Airway mucus: From production to secretion.

Mucus hypersecretion is a phenotype associated with multiple obstructive lung diseases. However, in spite of its nefarious reputation under pathologic conditions, there are significant benefits to having low levels of mucus present in the airways at baseline, such as the ability to trap and eliminate inhaled particles and to prevent desiccation of airway surfaces. Mucins are high-molecular-weight glycoproteins that are the chief components that render viscoelastic and gel-forming properties to mucus. Recent advances in animal models and in vitro systems have provided a wealth of information regarding the identification of the mucin genes that are expressed in the lungs, the signal transduction pathways that regulate the expression of these mucins, and the secretory pathways that mediate their release into the airways. In addition, the clinical and pathologic literature has corroborated many of the basic laboratory findings. As a result, mucin overproduction and hypersecretion are moving away from being markers of disease and toward being testable as functional components of lung disease processes.

[1]  N. Letwin,et al.  Muc-5/5ac mucin messenger RNA and protein expression is a marker of goblet cell metaplasia in murine airways. , 2000, American journal of respiratory cell and molecular biology.

[2]  Jeffrey D. Morton,et al.  Viral induction of a chronic asthma phenotype and genetic segregation from the acute response. , 2002, The Journal of clinical investigation.

[3]  B. Celli,et al.  Exacerbations of chronic obstructive pulmonary disease , 2007, European Respiratory Journal.

[4]  V. Kim,et al.  Small airway morphometry and improvement in pulmonary function after lung volume reduction surgery. , 2005, American journal of respiratory and critical care medicine.

[5]  J. Littleton,et al.  ROP, the Drosophila Sec1 homolog, interacts with syntaxin and regulates neurotransmitter release in a dosage‐dependent manner , 1998, The EMBO journal.

[6]  M. Kluger,et al.  Cytokines and the acute phase response to influenza virus in mice. , 1995, The American journal of physiology.

[7]  J. D. Beckham,et al.  Respiratory viral infections in patients with chronic, obstructive pulmonary disease , 2004, Journal of Infection.

[8]  T. Seemungal,et al.  Acute Exacerbations of Chronic Obstructive Pulmonary Disease Are Accompanied by Elevations of Plasma Fibrinogen and Serum IL-6 Levels , 2000, Thrombosis and Haemostasis.

[9]  B. Rubin,et al.  MUC5AC and MUC5B Mucins Are Decreased in Cystic Fibrosis Airway Secretions. , 2004, American journal of respiratory cell and molecular biology.

[10]  Y. Ho,et al.  Stimulation of Airway Mucin Gene Expression by Interleukin (IL)-17 through IL-6 Paracrine/Autocrine Loop* , 2003, The Journal of Biological Chemistry.

[11]  I. Petersen,et al.  Expression of the Cell Adhesion Molecule CD146/MCAM in Non-Small Cell Lung Cancer , 2003, Analytical cellular pathology : the journal of the European Society for Analytical Cellular Pathology.

[12]  M. Aldrich,et al.  Pathogenesis of mucous cell metaplasia in a murine asthma model. , 2003, The American journal of pathology.

[13]  P. Barnes,et al.  High levels of interleukin-6 in the exhaled breath condensate of patients with COPD. , 2003, Respiratory medicine.

[14]  S. Randell,et al.  Mucins and their O-Glycans from human bronchial epithelial cell cultures. , 2004, American journal of physiology. Lung cellular and molecular physiology.

[15]  J. Hammer,et al.  Rabs grab motors: defining the connections between Rab GTPases and motor proteins. , 2002, Current opinion in cell biology.

[16]  T. Shuto,et al.  Transforming Growth Factor-β-Smad Signaling Pathway Cooperates with NF-κB to Mediate NontypeableHaemophilus influenzae-induced MUC2 Mucin Transcription* , 2002, The Journal of Biological Chemistry.

[17]  M. Gallup,et al.  Tobacco Smoke Control of Mucin Production in Lung Cells Requires Oxygen Radicals AP-1 and JNK* , 2004, Journal of Biological Chemistry.

