Trophic Slime, Allergic Slime

The epithelium of the respiratory mucosa provides a barrier against injurious luminal agents, including bacteria, enzymes, and toxins. The normal respiratory epithelium is coated with mucus, which provides a variety of protective functions, including protection of the lower airways from dehydration and from damaging airborne irritants, particles, and microorganisms. The adhesive and viscoelastic properties of mucus glycoproteins (mucins), the major protein components of airway mucus, allow the trapping of foreign substances and their transport and removal on the tips of beating cilia toward the throat, a process termed mucociliary clearance. However, overzealous production of mucus may significantly contribute to the morbidity and mortality associated with certain respiratory diseases. In particular, mucus hypersecretion and plugging of the airways are characteristic features of patients who die from asthma (1, 2), chronic bronchitis, and cystic fibrosis (2). In human airways, mucins are produced and secreted by specialized cells in the epithelium, including the goblet cells in the surface airway epithelium and the secretory (mucous and serous) cells in the submucosal glands. Because of their greater prominence in histologic sections, submucosal glands, rather than goblet cells, have been thought to contribute the greater quantity of mucus to airway surface fluid (3). However, recent studies suggest that goblet cells may contribute more to the overall quantity of mucus produced than do the submucosal glands. Mucins constitute a heterogeneous group of high molecular weight, richly glycosylated molecules. To date, nine human mucin genes ( MUC1 , MUC2 , MUC3 , MUC4 , MUC5/5AC , MUC5B , MUC6 , MUC7 , and MUC8 ) encoding the protein core of mucin have been identified (reviewed in Reference 4). The biologic importance of these diverse mucin proteins is not currently known. Nonetheless, there appears to be some degree of specificity in the tissue expression of the various MUC genes. In the respiratory tract, seven of the nine MUC genes are expressed ( MUC1 , MUC5/5AC , MUC2 , MUC4 , MUC5B , MUC7 , and MUC8 ) (reviewed in Reference 4). The mechanisms governing mucin glycoprotein synthesis and secretion are not well understood in either health or disease. Control of mucus secretion is a complex process involving regulation at many different levels, including ( 1 ) cell proliferation and differentiation, ( 2 ) mucin gene expression, and ( 3 ) release of mature mucin molecules from storage granules (3). Under normal conditions, there are relatively few goblet cells in the human airway and virtually none in the airways of animals kept in clean environments. In response to a wide variety of stimuli, including proteinases, irritant gases, inflammatory mediators, reactive oxygen species, and cholinergic and nonadrenergic, noncholinergic nerve activation, a rapid increase in the number of airway goblet cells is observed via both hyperplastic (cell division) and metaplastic (cell differentiation) mechanisms. In the airways of rodents, these increases are primarily due to metaplasia, since goblet cells are not normally seen in the airways of clean animals. Secondly, MUC gene transcription has been shown to be induced upon exposure of the airways to a number of substances that induce mucus secretion, such as endotoxin, SO 2 , and allergens (5, 6). Thus, it is hypothesized that an important point of control of mucus secretion is the synthesis of these protein backbones of the mature mucin glycoproteins. Although the exact molecular mechanisms regulating mucin-gene expression are virtually unknown, there is evidence that the individual genes may be differentially regulated. For example, Muc-2 expression is induced in the lungs of rats exposed to SO 2 and Sendai virus, but not by allergen exposure (5, 6). Conversely, allergen challenge has been shown to induce MUC5 gene expression (6). Lastly, secretion of mature mucin molecules requires their release from the intracellular granules in which they are stored. To date, there are a number of inflammatory mediators implicated in the allergic diathesis that are known to influence goblet-cell secretion, including the prostaglandins E2 and F2a, leukotrienes, 15-HETES, platelet-activating factor, mast-cell and neutrophil proteases, eosinophil cationic protein, and the cytokines interleukin (IL)-1 and tumor necrosis factor (TNF) (3). As stated above, mucus hypersecretion is a key feature of allergic asthma and is associated with the clinical symptoms, airway obstruction, and mortality of the disease. Because of the difficulty of studying molecular processes in the human lung, much of our current knowledge of mucus regulation has come from the study of murine models of allergic disease. Recently, several groups of investigators have shown that respiratory challenge with allergens causes physiologic and pathologic changes similar to those seen in human allergic asthma, including airway hyperresponsiveness, airway inflammation, and airway goblet-cell metaplasia (GCM), as evidenced by periodic acid-Schiff (PAS) ( Received in original form May 3, 2000 )