CFTR is a modulator of airway inflammation.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
Bruce K Rubin
Publications and source records attributed to Bruce K Rubin.
Secretory phospholipases A2 stimulate mucus secretion, induce airway inflammation, and produce secretory hyperresponsiveness to neutrophil elastase in ferret trachea.
Secretory phospholipases A(2) (sPLA(2)) are increased in the bronchoalveolar lavage fluid of patients with asthma and acute respiratory distress syndrome. Intratracheal sPLA(2) instillation induces acute lung injury in the rat and guinea pig. We hypothesized that sPLA(2) would stimulate mucus secretion in vitro and that intratracheal sPLA(2) exposure would induce mucus hypersecretion and airway inflammation in the ferret trachea in vivo. In vitro, porcine pancreatic sPLA(2) at a concentration of 0.5 or 5 U/ml significantly increased mucous glycoconjugate (MG) secretion from the excised ferret trachea. P-bromophenacylbromide (a sPLA(2) inhibitor), quercetin (a lipoxygenase inhibitor), or MK-886 (a 5-lipoxygenase inhibitor), each at 10(-4) M, significantly reduced sPLA(2)-induced MG secretion. sPLA(2)-stimulated MG secretion was decreased in Ca(2+)-free medium. In vivo, ferrets were intubated for 30 min once per day for 3 days using an ETT coated with 20 units of porcine pancreatic sPLA(2) mixed in water-soluble jelly. Constitutive MG secretion increased 1 day after sPLA(2) exposure and returned to control 5 days later. Human neutrophil elastase (HNE) at 10(-8) M increased MG secretion in the sPLA(2)-exposed trachea compared with that in the control trachea, but methacholine at 10(-7) M did not. sPLA(2)-induced secretory hyperresponsiveness continued for at least 5 days after sPLA(2) exposure ended. sPLA(2) increased tracheal inflammation, MG secretion, and secretory hyperresponsiveness to HNE probably through enzymatic action rather than by activation of its receptor.
Animals↗
Other medications for aerosol delivery.
Although aerosol therapy is most commonly used to treat asthma and COPD, there are a large number of aerosol medications now used or in development for other diseases. Mucoactive agents have long been available by aerosol, but now we have truly effective drugs to improve effective airway clearance including dornase alfa, hyperosmolar saline, and aerosol surfactant. Inhaled antibiotics are available for the treatment of cystic fibrosis, bronchiectasis and other chronic airway infections. With the development of devices that can target aerosol to the deep lung, the opportunity to deliver medications systemically by the aerosol route has become a reality. Insulin, recently approved in the US as aerosol therapy, and other peptides are systemically absorbed from the distal airway and alveolus. Aerosol gene transfer therapy to correct abnormalities associated with cystic fibrosis, primary ciliary dyskinesia and other airway diseases also holds great potential.
Administration, Inhalation↗
The pharmacologic approach to airway clearance: mucoactive agents.
The term "mucoactive agent" refers to any medication used to improve the clearance of airway secretions. It is not synonymous with the word "mucolytic" as this strictly means a drug that decreases the viscosity of secretions. In many cases, decreased viscosity will adversely affect cough transport. For this reason many of the older mucolytic agents such as acetylcysteine are not effective for the therapy of lung disease and their use is not recommended. I review here the many classes of mucoactive agents and identify a number of medications with great promise for the treatment of chronic airway disease.
Expectorants↗
Vasoactive intestinal peptide stimulates mucus secretion, but nitric oxide has no effect on mucus secretion in the ferret trachea.
Vasoactive intestinal peptide (VIP) and nitric oxide (NO) are neurotransmitters involved in the regulation of bronchial and pulmonary vascular tone. Published studies of the effects of VIP on airway mucus secretion have yielded conflicting results. The purpose of this study was to determine the effect of VIP on mucus secretion in the ferret trachea and if this effect was influenced by NO. We used a sandwich enzyme-linked lectin assay to measure mucin secretion and a turbidimetric assay to measure lysozyme (serous cell) secretion from ferret tracheal segments. VIP (10(-7) M) increased mucin secretion over 2 h. VIP (10(-9) to 10(-5) M) stimulated mucin secretion in a dose-dependent fashion. VIP-induced mucin secretion was partially blocked by a VIP receptor antagonist (a chimeric VIP-pituitary adenylate cyclase-activating peptide analog, VIP receptor antagonist) at a 10-fold excess concentration. At all concentrations tested, neither NG-nitro-L-arginine methyl ester, an inhibitor of NO synthase, nor S-nitroso-N-acetyl-penicillamine, an NO donor, had any significant effect on constitutive or VIP-induced mucus secretion. We conclude that VIP-stimulated mucin and lysozyme secretion was both time dependent and dose dependent and that NO neither stimulates nor inhibits mucus secretion in the ferret trachea.
