Pathophysiological relevance of sputum MUC5AC and MUC5B levels in patients with mild asthma

BackgroundAirway mucus hypersecretion is an important pathophysiological feature of asthma. MUC5AC and MUC5B are the major secreted polymeric mucins in airways, and their compositions affect mucus properties. Despite the increasing appreciation of MUC5AC and MUC5B compositions in asthmatic airways, their pathophysiological relevance remains to be fully understood in humans.MethodsIn this cross-sectional study, we prospectively enrolled newly referred steroid-untreated patients with mild asthma and healthy controls. We compared induced sputum MUC5AC and MUC5B levels between patients and controls. Subsequently, we assessed the correlation between MUC5AC and MUC5B levels and clinical indices in patients. Sputum MUC5AC and MUC5B levels were measured using enzyme-linked immunosorbent assays.ResultsSputum MUC5AC and MUC5B levels were significantly higher in patients (n = 87) than in controls (n = 22) (p = 0.0002 and p = 0.006, respectively). The ratio of sputum MUC5AC to MUC5B tended to be higher in patients than in controls (p = 0.07). Sputum MUC5AC levels significantly and positively correlated with fractional exhaled nitric oxide at expiratory flow of 50 mL/s (Spearman's rho = 0.29, p = 0.006), sputum eosinophil proportion (rho = 0.34, p = 0.0013), and airway sensitivity (rho = 0.39, p = 0.0005). By contrast, sputum MUC5B levels significantly and positively correlated with airway sensitivity (rho = 0.35, p = 0.002) and negatively correlated with airway reactivity (rho = ?0.33, p = 0.004).ConclusionsSputum MUC5AC is increased by protein levels and involved in airway type 2/eosinophilic inflammation and airway hyperresponsiveness in steroid-untreated patients with mild asthma.     

粘蛋白MUC1、MUC2、MUC4和MUC5AC在胰腺导管腺癌中的表达及意义

目的 研究胰腺导管腺癌(pancreatic ductal adenocarcinoma,PDA)组织中粘蛋白MUC1、MUC2、MUC4和MUC5AC的表达及其与临床病理参数间的关系.方法 应用SP免疫组织化学方法检测26例PDA、4例CP、16例正常胰腺组织、2例导管内乳头状黏液性肿瘤(IPMN)、4例实性假乳头状瘤(SPT)和1例浆液性囊性肿瘤(SCN)组织中MUC1、MUC2、MUC4、MUCSAC的表达.结果 正常胰腺和CP组织仅有MUC1表达,表达率均为100%;PDA中MUC1、MUC4和MUC5AC表达率分别为100%、88.5%(23/26)和76.9%(20/26);2例IPMN均见MUC2和MUC5AC表达;SPT和SCN中4种粘蛋白均无表达.MUC4和MUC5AC表达同PDA的临床病理参数之间无相关性(P＞0.05).结论 PDA时存在多种粘蛋白的表达,联合检测MUC1、MUC2、MUC4和MUC5AC的表达可能有助于对PDA的诊断和鉴别诊断.     

MUC1,MUC2和MUC3在胃增生性息肉中的表达模式

目的:研究MUC1,MUC2和MUC3在胃增生性息肉(gastric hyperplastic polyp,GHP)中的表达模式,旨在发现可以提示GHP发生癌变的有价值的标志物.方法:选用明确诊断的经手术切除或胃镜活检的GHP标本238例,其中包括GHP未伴有不典型增生188例,GHP伴低级别不典型增生(low grade dysplasia,LGD)35例,GHP伴高级别不典型增生(high grade dysplasia,HGD)8例及GHP伴局灶癌变(carcinoma,Ca)7例.同时选取30例正常胃黏膜标本为正常对照.采用免疫组织化学方法评价MUC1,MUC2及MUC3的阳性表达百分率及其表达模式.结果:MUC1呈现2种表达模式.模式1:细胞质和细胞膜弥漫阳性;模式2:腔缘侧细胞膜阳性.所有正常的胃黏膜和85.6%的未伴有不典型增生的GHP,MUC1表达呈模式1.80%的GHP伴LGD和100%的GHP伴高级别不典型增生或癌变(HGD/Ca)其MUC1的表达呈模式2(P<0.001).MUC2在GHP中表达阳性率为8.11%,GHP伴LGD为21.93%,GHP伴HGD/Ca为31.42%(P<0....     

