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Abstract Rationale Cystic fibrosis (CF) is believed to be associated with mucus hypersecretion; thus, the principal airway gel-forming mucins, MUC5AC and MUC5B, are also expected to be increased relative to non-CF secretions. However, we have shown that these mucins are decreased during stable CF disease. Objectives In this study, we determine if these mucins increase during a pulmonary exacerbation of CF. Methods Expectorated sputum was collected from 11 adults with CF during stable disease and then during a pulmonary exacerbation and from 12 healthy control subjects. MUC5AC and MUC5B proteins were measured by Western blot. DNA content was measured using microfluorimetry. Results MUC5AC protein increased by 908% and MUC5B by 59% (p < 0.05 for both) during an exacerbation compared with periods of stable disease. During stable disease, the vol/vol quantity of MUC5AC protein was 89% less than normal mucus, and the mucin-associated sugars, measured using a lectin binding assay, were 46% less compared with normal mucus. The concentration of DNA in CF sputum did not increase during an exacerbation. Conclusions During a CF exacerbation, concentration of secreted mucin increased to the amount found in mucus from normal subjects, suggesting that the capacity to secrete mucin in response to an infection or inflammatory stimulus is preserved in CF airways. This might help to protect the airway from injury.

The use of troleandomycin as adjunctive therapy for the treatment of patients with corticosteroid-dependent asthma first suggested an immunomodulatory effect of the macrolide antibiotics. This led to studies of the macrolides in other chronic airway diseases, such as diffuse panbronchiolitis (DPB), a disease occurring primarily in East Asia. The use of macrolides for the therapy of patients with DPB has led to dramatic improvements in pulmonary function and prolonged survival. Similar benefits have been documented in Japanese studies of bronchiectasis, chronic bronchitis, and sinobronchial syndrome. Clinical and pathologic similarities between DPB and cystic fibrosis (CF) led to the investigation of macrolides for the treatment of CF. Data now suggest that persons with CF will benefit from macrolide therapy. In vitro and in vivo studies suggest that macrolides may inhibit the pulmonary influx of neutrophils, inhibit the release of proinflammatory cytokines, protect the epithelium from bioactive phospholipids, and improve the transportability of airway secretions. The immunomodulatory effects of the macrolides also may be beneficial for the treatment of other chronic inflammatory conditions.

Cystic fibrosis (CF) is characterized by progressive airway obstruction. Although it has been postulated that this is due in part to mucus hypersecretion, there are no published data showing an increase in the gel-forming mucins MUC5AC or MUC5B in CF secretions. We used confocal microscopy to assess the amount of mucin-like glycoprotein and DNA in CF sputum and found more mucin in bronchitis sputum and a much greater amount of DNA in CF sputum. We then used antibodies to MUC5AC and MUC5B with Western gels and dot-blot to quantify mucin in sputum from 12 patients with CF and 11 subjects without lung disease. There was a 70% decrease in MUC5B and a 93% decrease in MUC5AC in CF sputum (P < 0.005 for both). We conclude that the vol/vol concentration of MUC5AC and MUC5B are decreased in the CF airways relative to normal mucus. This may be due to a relative increase in other components of sputum in the CF airway or to a primary defect in mucin secretion in CF.

Airway epithelial cells contribute to the inflammatory response of the lung, and their innate immune response is primarily mediated via Toll-like receptor (TLR) signaling. Cystic fibrosis (CF) airways are chronically infected with Pseudomonas aeruginosa, suggesting a modified immune response in CF. We investigated the TLR-4 expression and the inflammatory profile (IL-8 and IL-6 secretion) in CF bronchial epithelial cell line CFBE41o- and its CF transmembrane ion condcutance regulator (CFTR)-corrected counterpart grown under air–liquid interface conditions after stimulation with lipopolysaccharide (LPS) from gram-negative bacteria. In CFTR-corrected cells, IL-8 and IL-6 secretions were constitutively activated but significantly increased after LPS stimulation compared with CFBE41o-. Blocking TLR-4 by a specific antibody significantly inhibited IL-8 secretion only in CFTR-corrected cells. Transfection with specific siRNA directed against TLR-4 mRNA significantly reduced the response to LPS in both cell lines. Fluorescence-activated cell sorter analysis revealed significantly higher levels of TLR-4 surface expression in CFTR-corrected cells. In histologic lung sections of patients with CF, the TLR-4 expression in the bronchial epithelium was significantly reduced compared with healthy control subjects. In CF the loss of CFTR function appears to decrease innate immune responses, possibly by altering the expression of TLR-4 on airway epithelial cells. This may contribute to chronic bacterial infection of CF airways.

