5AC and MUC6) may have a role in epithelial wound healing after mucosal injury in inflammatory bowel diseases in addition to mucosal protection.     

水通道蛋白敲除对支气管哮喘小鼠气道黏蛋白谱表达的影响

目的 水通道蛋白5(aquaporin 5,AQP5)敲除对支气管哮喘(简称哮喘)小鼠气道黏蛋白(MUC)谱表达的影响.方法 用卵白蛋白致敏和激发制备AQP5敲除鼠的哮喘高分泌模型.用苏木精-伊红染色观察气道及血管周围炎性细胞浸润.阿辛兰-过碘酸雪夫检测显示气道上皮细胞总黏液分泌,免疫组织化学检测气道上皮MUC5AC,MUC5B,MUC2的表达情况.结果 哮喘小鼠气道和血管周围可见大量中性粒细胞,淋巴细胞和嗜酸粒细胞浸润,气道上皮有大量的紫红色中性黏液分布,其中以AQP5敲除鼠总黏液分布更多.免疫组织化学显示小鼠哮喘高分泌模型中MUC谱主要为MUC5AC和MUC5B,未见MUC2分布.与野生型哮喘小鼠比较,MUC5AC、MUC5B在AQP5敲除鼠中表达更丰富.结论 AQP5基因缺失可能使小鼠气道对过敏原的应激性提高,从而促进黏液高分泌.     

Helicobacter pylori and gastric mucin expression: A systematic review and meta-analysis

AIM: To investigate the relationship between Helicobacter pylori (H. pylori) and mucin expression in gastric mucosa.METHODS: English Medical literature searches were conducted for gastric mucin expression in H. pylori infected people vs uninfected people. Searches were performed up to December 31^th 2014, using MEDLINE, PubMed, EMBASE, Scopus, and CENTRAL. Studies comparing mucin expression in the gastric mucosa in patients positive and negative for H. pylori infection, were included. Meta-analysis was performed by using Comprehensive meta-analysis software (Version 3, Biostat Inc., Englewood, NJ, United States). Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated compared mucin expression in individual studies by using the random effects model. Heterogeneity between studies was evaluated using the Cochran Q-test, and it was considered to be present if the Q-test P value was less than 0.10. I² statistic was used to measure the proportion of inconsistency in individual studies, with I² > 50% representing substantial heterogeneity. We also calculated a potential publication bias.RESULTS: Eleven studies, which represent 53 sub-studies of 15 different kinds of mucin expression, were selected according to the inclusion criteria. Every kind of mucin has been considered as one study. When a specific mucin has been studied in more than one paper, we combined the results in a nested meta-analysis of this particular mucin: MUC2, MUC6, STn, Paradoxical con A, Tn, T, Type 1 chain mucin, LeA, SLeA, LeB, AB-PAS, MUC1, and MUC5AC. The odds ratio of mucin expression in random analysis was 2.33, 95%CI: 1.230-4.411, P = 0.009, higher expression in H. pylori infected patients. Odds ratio for mucin expression in H. pylori positive patients was higher for MUC6 (9.244, 95%CI: 1.567-54.515, P = 0.014), and significantly lower for MUC5AC (0.447, 95%CI: 0.211-0.949, P = 0.036). Thus, H. pylori infection may increase MUC6 expression and decrease MUC5AC expression by 924% and 52%, respectively.CONCLUSION: H. pylori inhibits MUC5AC expression in the gastric epithelium, and facilitates colonization. In contrast, increased MUC6 expression may help inhibiting colonization, using MUC6 antibiotics properties.     

From mucins to mucus: toward a more coherent understanding of this essential barrier

Mucus is essential for protection of the airways; however, in chronic airway disease mucus hypersecretion is an important factor in morbidity and mortality. The properties of the mucus gel are dictated in large part by the oligomeric mucins and, over the past decade, we have gained a better understanding of the molecular nature of these complex O-linked glycoproteins. We know now that MUC5AC mucins, as well as different glycoforms of the MUC5B mucin, are the predominant gel-forming glycoproteins in airways mucus. Furthermore, the amount, molecular size, and morphology of these glycoproteins can be altered in disease. From more recent data, it has become clear that oligomeric mucins alone do not constitute mucus, and other mucin and nonmucin components must be important contributors to mucus organization and hence airways defense. Therefore, the challenge over the coming decade will be to investigate how the oligomeric mucins are organized to yield "functional" mucus. Such studies will provide a clearer perception of airways mucosal protection and may highlight specific components as potential targets for therapeutic strategies for the treatment of hypersecretory disease.