Polymorphisms of TGFB1, TLE4 and MUC22 are associated with childhood asthma in Chinese population

ObjectiveTo investigate whether the genetic variants of TGFB1, TLE4, MUC22 and IKZF3 are associated with the development of asthma in Chinese children.Methods572 adolescent asthma patients and 590 age-matched healthy controls were included in this study. A total of four SNPs were genotyped, including rs2241715 of TGFB1, rs2378383 of TLE4, rs2523924 of MUC22, and rs907092 of IKZF3. Allele frequencies of the patients and the control group were compared by the Chi-square test. The Student t test was used to analyse the relationship between genotypes and clinical feature of the patients.ResultsPatients were found to have significantly different frequencies of allele A of rs2241715, allele G of rs2378383 and allele A of rs2523924 as compared with the controls (40.4% vs. 45.9%, p = 0.01 for rs2241715; 17.2% vs. 13.4%, p = 0.01 for rs2378383; 15.3% vs. 11.9%, p = 0.02 for rs2523924). For patients with severe asthma, those with genotype AA/AG of rs2241715 had remarkably higher FEV1% as compared with those with genotype GG (59.1 ± 4.3% vs. 55.4 ± 3.7%, p < 0.001). Moreover, those with genotype GG/GA of rs2378383 had remarkably lower FEV1% as compared with those with genotype AA (54.6 ± 2.9% vs. 58.6 ± 4.1%, p < 0.001).ConclusionsGenes TGFB1, TLE4 and MUC22 are associated with the risk of childhood asthma in Chinese population. Our results associating TGFB1 and TLE4 with clinical features of asthma suggest potential application of these parameters in the management of asthma children.     

血清MUC1、MUC2及MUC5AC表达与胃癌的关系

目的:探讨胃癌血清中MUC1、MUC2及MUC5AC与胃癌的关系.方法:利用黏蛋白MUC1、MUC2及MUC5AC的单抗及多抗,制备黏蛋白芯片,用免疫荧光原理进行检测,并用CEA作为指示指标,对30例胃癌患者及30例健康人进行黏蛋白血清水平的检测.结果:胃癌组与对照组相比,3种黏蛋白血清水平均增高,两组间差异显著.MUC1的阳性表达与胃癌TNM分期相关(P=0.0047),MUC2和MUC5AC的阳性表达与TNM分期无关(P=0.136.P=0.201).3种黏蛋白的表达均随胃癌分化程度降低而阳性表达增高的趋势,各单一黏蛋白以及黏蛋白两两之间联合用于胃癌诊断的敏感性及特异性均较高,其中单一黏蛋白中,MUC1的的敏感性和特异性最好,分别达到81.5%、75.8%,联合诊断(3种黏蛋白中至少2种阳性)的敏感性和特异性达到96.0%、82.9%.结论:检测血清黏蛋白MUC1、MUC2及MUC5AC水平,可以提高胃癌诊断的敏感性及特异性,为早期诊断提供新的思路,并对判断分期及预后提供帮助.     