[18]  H. Deshmukh,et al.  Metalloproteinases mediate mucin 5AC expression by epidermal growth factor receptor activation. , 2005, American journal of respiratory and critical care medicine.

[19]  J. D. Li,et al.  Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[20]  F. Escande,et al.  Alternative splicing generates a family of putative secreted and membrane-associated MUC4 mucins. , 2000, European journal of biochemistry.

[21]  S. Wenzel,et al.  Transforming growth factor-beta2 induces bronchial epithelial mucin expression in asthma. , 2004, The American journal of pathology.

[22]  E. Walsh,et al.  Respiratory syncytial virus infection in elderly and high-risk adults. , 2005, The New England journal of medicine.

[23]  G. Vawter,et al.  Cystic fibrosis in adults: an autopsy study. , 1979, Pathology annual.

[24]  J. Costerton,et al.  Production of mucoid microcolonies by Pseudomonas aeruginosa within infected lungs in cystic fibrosis , 1980, Infection and immunity.

[25]  D. Thornton,et al.  Physical characterization of the MUC5AC mucin: a highly oligomeric glycoprotein whether isolated from cell culture or in vivo from respiratory mucous secretions. , 2000, The Biochemical journal.

[26]  T. Südhof,et al.  A Complete Genetic Analysis of Neuronal Rab3 Function , 2004, The Journal of Neuroscience.

[27]  Y. Kim,et al.  Membrane-bound (MUC1) and secretory (MUC2, MUC3, and MUC4) mucin gene expression in human lung cancer. , 1996, Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine.

[28]  Richard C Boucher,et al.  Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice , 2004, Nature Medicine.

[29]  Jian-Dong Li,et al.  Mucin gene (MUC 2 and MUC 5AC) upregulation by Gram-positive and Gram-negative bacteria. , 1998, Biochimica et biophysica acta.

[30]  D. Thornton,et al.  Identification of Two Glycoforms of the MUC5B Mucin in Human Respiratory Mucus , 1997, The Journal of Biological Chemistry.

[31]  T. Boat,et al.  Increased adherence of Staphylococcus aureus from cystic fibrosis lungs to airway epithelial cells. , 1993, The American review of respiratory disease.

[32]  L. Fabbri,et al.  Goblet cell hyperplasia and epithelial inflammation in peripheral airways of smokers with both symptoms of chronic bronchitis and chronic airflow limitation. , 2000, American journal of respiratory and critical care medicine.

[33]  W. Hong SNAREs and traffic. , 2005, Biochimica et biophysica acta.

[34]  D. Lamb,et al.  Goblet and Clara cells of human distal airways: evidence for smoking induced changes in their numbers. , 1984, Thorax.

[35]  M. Gilmore,et al.  A novel human airway mucin cDNA encodes a protein with unique tandem-repeat organization. , 1994, The Biochemical journal.

[36]  S. Gould,et al.  Developmental expression of mucin genes in the human respiratory tract. , 1997, American journal of respiratory cell and molecular biology.

[37]  Joan Wilson,et al.  Respiratory viral infections in adults with and without chronic obstructive pulmonary disease. , 2000, American journal of respiratory and critical care medicine.

[38]  G. Spizz,et al.  MARCKS Protein Is a Key Molecule Regulating Mucin Secretion by Human Airway Epithelial Cells in Vitro * , 2001, The Journal of Biological Chemistry.

[39]  C. Agustí,et al.  Neutrophil-dependent goblet cell degranulation: role of membrane-bound elastase and adhesion molecules. , 1998, American journal of physiology. Lung cellular and molecular physiology.

[40]  L. Fabbri,et al.  Remodeling in response to infection and injury. Airway inflammation and hypersecretion of mucus in smoking subjects with chronic obstructive pulmonary disease. , 2001, American journal of respiratory and critical care medicine.

[41]  B. Stripp,et al.  Mucin is produced by clara cells in the proximal airways of antigen-challenged mice. , 2004, American journal of respiratory cell and molecular biology.

