My research interests center around the effects of viral infections on mucus secretion in the airways. Histochemical studies have shown alterations in the staining characteristics of the mucus-producing cells (goblet cells and mucous cells of the submucosal glands) during chronic infections, suggesting changes in the biochemical composition of mucin. Morphologic studies have described depletion of mucin in goblet cells during viral infection and hyperplasia of goblet cells during recover from infection. These findings suggest a viral-induced hypersecretion of mucin. During Phase I of this project, I propose to characterize the qualitative and quantitative changes in mucin during and after influenza infection. During Phase II, I will investigate the mechanisms producing these changes. The ferret, a well-established model for influenza studies, will be used for these studies. Using histochemical and morphometric techniques, the viral induced changes in the mucus secreting elements will be quantitated. Then, tracheal and bronchial explants of infected and unifected ferrets will be equilibrated with radiolabelled precursors of mucins. Secreted mucins will be purified by automated column chromatography and quantified. The relative rates of secretion of infected and control epithelium will be assessed under baseline and stimulated conditions. Isolated mucous glycoproteins will be characterized with respect to composition, size, acidic properties, and molecular interactions. After assessing alterations of the secretory rate and biochemical characteristics of the mucus, I will investigate mechanism(s) for these changes by selectively mimicking and blocking potential neural and inflammatory influences (eg, adrnergic and cholinergic agents, metabolites of arachadonic acid, proteinases). One established, these techniques can be applied to other infections of the respiratory tract. Accumulation of mucus secondary to hypersecretion and possibly to alterations of the physicochemical properties of mucin causes much of the symptomatology of acute viral infections and may be a major underlying cause for the morbidity and mortality associated with these illnesses. Understanding the nature and mechanisms of changes in mucus secreted by epithelium infected with virus ultimately will afford opportunities to develop more rational and hopefully more effective therapy of these symptoms and better prevention of the major complications.
