![]() Therapies designed to specifically restore function of the mutant cystic fibrosis transmembrane conductance regulator (CFTR) have become available ( 2– 5). The ion transport abnormalities that produce airway surface dehydration differ per disease, with CF being perhaps the best-described mechanism ( 1). The common pathophysiological cascade describing these diseases reflects abnormalities of airway epithelial ion transport and/or increased mucin secretion that produce mucus dehydration, mucus stasis, and ultimately airway inflammation and bacterial infection. Cystic fibrosis (CF) is the prototype of such diseases, but others would include cigarette smoke–induced chronic bronchitis, primary ciliary dyskinesia, and non-CF bronchiectasis. Mucoobstructive pulmonary diseases include a complex of diseases characterized by cough and sputum production, airflow obstruction, airway inflammation, and intermittent/continuous infection. Thus, the new insights into a unifying process, that is, mucus hyperconcentration, that drives a significant component of the pathogenesis of mucoobstructive diseases promise multiple new therapeutic strategies to aid patients with this syndrome. Similarly, strategies designed to reduce the mucin burden in the airways, either by reducing mucin production/secretion or by clearing accumulated mucus (e.g., reducing agents), are under development. Strategies to rehydrate mucus range from the inhalation of osmotically active solutes, designed to draw water into airway surfaces, to strategies designed to manipulate the relative rates of sodium absorption versus chloride secretion to endogenously restore epithelial hydration. ![]() Novel therapies to treat mucoobstructive diseases focus on restoring mucus concentration. Anaerobes ultimately may condition mucus to provide the environment for a succession to classic airway pathogens, including Staphylococcus aureus, Haemophilus influenzae, and ultimately Pseudomonas aeruginosa. The infectious component of mucoobstructive diseases may be initiated by anaerobic bacteria that proliferate within the nutrient-rich hypoxic mucus environment. Data suggest that concentrated mucus plaques/plugs are proinflammatory, in part mediated by release of IL-1α from hypoxic cells. These mucus plaques/plugs generate long diffusion distances for oxygen, producing hypoxic niches within adherent airway mucus and subjacent epithelia. A common theme for these diseases appears to be the failure to properly regulate mucus concentration, producing mucus hyperconcentration that slows mucus transport and, importantly, generates plaque/plug adhesion to airway surfaces. A spectrum of intrapulmonary airway diseases, for example, cigarette smoke–induced bronchitis, cystic fibrosis, primary ciliary dyskinesia, and non–cystic fibrosis bronchiectasis, can be categorized as “mucoobstructive” airway diseases.
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