[42]  P. Paré,et al.  Characterization of airway plugging in fatal asthma. , 2003, The American journal of medicine.

[43]  R. Wu,et al.  Characterization of human mucin 5B gene expression in airway epithelium and the genomic clone of the amino-terminal and 5'-flanking region. , 2001, American journal of respiratory cell and molecular biology.

[44]  A. Jackson Airway goblet-cell mucus secretion. , 2001, Trends in pharmacological sciences.

[45]  S. Greenberg,et al.  The lung in cystic fibrosis. A quantitative study including prevalence of pathologic findings among different age groups. , 1976, Human pathology.

[46]  C. Agustí,et al.  Epidermal growth factor system regulates mucin production in airways. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[47]  F. Escande,et al.  The mouse secreted gel-forming mucin gene cluster. , 2004, Biochimica et biophysica acta.

[48]  N. McNamara,et al.  Signaling networks controlling mucin production in response to Gram-positive and Gram-negative bacteria , 2001, Glycoconjugate Journal.

[49]  D. Kufe,et al.  Interaction of Glycogen Synthase Kinase 3β with the DF3/MUC1 Carcinoma-Associated Antigen and β-Catenin , 1998, Molecular and Cellular Biology.

[50]  J. Bernaudin,et al.  Ciliary abnormalities in bronchial epithelium of smokers, ex-smokers, and nonsmokers. , 1995, American journal of respiratory and critical care medicine.

[51]  J. Vestbo Epidemiological studies in mucus hypersecretion. , 2002, Novartis Foundation symposium.

[52]  Thomas C. Südhof,et al.  Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles , 1999, Nature.

[53]  P. Gilligan,et al.  Microbiology of airway disease in patients with cystic fibrosis , 1991, Clinical Microbiology Reviews.

[54]  Reen Wu,et al.  Genome-wide search and identification of a novel gel-forming mucin MUC19/Muc19 in glandular tissues. , 2004, American journal of respiratory cell and molecular biology.

[55]  K. Yanagihara,et al.  Lipopolysaccharide Induces Mucus Cell Metaplasia in Mouse Lung. , 2001, American journal of respiratory cell and molecular biology.

[56]  Weiliang Tang,et al.  Rhinovirus stimulation of interleukin-6 in vivo and in vitro. Evidence for nuclear factor kappa B-dependent transcriptional activation. , 1996, The Journal of clinical investigation.

[57]  T. Südhof,et al.  Synaptic assembly of the brain in the absence of neurotransmitter secretion. , 2000, Science.

[58]  Jack A. Elias,et al.  Acidic Mammalian Chitinase in Asthmatic Th2 Inflammation and IL-13 Pathway Activation , 2004, Science.

[59]  B. Becker,et al.  Upregulation of MCAM in primary bronchial epithelial cells from patients with COPD , 2003, European Respiratory Journal.

[60]  C. Owen Proteinases and oxidants as targets in the treatment of chronic obstructive pulmonary disease. , 2005, Proceedings of the American Thoracic Society.

[61]  D. Thornton,et al.  Analysis of respiratory mucus glycoproteins in asthma: a detailed study from a patient who died in status asthmaticus. , 1995, American journal of respiratory cell and molecular biology.

[62]  J. Fahy Goblet cell and mucin gene abnormalities in asthma. , 2002, Chest.

[63]  T. Saga,et al.  Normal bronchial mucus contains high levels of cancer‐associated antigens, CA125, CA19‐9, and carcinoembryonic antigen , 1990, Cancer.

[64]  R. Wu,et al.  Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression. , 2001, American journal of respiratory and critical care medicine.

[65]  J. Lloreta,et al.  Mucins as differentiation markers in bronchial epithelium. Squamous cell carcinoma and adenocarcinoma display similar expression patterns. , 2001, American journal of respiratory cell and molecular biology.

[66]  T. Südhof The synaptic vesicle cycle , 2004 .

[67]  A. Gruber,et al.  A MARCKS-related peptide blocks mucus hypersecretion in a mouse model of asthma , 2004, Nature Medicine.

