MUC5AC Overexpression Research Articles

Mucus and MUC in asthma

Asthma is characterized by chronic airway inflammation and a mucus hypersecretory phenotype comprising excess mucus secretion, goblet cell hyperplasia and submucosal gland hypertrophy. This augmented mucus secretion has been relatively undervalued in asthma compared with airway inflammation. However, mucus plugging contributes to airflow limitation and airway hyperresponsiveness, and to morbidity and mortality in asthma. We review recent contributions to this field and therapeutic avenues to control mucus hypersecretion. A distinct mucus hypersecretory phenotype may present in asthma. Overexpression of MUC5AC, MUC5B and MUC2 have been described in asthma secretions, but identification of defined biochemical abnormalities and polymorphisms of mucin genes linked to asthma remains elusive. Activation of epidermal growth factor receptor (EGFR) activation appears central in transducing many different stimuli, including oxidative stress, proteases and cytokines. In contrast, nitrosative stress has barely been investigated. The existence of crosstalk between EGFR and other receptor systems may provide new clues regarding the activity of acetylcholine, adenosine and other agonists of G-protein-coupled receptors and other receptor families on mucin secretion. Modern techniques for noninvasive detection of mucus pathology will advance clinical research in this field. Airway mucus hypersecretion as a part of airway remodelling represents a problem in asthma, and studies of pathophysiology and therapeutic approaches are therefore warranted. Identification of targets such as the EGFR cascade, which are crucial in excessive and abnormal mucus secretion, may lead to the rational design of new antihypersecretory drugs that may enhance future asthma treatment.

Interleukin-1β and Tumor Necrosis Factor-α Induce MUC5AC Overexpression through a Mechanism Involving ERK/p38 Mitogen-activated Protein Kinases-MSK1-CREB Activation in Human Airway Epithelial Cells

Mucin hypersecretion is commonly observed in many inflammatory diseases of the respiratory tract. MUC5AC is generally recognized to be a major airway mucin because MUC5AC is highly expressed in the goblet cells of human airway epithelium. Moreover, it is regulated by various inflammatory cytokines. However, the mechanisms by which the interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha induce MUC5AC gene expression in normal nasal epithelial cells, and the signal molecules involved, especially in the downstream signaling of mitogen-activated protein (MAP) kinases, remain unclear. Here we show that pharmacologic or genetic inhibition of either ERK or p38 MAP kinase pathway abolished IL-1beta- and TNF-alpha-induced MUC5AC gene expression in normal human nasal epithelial cells. Our results also indicate that the activation of mitogen- and stress-activated protein kinase 1 (MSK1) and cAMP-response element-binding protein and cAMP-response element signaling cascades via ERK and p38 MAP kinases are crucial aspects of the intracellular mechanisms that mediate MUC5AC gene expression. Taken together, these studies give additional insights into the molecular mechanism of IL-1beta- and TNF-alpha-induced MUC5AC gene expression and enhance our understanding on mucin hypersecretion during inflammation.

Differential regulation by glucocorticoid of interleukin-13-induced eosinophilia, hyperresponsiveness, and goblet cell hyperplasia in mouse airways.

Interleukin (IL)-13 induces important features of bronchial asthma such as eosinophilic infiltration, airway hyperresponsiveness (AHR), and mucus hypersecretion. Although glucocorticoids suppress airway inflammation and remain the most effective therapy for asthma, the effects of glucocorticoids on the IL-13-dependent features are unknown. We studied the effects of dexamethasone on eotaxin production, eosinophil accumulation, goblet cell hyperplasia, and AHR after IL-13 administration into the airways of mice in vivo. MUC5AC gene expression, a marker of goblet cell hyperplasia, was also analyzed. IL-13 alone dose dependently induced AHR. Treatment with dexamethasone inhibited eotaxin expression and completely abolished eosinophil accumulation, but it did not affect AHR, MUC5AC overexpression, or goblet cell hyperplasia induced by IL-13. The effects of tumor necrosis factor-alpha on IL-13-induced AHR were also examined. Tumor necrosis factor-alpha did not affect AHR despite marked enhancement of eosinophil infiltration in IL-13-treated mice. These findings suggest that glucocorticoid is not sufficient to suppress IL-13-induced AHR or goblet cell hyperplasia and that eotaxin expression and eosinophilic inflammation do not have a causal relationship to the induction of AHR or goblet cell hyperplasia by IL-13. Control of steroid-resistant features induced by IL-13, including AHR and mucus production, may provide new therapeutic modalities for asthma.

Lipopolysaccharide Induces Overexpression of MUC2 and MUC5AC in Cultured Biliary Epithelial Cells: Possible Key Phenomenon of Hepatolithiasis

Bacterial infection, bile stasis, mucin hypersecretion, and an alteration of the mucin profile such as an aberrant expression of gel-forming apomucin (MUC2 and MUC5AC) in the intrahepatic biliary tree are thought to be important in the lithogenesis of hepatolithiasis. So far, there have been no detailed studies linking bacterial infection to altered mucus secretion of biliary epithelium. In this study, the influence of lipopolysaccharide (LPS), a bacterial component, on apomucin expression in cultured murine biliary epithelial cells was examined with emphasis on the participation of tumor necrosis factor (TNF)-alpha. It was found that LPS up-regulated the expression of MUC2 and MUC5AC in cultured murine biliary epithelial cells. LPS also induced the expression of TNF-alpha in biliary epithelial cells and its secretion into the culture medium. The up-regulation of these apomucins was inhibited by pretreatment with TNF-alpha antibody. TNF-alpha alone also induced the overexpression of MUC2 and MUC5AC in cultured biliary epithelial cells. This overexpression was inhibited by pretreatment with calphostin C, an inhibitor of protein kinase C. These findings suggest that LPS can induce overexpression of MUC2 and MUC5AC in biliary epithelial cells via synthesis of TNF-alpha and activation of protein kinase C. This mechanism might be involved in the lithogenesis of hepatolithiasis.