Animals↗
Editorial: respecting the middle lobe syndrome.
Explore the source record for details and available documents.
Child↗
Up-regulation of S100A8 and S100A9 protein in bronchial epithelial cells by lipopolysaccharide.
Increased serum levels of the S100A8 (MRP-8) protein have been reported in inflammatory conditions including bacterial infection, arthritis, and cystic fibrosis (CF). This protein is expressed constitutively with S100A9 (MRP-14) in neutrophils and is regulated by inflammatory stimulants. It has been hypothesized that increased inflammatory response to persistent bacterial infection is a major feature of CF lung disease. Therefore, the authors wished to determine the involvement of these two proteins in the innate defense response of the bronchial epithelium to lipopolysaccharide (LPS). Human bronchial epithelial cells (16HBE14o-) and primary bronchial epithelial cells (NHBE) were grown at air-liquid interface (ALI) and stimulated for up to 96 hours with LPS from Pseudomonas aeruginosa. The 16HBE14o- cells responded to LPS with a 2.9-fold increase in S100A8 mRNA production after 12 hours. S100A9 mRNA production was increased by 1.8-fold after 12 hours and 2.9-fold after 24 hours. It was also found that the S100A8 and S100A9 proteins were increased in the secretions of the 16HBE14o- and NHBE cells after LPS stimulation. This finding suggests that S100A8 and S100A9 are involved in the innate defense of the bronchial epithelium.
Bronchi↗
Clarithromycin delays progression of bronchial epithelial cells from G1 phase to S phase and delays cell growth via extracellular signal-regulated protein kinase suppression.
The nonsteroidal anti-inflammatory drugs have been shown to support cytoprotection of cells by shifting cells toward a quiescent state (G(0)/G(1)). Extracellular signal-regulated kinase (ERK) is required for cells to pass from G(1) phase into S phase, and macrolide antibiotics can inhibit ERK1/2 phosphorylation. However, previous reports suggest that macrolide antibiotics do not affect cell growth in bronchial epithelial cells. Therefore, we studied normal human bronchial epithelial (NHBE) cells to determine whether clarithromycin (CAM) suppresses ERK, delays bronchial epithelial cells from progressing to S phase, and delays cell growth. Exposure to CAM at 10 microg/ml daily over 4 days irreversibly decreased the cell proliferation with and without growth supplements (P < 0.0001). CAM also inhibited ERK1/2 phosphorylation over the first 90 min of exposure (P < 0.05 for 30 min, P < 0.0001 for 60 min, and P < 0.01 for 90 min) and decreased the ratio of phosphorylated ERK1/2 (pERK1/2) to total ERK1/2 (tERK1/2) (P < 0.0001). Incubation with CAM for 48 h increased the proportion of cells in G(1) phase (means +/- standard deviations) from 63.5% +/- 0.9% to 79.1% +/- 1.4% (P < 0.0001), decreased that in S phase from 19.8% +/- 1.2% to 10.0% +/- 2.1% (P < 0.01), and decreased that in G(2)/M phase from 16.7% +/- 0.4% to 11.0% +/- 0.8% (P < 0.001). In contrast, the ratio of pMEK1/2 to tMEK1/2 was not altered after exposure to CAM. These results suggest that macrolide antibiotics can delay the progression of NHBE cells from G(1) phase to S phase and can slow cell growth, probably through the suppression of ERK1/2.
Anti-Bacterial Agents↗
Mucus properties in children with primary ciliary dyskinesia: comparison with cystic fibrosis.
OBJECTIVE: 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. DESIGN, SETTING, PARTICIPANTS: 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. MEASUREMENTS: 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. RESULTS: 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. CONCLUSIONS: 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.
Biomarkers↗
Pediatricians are not just small internists.
Explore the source record for details and available documents.
Adolescent↗
Pulmonary function is negatively correlated with sputum inflammatory markers and cough clearability in subjects with cystic fibrosis but not those with chronic bronchitis.