[68]  H. Gerdes,et al.  Myosin Va facilitates the distribution of secretory granules in the F-actin rich cortex of PC12 cells , 2003, Journal of Cell Science.

[69]  M. Dunnill THE PATHOLOGY OF ASTHMA, WITH SPECIAL REFERENCE TO CHANGES IN THE BRONCHIAL MUCOSA , 1960, Journal of clinical pathology.

[70]  D. Thornton,et al.  Physical characterization of a low-charge glycoform of the MUC5B mucin comprising the gel-phase of an asthmatic respiratory mucous plug. , 1999, The Biochemical journal.

[71]  W. M. Foster,et al.  Neutrophil elastase induces mucus cell metaplasia in mouse lung. , 2004, American journal of physiology. Lung cellular and molecular physiology.

[72]  C. A. Carraway,et al.  Muc4/sialomucin complex, the intramembrane ErbB2 ligand, in cancer and epithelia: to protect and to survive. , 2002, Progress in nucleic acid research and molecular biology.

[73]  Y. Ishikawa,et al.  Pulmonary Adenocarcinomas With Enteric Differentiation: Histologic and Immunohistochemical Characteristics Compared With Metastatic Colorectal Cancers and Usual Pulmonary Adenocarcinomas , 2005, The American journal of surgical pathology.

[74]  D. Sheppard,et al.  Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma , 2002, Nature Medicine.

[75]  A. Oliver,et al.  High frequency of hypermutable Pseudomonas aeruginosa in cystic fibrosis lung infection. , 2000, Science.

[76]  J. Wedzicha,et al.  Exacerbations of chronic obstructive pulmonary disease. , 2003, Respiratory care.

[77]  S. Randell,et al.  Mucin gene expression during differentiation of human airway epithelia in vitro. Muc4 and muc5b are strongly induced. , 1999, American journal of respiratory cell and molecular biology.

[78]  L. Lapensee,et al.  Allelic polymorphism and chromosomal localization of the human oviductin gene (MUC9). , 1997, Fertility and sterility.

[79]  J. Zieleński,et al.  Cystic fibrosis: genotypic and phenotypic variations. , 1995, Annual review of genetics.

[80]  M. Fukuda,et al.  Slac2-c (Synaptotagmin-like Protein HomologueLacking C2 Domains-c), a Novel Linker Protein that Interacts with Rab27, Myosin Va/VIIa, and Actin* , 2002, The Journal of Biological Chemistry.

[81]  J. Lafitte,et al.  The sialylation of bronchial mucins secreted by patients suffering from cystic fibrosis or from chronic bronchitis is related to the severity of airway infection. , 1999, Glycobiology.

[82]  A. Ambergen,et al.  Number and proliferation of clara cells in normal human airway epithelium. , 1999, American journal of respiratory and critical care medicine.

[83]  D. Mannino,et al.  Chronic obstructive pulmonary disease surveillance--United States, 1971-2000. , 2002, Morbidity and mortality weekly report. Surveillance summaries.

[84]  Chang-Hoon Kim,et al.  MUC8 as a ciliated cell marker in human nasal epithelium , 2005 .

[85]  J. Olsen,et al.  Barrier role of actin filaments in regulated mucin secretion from airway goblet cells. , 2005, American journal of physiology. Cell physiology.

[86]  D. Thornton,et al.  Mucin structure. The structure and heterogeneity of respiratory mucus glycoproteins. , 1991, The American review of respiratory disease.

[87]  P. Paré,et al.  The nature of small-airway obstruction in chronic obstructive pulmonary disease. , 2004, The New England journal of medicine.

[88]  A. Dell,et al.  Mucin glycosylation and sulphation in airway epithelial cells is not influenced by cystic fibrosis transmembrane conductance regulator expression. , 2005, American journal of respiratory cell and molecular biology.

[89]  B. Fischer,et al.  Neutrophil elastase increases MUC5AC mRNA and protein expression in respiratory epithelial cells. , 1999, American journal of physiology. Lung cellular and molecular physiology.