Background Proteases have been shown to degrade airway mucin proteins and to damage the epithelium impairing mucociliary clearance. There are increased proteases in the COPD airway but changes in protease-antiprotease balance and mucin degradation have not been investigated during the course of a COPD exacerbation. We hypothesized that increased protease levels would lead to mucin degradation in acute COPD exacerbations. Methods We measured neutrophil elastase (NE) and alpha 1 protease inhibitor (A1-PI) levels using immunoblotting, and conducted protease inhibitor studies, zymograms, elastin substrate assays and cigarette smoke condensate experiments to evaluate the stability of the gel-forming mucins, MUC5AC and MUC5B, before and 5–6 weeks after an acute pulmonary exacerbation of COPD ( n  = 9 subjects). Results Unexpectedly, mucin concentration and mucin stability were highest at the start of the exacerbation and restored to baseline after 6 weeks. Consistent with these data, immunoblots and zymograms confirmed decreased NE concentration and activity and increased A1-PI at the start of the exacerbation. After recovery there was an increase in NE activity and a decrease in A1-PI levels. In vitro, protease inhibitor studies demonstrated that serine proteases played a key role in mucin degradation. Mucin stability was further enhanced upon treating with cigarette smoke condensate (CSC). Conclusion There appears to be rapid consumption of secreted proteases due to an increase in antiproteases, at the start of a COPD exacerbation. This leads to increased mucin gel stability which may be important in trapping and clearing infectious and inflammatory mediators, but this may also contribute acutely to mucus retention.

It has been assumed that cystic fibrosis (CF) lung disease is due in part to abnormal airway mucus. Primary ciliary dyskinesia (PCD) is a form of bronchiectasis that is similar to CF in many ways but is caused by congenital defects in mucociliary clearance. Our objective was to compare the biophysical and transport properties of CF and PCD sputa in subjects matched for age and degree of lung function impairment. PCD patients (n = 19; mean age, 9.5 +/- 3.0 years [+/- SD]; FEV1, 65.0 +/- 7.8 L) were recruited from the clinic at the Royal Brompton Hospital. Patients with CF (n = 30, mean age, 10.8 +/- 2.6 years; FEV1, 61.8 +/- 22.8 L) were identified from the Wake Forest University School of Medicine CF Center. Pulmonary function testing and sputum collection were performed as part of routine, scheduled clinic visits. Pulmonary function was measured by spirometry, and sputum was collected during the pulmonary function test maneuver. Some patients were longitudinally assessed at visits during the course of 3 years. Sputum properties measured were dynamic viscoelasticity, wettability, cohesivity, interfacial (surface) tension, solids composition, DNA and interleukin (IL)-8 concentration, in vitro mucociliary transportability, and cough transportability. Inflammation as measured by IL-8 concentration was three times greater in the PCD sputa (p < 0.0001). There were no significant differences in the sputum biophysical or transport properties comparing CF with PCD sputum. It is unlikely that established CF lung disease is principally due to abnormal sputum properties, and it is more likely that the biophysical and transport properties reflect disease severity regardless of whether bronchiectasis is due to CF or PCD.

It has been assumed that cystic fibrosis (CF) lung disease is due in part to abnormal airway mucus. Primary ciliary dyskinesia (PCD) is a form of bronchiectasis that is similar to CF in many ways but is caused by congenital defects in mucociliary clearance. Our objective was to compare the biophysical and transport properties of CF and PCD sputa in subjects matched for age and degree of lung function impairment. PCD patients (n = 19; mean age, 9.5 ± 3.0 years [± SD]; FEV1, 65.0 ± 7.8 L) were recruited from the clinic at the Royal Brompton Hospital. Patients with CF (n = 30, mean age, 10.8 ± 2.6 years; FEV1, 61.8 ± 22.8 L) were identified from the Wake Forest University School of Medicine CF Center. Pulmonary function testing and sputum collection were performed as part of routine, scheduled clinic visits. Pulmonary function was measured by spirometry, and sputum was collected during the pulmonary function test maneuver. Some patients were longitudinally assessed at visits during the course of 3 years. Sputum properties measured were dynamic viscoelasticity, wettability, cohesivity, interfacial (surface) tension, solids composition, DNA and interleukin (IL)-8 concentration, in vitro mucociliary transportability, and cough transportability. Inflammation as measured by IL-8 concentration was three times greater in the PCD sputa (p < 0.0001). There were no significant differences in the sputum biophysical or transport properties comparing CF with PCD sputum. It is unlikely that established CF lung disease is principally due to abnormal sputum properties, and it is more likely that the biophysical and transport properties reflect disease severity regardless of whether bronchiectasis is due to CF or PCD.

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene, encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. These mutations disrupt CFTR function within epithelial cells. Although the defect affects ion transport in many organs, the major cause of morbidity and mortality in individuals with CF is the progressive lung disease characterized by inflammation and unremitting bacterial infection with Pseudomonas, Staphylococcus, Haemophilus, Aspergillus and Burkholderia species. Although CF airways exhibit high numbers of immune cells and elevated levels of proinflammatory cytokines, the lung's innate immune defenses fail to clear bacterial infections. These observations suggest a modified immune response in the CF lung (due to the CFTR mutation and associated secondary alterations of the airway epithelium). Airway epithelial cells not only function as a physical barrier against inhaled pathogens, but also play an important role in innate immune responses of the host. Microorganisms are recognized through a variety of pattern recognition receptors (PRR), mainly Toll-like receptors (TLRs) that are abundantly expressed in airway epithelial cells. TLR activation in a milieu potentially rich in microbial (and endogenous) TLR agonists probably adds to the chronic inflammatory phenotype in CF airway epithelia. Therefore, the expression, function and activation of TLRs in CF airway epithelia have become the focus of intensive research. In this chapter, we give an overview of the current understanding of TLR signaling in CF and its potential role in the pathogenesis of CF lung disease.