Epithelial mucus-hypersecretion and respiratory disease.

Mucus production, secretion and clearance are considered to play a critical role in maintenance of airway health, however in diseases such as COPD, epidemiological and pathological studies suggest that excess mucus contributes to airway plugging and decline in lung health. The airway surface epithelium is composed of a heterogeneous mix of cell types one of which, the goblet cell, is dedicated to the production of secretory gel-forming mucins. Changes in epithelial cellular composition and function in response to irritants and microbes generally leads to enhanced co-ordinated functioning of the major facets of the mucociliary clearance (MCC) system i.

Membrane capacitance and conductance changes parallel mucin secretion in the human airway epithelium.

Measurement of the magnitude and kinetics of exocytosis from intact epithelia has historically been difficult. Using well-differentiated cultures of human bronchial epithelial cells, we describe the use of transepithelial impedance analysis to enable the real-time quantification of mucin secretagogue-induced changes in membrane capacitance (surface area) and conductance. ATPgammaS, UTP, ionomycin, and PMA induced robust increases in total cellular capacitance that were demonstrated to be dominated by a specific increase in apical membrane surface area.

Inhibition of chloride secretion in human bronchial epithelial cells by cigarette smoke extract.

Chronic bronchitis, a disease mainly of cigarette smokers, shares many clinical features with cystic fibrosis, a disease of altered ion transport, suggesting that the negative effects of cigarette smoke on mucociliary clearance may be mediated through alterations in ion transport. We tested the hypothesis that cigarette smoke extract would inhibit chloride secretion in human bronchial epithelial cells. In agreement with studies in canine trachea, cigarette smoke extract inhibited net chloride secretion without affecting sodium transport.

Nucleotide-mediated mucin secretion from differentiated human bronchial epithelial cells.

Most current cell-based models for examining the regulation of mucin secretion demonstrate low signal-to-noise ratios, making experimental manipulation and data interpretation difficult. Using adenosine triphosphate (ATP) as a mucin secretagogue, we have developed a model of agonist-induced mucin secretion in differentiated human bronchial epithelial cells. Mucin secretory signals were estimated using enzyme-linked lectin assay, and typical signals of 300-400% of baseline were observed in response to a 30-min exposure to ATP (100 microM).

Noninvasive detection of endotoxin-induced mucus hypersecretion in rat lung by MRI.

Using magnetic resonance imaging (MRI), we detected a signal in the lungs of Brown Norway rats after intratracheal administration of endotoxin [lipopolysaccharide (LPS)]. The signal had two components: one, of diffuse appearance and higher intensity, was particularly prominent up to 48 h after LPS; the second, showing an irregular appearance and weaker intensity, was predominant later. Bronchoalveolar lavage fluid analysis indicated that generalized granulocytic (especially neutrophilic) inflammation was a major contributor to the signal at the early time points, with mucus being a major factor contributing at the later time points.

Pulmonary inflammation monitored noninvasively by MRI in freely breathing rats.

A detailed analysis has been carried out of the correlation between the signals detected by MRI in the rat lung after allergen or endotoxin challenge and parameters of inflammation determined in the broncho-alveolar lavage (BAL) fluid. MRI signals after allergen correlated highly significantly with the BAL fluid eosinophil number, eosinophil peroxidase activity and protein concentration. Similar highly significant correlations were seen when the anti-inflammatory glucocorticosteroid, budesonide, manifested against allergen.