BACKGROUND: Polymorphonuclear neutrophil (PMN)-dominated inflammation is prominent in the airways of subjects with cystic fibrosis (CF) and chronic bronchitis (CB). Interleukin (IL)-8, myeloperoxidase (MPO), and DNA are markers of neutrophilic inflammation. We hypothesized that sputum MPO, DNA, and IL-8 concentrations would negatively correlate with pulmonary function and sputum transportability. METHODS: We measured pulmonary function and analyzed sputum IL-8, MPO, and DNA concentrations, as well as the transport properties of sputum samples obtained from 16 subjects with CF and 15 subjects with CB. We also evaluated changes in these measurements in paired sputum samples from these subjects obtained 2 to 12 months apart. RESULTS: IL-8 and MPO concentrations in the sputum of CF subjects was inversely correlated with FEV(1) percent predicted (IL-8: r = -0.40; p = 0.003; MPO: r = -0.38; p = 0.003) and FVC percent predicted (IL-8: r = -0.4; p = 0.02; MPO: r = -0.4; p = 0.02). IL-8 and DNA concentrations were inversely correlated with sputum cough transportability (CTR) [IL-8: r = -0.4; p = 0.02; DNA: r = -0.36; p = 0.048]. Changes in DNA concentration in sputum samples from CF subjects over time were inversely correlated with changes in FEV(1) percent predicted (r = -0.58; p = 0.02), FVC percent predicted (r = -0.74; p = 0.002), and CTR (r = -0.59; p = 0.02). There was no correlation among pulmonary function, sputum properties, and inflammatory markers in the sputum from subjects with CB. CONCLUSIONS: The sputum concentrations of IL-8, MPO, and DNA appear to be closely associated with pulmonary function in subjects with CF but not in subjects with CB.
Adolescent↗
Did Lady Windermere have cystic fibrosis?
Explore the source record for details and available documents.
Adult↗
Thymosin beta4 sequesters actin in cystic fibrosis sputum and decreases sputum cohesivity in vitro.
BACKGROUND: Filamentous actin (F-actin) forms polymers that contribute to the abnormal biophysical properties of sputum. Thymosin beta4 (Tbeta4) is the major monomeric actin-sequestering peptide in cells and can depolymerize F-actin. Tbeta4 could potentially decrease sputum viscoelasticity and adhesivity and improve sputum clearance. METHODS: Sputum was collected during pulmonary function testing from 17 subjects during a cystic fibrosis (CF) center visit. Sputum rheology, cough and ciliary transportability, and interfacial tension were measured before and after the addition of dornase alfa at 30 microg/mL; Tbeta4 at 0.3, 3, 30, and 150 microg/mL; and Tbeta4 with dornase alfa at 1.5 microg/mL each. Sputum was separately incubated with Tbeta4 at 30 microg/mL for 0, 10, 20, or 60 min. RESULTS: There was a direct relationship between actin filament length and sputum cohesivity. There was a dose-dependent threshold decrease in cohesivity with Tbeta4 and a time-dependent decrease in cohesivity over 60 min at 30 microg/mL. With the combination of dornase alfa and Tbeta4 at 1.5 microg/mL each, there was a 70% decrease in G*s and a 65% decrease in G' at 1 rad/s (p = 0.013). There was a 44% increase in cough transportability of sputum in vitro (p = 0.037) and a 71% increase in mucociliary transportability of sputum in vitro (p = 0.013) relative to control with the combination of dornase alfa and Tbeta4, but no significant change with dornase alfa or Tbeta4 alone at any concentration. CONCLUSIONS: Actin polymer filament length is correlated with sputum cohesivity. Tbeta4 depolymerizes CF sputum actin in both a dose-dependent and a time-dependent manner. An apparent synergy of Tbeta4 on actin and dornase on DNA may be explained by the combined effect of actin depolymerization and DNA filament severing or by virtue of actin depolymerization increasing the effectiveness of dornase alfa.
Actins↗
Force-dependent static dead space of face masks used with holding chambers.
BACKGROUND: Pressurized metered-dose inhalers with valved holding chambers and masks are commonly used for aerosol delivery in children. Drug delivery can decrease when the dead-space volume (DSV) of the valved holding chamber is increased, but there are no published data evaluating force-dependent DSV among different masks. METHODS: Seven masks were studied. Masks were sealed at the valved holding chamber end and filled with water to measure mask volume. To measure mask DSV we used a mannequin of 2-year-old-size face and we applied the mask with forces of 1.5, 3.5, and 7 pounds. Mask seal was determined by direct observation. Intra-brand analysis was done via analysis of variance. RESULTS: At 3.5 pounds of force, the DSV ranged from 29 mL to 100 mL, with 3 masks having DSV of < 50 mL. The remaining masks all had DSV > 60 mL. At 3.5 pounds of force, DSV percent of mask volume ranged from 33.7% (Aerochamber, p < 0.01 compared with other masks) to 100% (Pocket Chamber). DSV decreased with increasing force with most of the masks, and the slope of this line was inversely proportional to mask flexibility. Mask fit was 100% at 1.5 pounds of force only with the Aerochamber and Optichamber. Mask fit was poorest with the Vortex, Pocket Chamber, and BreatheRite masks. CONCLUSION: Rigid masks with large DSV might not be not suitable for use in children, especially if discomfort from the stiff mask makes its use less acceptable to the child.