Mucus hypersecretion and viscoelasticity changes in cigarette-smoking dogs

Chronic cigarette smoke exposure is well known to cause mucus hypersecretion in experimental animals, but the alterations in mucus rheology have not been described. We studied mucus hypersecretion and viscoelasticity changes in nine tracheostomized beagle dogs exposed to cigarette smoke. The dogs were trained to stand quietly in a harness, and smoke was delivered via a cuffed tracheostomy tube. A 35-cm3 bolus was introduced to the inspiratory line each 20 s, using unfiltered 70-mm cigarettes (20 mg tar, 1.2 mg nicotine). Each dog smoked 10 cigarettes per day over 2.5 h, 5 days per week. Two dogs were exposed for 6 months; 7 dogs were exposed for 10 months. Five dogs served as sham-smoking controls. Mucus was collected twice weekly without drugs by resting a cytology brush on the lower trachea for 2-5 min. The rheological properties of the mucus samples were determined by magnetic rheometry, which yields elasticity and viscosity as a function of frequency. The mucus was also weighed, and the galactose content was determined by phenolsulfuric acid assay. The mucus collection rate served as an index of tracheal mucus flux, and the galactose assay as a marker of mucous glycoprotein content. The tracheal mucus linear velocity (TMV) was determined periodically under xylazine analgesia by observing charcoal particle transport bronchoscopically. Eight of 9 smoking dogs developed mucus hypersecretion (flux greater than 2 X control) versus 1 of 5 controls (p less than .01). TMV did not change significantly in 10 months of exposure. In the first 2-4 months of smoking, the elasticity and viscosity of the mucus both decreased (mean at 4 months = 42% control, p less than .001), as did the galactose content (mean at 4 months = 48% control, p less than .01). At this stage, according to model studies, the mucus should have been more easily clearable by ciliary action. After 6 months, the viscoelasticity returned toward the initial control level, while the galactose content remained low, suggesting an alteration in the nature of the mucous glycoprotein.     

MUC1 and MUC5AC mucin expression in liver fluke-associated intrahepatic cholangiocarcinoma

AIM: To investigate the expressions of MUC1 and MUC5AC in intrahepatic cholangiocarcinoma (ICC). Association of expressions of mucins MUC1 and MUC5AC with clinical findings, metastasis, and survival of the liver fluke-associated ICC patients was determined. METHODS: The expressions of MUC1 and MUC5AC mucins were examined by immunohistochemical staining in 87 cases of histologically-proven ICC. The expressions of mucins in relationship between clinicopathological significance and prognosis of the patients were evaluated. RESULTS: Fifty-two patients (60%) exhibited both MUC1 and MUC5AC expressions, whereas 31% expressed either MUC1 or MUC5AC, and 9% expressed neither. High MUC1 immunoreactivity displayed a significant correlation with tumor progression as reflected by vascular invasion (P<0.01), whereas high expression of MUC5AC significantly correlated with neural invasion (P = 0.022) and advanced ICC stage (P= 0.008). Patients with high expression of MUC1 had a significantly shorter survival (P = 0.0002). According to multivariate analyses, MUC1 reactivity (P = 0.026), histological grading and stage of tumor represented the least probability of survival. CONCLUSION: MUC1 is overexpressed in liver fluke-associated cholangiocarcinoma and relates to vascular invasion and poor prognosis, whereas MUC5AC mucin is neoexpressed and relates to neural invasion and advanced ICC stage. High MUC1 expression in tumor may be useful for predicting the poor outcome of ICC patients.     

Mucus,mucins, and cystic fibrosis

Cystic fibrosis (CF) is both the most common and most lethal genetic disease in the Caucasian population. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and is characterized by the accumulation of thick, adherent mucus plaques in multiple organs, of which the lungs, gastrointestinal tract and pancreatic ducts are the most commonly affected. A similar pathogenesis cascade is observed in all of these organs: loss of CFTR function leads to altered ion transport, consisting of decreased chloride and bicarbonate secretion via the CFTR channel and increased sodium absorption via epithelial sodium channel upregulation. Mucosa exposed to changes in ionic concentrations sustain severe pathophysiological consequences. Altered mucus biophysical properties and weakened innate defense mechanisms ensue, furthering the progression of the disease. Mucins, the high‐molecular‐weight glycoproteins responsible for the viscoelastic properties of the mucus, play a key role in the disease but the actual mechanism of mucus accumulation is still undetermined. Multiple hypotheses regarding the impact of CFTR malfunction on mucus have been proposed and are reviewed here. (a) Dehydration increases mucin monomer entanglement, (b) defective Ca²⁺ chelation compromises mucin expansion, (c) ionic changes alter mucin interactions, and (d) reactive oxygen species increase mucin crosslinking. Although one biochemical change may dominate, it is likely that all of these mechanisms play some role in the progression of CF disease. This article discusses recent findings on the initial cause(s) of aberrant mucus properties in CF and examines therapeutic approaches aimed at correcting mucus properties.     