MUC2 Is a Molecular Marker for Pseudomyxoma Peritonei

Pseudomyxoma peritonei, a syndrome first described by Rokitansky in 1842, is an enigmatic, often fatal intra-abdominal disease characterized by dissecting gelatinous ascites and multifocal peritoneal epithelial implants secreting copious globules of extracellular mucin. Although much past interest in the syndrome has focused on the question of whether the disease arises from primary appendiceal or ovarian mucinous tumors of varying malignant potential, the accumulation of extracellular mucin with its resulting obstruction of abdominal viscera and adhesion formation is one major cause of this disease's morbidity and mortality irrespective of the origin or transformed status of the epithelium secreting it. Because of this and because of the recent discovery and cloning of a series of specific mucin genes responsible for mucin secretion and extracellular deposition, we decided to analyze cases of pseudomyxoma peritonei with specific mucin cDNAs and corresponding antibodies to identify a characteristic marker for this disease which ultimately might be targeted therapeutically. Our study specifically investigated MUC2 and MUC5AC because these two mucins possessed the physicochemical property of being gel-forming, a property exhibited by pseudomyxoma peritonei grossly. Expression of MUC2 and MUC5AC in pseudomyxoma peritonei and in accompanying and non-accompanying appendiceal and ovarian mucinous neoplasms were analyzed by in situ hybridization, immunocytochemistry and digital image analysis. A striking overexpression of both MUC2 and MUC5AC was observed in nearly all cases of pseudomyxoma peritonei of unknown and appendiceal origin. In these cases, however, MUC2 gene expression was more prominent. The mucin:cell ratio averaged 10 to 1 in these cases. The primary ovarian mucinous tumors, some of which exhibited pseudomyxoma ovarii and/or peritoneal implants but not classic pseudomyxoma peritonei, in contrast, expressed only MUC5AC and gave rise to implants where the mucin:cell ratio averaged only 1 to 1. MUC2 overexpression then supported an intestinal rather than ovarian origin for true pseudomyxoma peritonei, irrespective of whether an appendiceal primary was documented. In all cases studied, the fidelity of MUC2 and MUC5AC expression held irrespective of the degree of malignant transformation which was present. MUC2 is therefore a reliable molecular marker for pseudomyxoma peritonei.

What does mucin have to do with lung disease?

Mucin glycoproteins are a major macromolecular component of mucus. Mucins are large, heavily glycosylated glycoproteins that are expressed in two major forms: the membrane-tethered mucins and the secreted mucins. In the airways, MUC1 and MUC4 are the predominant membrane-tethered mucins that are present on epithelial cell surfaces; MUC5AC, MUC5B and MUC2 are the predominant secreted mucins that contribute to the mucus gel. Although the role of MUC1 and MUC4 in the airway is not known, they may function as receptors or receptor ligands and activate intracellular signalling cascades affecting epithelial functions. Several inflammatory mediators increase expression of the secreted mucin genes, MUC5AC and MUC2. Furthermore, overexpression of MUC5AC, MUC5B and MUC2 correlates strongly with secretory cell hyperplasia and metaplasia in human and murine airways. The insights gleaned from the investigations of mucin function and gene regulation should be useful for elucidating the cellular mechanisms leading to airway remodelling and mucus obstruction.

Normal respiratory mucosa, precursor lesions and lung carcinomas: differential expression of human mucin genes.

Mucins are glycoproteins synthesized by epithelial cells and thought to promote tumor-cell invasion. Eight human mucin genes have been well characterized: MUC2, MUC5AC, MUC5B, MUC6 map to 11p15.5 and encode secretory gel forming mucins while MUC1, MUC3, MUC4, MUC7 are scattered on different chromosomes and encode membrane-bound or secreted mucins. The expression pattern of the mucin genes is complex in normal airways involving six genes, mainly MUC5AC and MUC5B in mucus-producing cells and MUC4 in a wide array of epithelial cells. MUC5AC overexpression in metaplasia, dysplasia and normal epithelium adjacent to squamous cell carcinoma provides additional arguments for a mucous cell origin of preneoplastic squamous lesions. MUC5AC and MUC5B expression is related to mucus formation in adenocarcinomas. Mucinous bronchioloalveolar carcinoma (BAC) has a particular pattern of mucin gene expression indicating that it has sustained a well-differentiated phenotype similar to the goblet cell, correlated with distinctive features i.e. a noninvasive pattern and a better prognosis than nonBACs. MUC4 is the earlier mucin gene expressed in the foregut, before epithelial differentiation and is expressed independently of mucus secretion both in normal adult airways and carcinomas. These findings are in favor the histogenetic theory of non-small-cell carcinoma originating from a pluripotent mucous cell.