Administration, Inhalation↗
Plastic bronchitis: new insights and a classification scheme.
Plastic bronchitis is a rare disease in which there is the formation of large gelatinous or rigid branching airway casts. The history of the disease is reviewed and a classification system is proposed based on our current understanding. This system classifies plastic bronchitis by clinical disease association and cast histology. A summary of the medical literature is included together with guidelines for treatment. The evidence for these treatment decisions is reviewed.
Anemia, Sickle Cell↗
Macrolide antibiotics modulate ERK phosphorylation and IL-8 and GM-CSF production by human bronchial epithelial cells.
Macrolide antibiotics decrease proinflammatory cytokine production in airway cells from subjects with chronic airway inflammation. However, in subjects with chronic obstructive pulmonary disease, short-term azithromycin (AZM) therapy causes a transient early increase in the blood neutrophil oxidative burst followed by a decrease in inflammatory markers with longer administration. We studied the effects of clarithromycin (CAM) and AZM on proinflammatory cytokine production from normal human bronchial epithelial (NHBE) cells. CAM decreased IL-8 over the first 6 h and then significantly increased interleukin (IL)-8 at 12-72 h after exposure (P < 0.0001). AZM also increased IL-8 at 24 and 48 h, and CAM increased granulocyte-macrophage colony-stimulating factor at 48 h. In the presence of LPS, both CAM and AZM dose-dependently increased IL-8 secretion over 24 h, but after 5 days of exposure to 10 microg/ml CAM there is suppression of IL-8 (P < 0.001). PD-98059, an inhibitor of MAP kinase/ERK kinase, inhibited CAM-induced IL-8 (P < 0.0001) and GM-CSF (P < 0.01) release. The p38 MAP kinase inhibitor SB-203580 increased CAM-induced IL-8 release (P < 0.001), and the c-jun NH2-terminal kinase inhibitor SP-600125 had no effect on IL-8. At 120 min and 6 h, CAM increased phospho-ERK1/2 (pERK) but not phospho-p38 or phospho-JNK. Over the first 90 min, CAM at 10 microg/ml inhibited pERK and then increased pERK in parallel with measured IL-8 secretion. After daily CAM exposure for 5 days, both IL-8 and pERK returned to baseline. The p38 MAP kinase inhibitor, SB-203580 increased ERK phosphorylation and IL-8 secretion. These results suggest that macrolide antibiotics can differentially modulate proinflammatory cytokine secretion in NHBE cells, in part through ERK.
Anti-Bacterial Agents↗
Effect of macrolides on in vivo ion transport across cystic fibrosis nasal epithelium.
Fourteen- and 15-member macrolide antibiotics are under investigation as potential therapeutic agents for cystic fibrosis (CF). The nonantibiotic mechanisms of action of these compounds in CF are not understood. We used nasal potential difference (NPD) measurements to test the effect of macrolides on airway epithelial ion (chloride, sodium) transport of CF mice and humans. We tested clarithromycin and azithromycin in mice, and clarithromycin in patients with CF. Baseline and post-treatment NPD was measured in two strains (C57Bl6 and BalbC) of CF transmembrane regulator "knockout" and littermate control mice, and in DeltaF508/DeltaF508 mice. In addition, NPD was measured in 18 human subjects with CF (17 DeltaF-508/DeltaF-508 and 1 DeltaF-508/other) who were undergoing a 12-month, randomized, double-blind crossover study of the effects of clarithromycin on pulmonary outcome in CF. Neither clarithromycin nor azithromycin affected ion transport characteristics of normal or CF nasal epithelium in either mouse or humans. We conclude that the apparent beneficial effects of macrolides on pulmonary outcome in CF are not mediated by their modulation of ion transport.
Adolescent↗
Macrolides and airway inflammation in children.
For more than 20 years macrolide antibiotics have been used to treat chronic inflammatory airway diseases based on their immunomodulatory activity. Macrolide antibiotics down-regulate damaging prolonged inflammation as well as increase mucus clearance, decrease bacterial virulence and prevent biofilm formation. Initially shown to decrease morbidity and mortality in diffuse panbronchiolitis and in steroid-dependent asthma, long-term macrolide therapy has now been shown to significantly reduce exacerbations and improve lung function and quality of life in children with cystic fibrosis. They have also proven beneficial in Japanese children and adults with chronic sinobronchitis especially when there is nasal polyposis. Long-term macrolides have also proven clinically beneficial in some patients with plastic bronchitis. Adverse reactions are few and generally self-limited when used at the recommended dosage for immunomodulation.
Anti-Bacterial Agents↗