Clinical Aspects of Mucus and Mucous Plugging in Asthma

Abnormalities in the production and transport of airway secretions play an important role in the pathophysiology of asthma, especially during acute exacerbations of the disease. The synthesis of mucus becomes disordered, and other constituents of airway contents, including eosinophils and shed bronchial epithelial cells, contribute to the abnormal sputum that is produced. Altered viscoelastic properties of asthmatic mucus lead to impaired mucus transport rates. In addition, ciliary function may be directly inhibited by factors within the secretions. The consequence of these derangements is often widespread plugging of small bronchi and bronchioles. Occasionally, segmental or subsegmental atelectasis develops, but in most series radi-ographically visible atelectasis is uncommon. A rare complication is mucoid impaction of the bronchi, in which a central masslike opacity on chest radiograph is the manifestation of a large mucous plug in a major bronchus. A hypersensitivity reaction to fungi has been implicated in the formation of at least some mucoid impactions. A variety of pharmacological and other methods have been used in attempts to modify abnormal airway secretions and to promote their clearance, but none is of proven benefit. The development of effective therapies will probably require a better understanding of the regulation of normal mucociliary transport and of the disturbances that occur in asthma.     

Altered expression of MUC2 and MUC5AC in progression of colorectal carcinoma

AIM:To study the expression profiles of MUC2 and MUC5AC in tumorigenesis of colorectal carcinoma and in its different pathologic types.METHODS:Formalin-fixed,paraffin-embedded human colorectal tissue specimens were immunostained with antibodies against MUC2 and MUC5AC.Six samples of normal mucosa(NM),12 samples of hyperplastic polyp(HP),15 samples of tubular adenoma with low-grade dysplasia(LGD),14 samples of tubular adenoma with high-grade dysplasia(HGD),26 samples of conventional colorectal adenocarcinoma...     

The Role of Mucus in Cough Research

Cough is a defense mechanism for promoting airway hygiene when mucociliary clearance is ineffective due to increased mucus secretion, inflammation, infection, or ciliary dysfunction. Secretions can contribute to airflow limitation and chronic hypersecretion can worsen airway inflammation with retained inflammatory cells and mediators. The focus of the Second Annual Cough Conference has been on cough as a troublesome symptom; but to understand the importance and effectiveness of cough clearance, it is critical to understand airway secretions. The biophysical properties of mucus and phlegm determine how readily these secretions can be cleared by coughing.     

Phenotype analysis by MUC2, MUC5AC, MUC6, and CD10 expression in Epstein-Barr virus-associated gastric carcinoma

Background Gastric marker mucins (MUC5AC and MUC6) and intestinal marker molecules (MUC2 and CD10) have been used to determine the cell lineage of epithelial cell of gastric carcinoma (GC). Methods To clarify the characteristics of Epstein-Barr virus (EBV)-associated GC, 18 cases were immunohistochemically evaluated along with 56 cases of EBV-negative GC. Results MUC2 expression was lower in EBV-associated GC: immunostaining grades 0, 1, 2, 3, and 4 were observed in 10, 6, 1, 1, and 0 cases of EBV-associated GC, respectively, and in 18, 11, 15, 6, and 6 cases of EBV-negative GC, respectively (P = 0.013). CD10 positivity (grades 2–4) in EBV-associated GC was 6%, significantly lower than in EBV-negative GC (34%) (P = 0.030). When phenotypes of GC were categorized by the combined positivities of gastric markers (either MUC5AC or MUC6) and intestinal markers (either MUC2 or CD10), EBV-associated GC included primarily null (44%) and gastric (39%) types, but EBV-negative GC comprised null (7%), gastric (30%), intestinal (27%), and mixed (36%) types. The age of patients with gastric types was significantly younger for both EBV-associated GC and EBV-negative GC cases. Conclusions Neoplastic epithelial cells of EBV-associated GC did not express MUC2 or CD10, and most of them were categorized as null or gastric types. EBV infection may occur in the epithelial cells of null or gastric phenotypes, which may be devoid of transdifferentiation potential toward intestinal phenotypes.