[90]  H. Horvitz,et al.  Caenorhabditis elegans rab-3 Mutant Synapses Exhibit Impaired Function and Are Partially Depleted of Vesicles , 1997, The Journal of Neuroscience.

[91]  S. Degroote,et al.  Sulfated oligosaccharides isolated from the respiratory mucins of a secretor patient suffering from chronic bronchitis. , 2003, Biochimie.

[92]  C. Bertrand,et al.  Time course of inflammatory and remodeling events in a murine model of asthma: effect of steroid treatment. , 2000, American journal of physiology. Lung cellular and molecular physiology.

[93]  K. Kaestner,et al.  Foxa2 regulates alveolarization and goblet cell hyperplasia , 2004, Development.

[94]  M. Riley,et al.  The emergence of a highly transmissible lineage of cbl+ Pseudomonas (Burkholderia) cepacia causing CF centre epidemics in North America and Britain , 1995, Nature Medicine.

[95]  D. Thornton,et al.  Heterogeneity of airways mucus: variations in the amounts and glycoforms of the major oligomeric mucins MUC5AC and MUC5B. , 2002, The Biochemical journal.

[96]  R. Peto,et al.  The natural history of chronic airflow obstruction. , 1977, British medical journal.

[97]  G. Rubin,et al.  Mutations in the drosophila Rop gene suggest a function in general secretion and synaptic transmission , 1994, Neuron.

[98]  B. Fischer,et al.  Neutrophil elastase induces MUC5AC gene expression in airway epithelium via a pathway involving reactive oxygen species. , 2002, American journal of respiratory cell and molecular biology.

[99]  Y. Takeshima,et al.  Expression of MUC1, MUC2, MUC5AC, and MUC6 in atypical adenomatous hyperplasia, bronchioloalveolar carcinoma, adenocarcinoma with mixed subtypes, and mucinous bronchioloalveolar carcinoma of the lung. , 2004, American journal of clinical pathology.

[100]  J. Nadel,et al.  Cigarette smoke induces MUC5AC mucin overproduction via tumor necrosis factor-alpha-converting enzyme in human airway epithelial (NCI-H292) cells. , 2004, American journal of physiology. Lung cellular and molecular physiology.

[101]  A. Nicholson,et al.  Expression of respiratory mucins in fatal status asthmaticus and mild asthma , 2002, Histopathology.

[102]  Kendal Broadie,et al.  Drosophila Unc-13 is essential for synaptic transmission , 1999, Nature Neuroscience.

[103]  K. Koessler,et al.  THE PATHOLOGY OF BRONCHIAL ASTHMA , 1922 .

[104]  J. Davies,et al.  Respiratory tract mucins: structure and expression patterns. , 2002, Novartis Foundation symposium.

[105]  M. Seabra,et al.  The melanosome as a model to study organelle motility in mammals. , 2004, Pigment cell research.

[106]  X. Mo,et al.  Induction of cytokines in mice with parainfluenza pneumonia , 1995, Journal of virology.

[107]  J. Vestbo,et al.  Chronic mucus hypersecretion in COPD and death from pulmonary infection. , 1995, The European respiratory journal.

[108]  J. Hogg,et al.  The detection of small airways disease. , 1984, The American review of respiratory disease.

[109]  I. Adcock,et al.  Mucin expression in peripheral airways of patients with chronic obstructive pulmonary disease , 2004, Histopathology.

[110]  D. Thornton,et al.  Identification of Molecular Intermediates in the Assembly Pathway of the MUC5AC Mucin* , 2004, Journal of Biological Chemistry.

[111]  B. Stripp,et al.  Airway epithelial cell expression of interleukin-6 in transgenic mice. Uncoupling of airway inflammation and bronchial hyperreactivity. , 1994, The Journal of clinical investigation.

[112]  N. Copeland,et al.  Genetic characterization of the murine Ym1 gene and identification of a cluster of highly homologous genes. , 1998, Genomics.