Search

For 50 years, macrolide antibiotics have been used to treat community acquired pneumonia and atypical infections such as Chlamydia pneumonia and Mycoplasma. In the late 1960s it was noted that when the 14-member ring macrolide antibiotic troleandomycin was given to asthma patients who required large doses of systemic corticosteroids, they could often reduce their steroid dose or even stop steroids completely without exacerbation of their asthma. Because of this experience, Prof. S. Kodoh and colleagues first used erythromycin as an immunomodulatory agent to treat diffuse panbronchiolitis (DPB). DPB is a cystic fibrosis (CF)-like condition seen predominantly in young, nonsmoking adults in Japan and Korea. The introduction of erythromycin profoundly improved survival, and in many of these very ill patients the illness disappeared. Since then, research has focused attention on many non-antibacterial, disease modifying effects of this class of compounds. These include downregulation of proinflammatory cytokines via an effect on nuclear transcription factors, reduction in adhesion molecule expression, suppression of inducible nitric oxide synthase (iNOS), reduced neutrophil chemotaxis and degranulation, inhibition of neutrophil elastase, cytoprotection against bioactive phospholipids, improvement in the rheological properties of mucus, reduction in bronchial hyperreactivity, and, perhaps, modulation of neutrophil death by apoptosis pathways, and in the end, airway remodeling. Additionally, they have unconventional effects on microorganisms, including inhibiting Pseudomonas aeruginosa twitching motility and thus biofilm formation. There are small case series and three large randomized controlled trials that have established unequivocal evidence of benefit in CF. There is less evidence for an immunomodulatory effect in bronchiectasis. Future work is likely to focus on the development of macrolides with disease-specific modes of action.

Background: Inhaled corticosteroids (ICS) may provide benefit in the therapy of acute asthma. The purpose of this study was to test the hypothesis that ICS are as effective as oral corticosteroids (OCS) in the management of acute childhood asthma., Methods: A randomized, masked, placebo-controlled study was conducted in children aged 6 to 16 years seeking emergent care for an acute exacerbation of asthma. Patients were randomized into one of two groups: group 1 (OCS), oral prednisone, 2 mg/kg (maximum of 60 mg/d) for 7 days, and placebo pressurized metered-dose inhaler with valved holding chamber, four inhalations bid; and group 2 (ICS), flunisolide, four inhalations (1 mg) bid for 7 days, and daily placebo tablets. Spirometry (FEV(1)) was performed at baseline, day 3, and day 7 of the study. A symptom diary and twice-daily peak expiratory flow were recorded., Results: A total of 58 subjects receiving ICS (n = 27) or OCS (n = 28) were enrolled. Baseline asthma severity, race, gender, and age were balanced between the two groups. chi(2) showed no significant difference in symptom severity between the two groups at any time during the study. FEV(1) percentage of predicted was lower in the ICS group on day 3 (65% vs 78%, p = 0.03) and on day 7 (77% vs 95%, p = 0.002)., Conclusion: ICS were found to be useful in the management of acute asthma in children; however, spirometry data suggested a more rapid resolution of asthma with OCS.

Study Objectives: Inhalation of hypertonic saline or mannitol solutions acutely increases mucociliary clearance. Because increased clearance is often coupled with increased mucus secretion, we hypothesized that hyperosmolar agents would stimulate mucus secretion., Setting and Subjects: The isolated tracheae of healthy young adult ferrets were studied in a basic research laboratory., Measurements and Results: We demonstrated that there was a dose-dependent increase in mucin secretion by enzyme-linked lectin assay after incubation with 1.69 g/dL (597 mOsm/L), 3.69 g/dL (1,192 mOsm/L), 5.69 g/dL (1,823 mOsm/L), and 10.69 g/dL (3,612 mOsm/L) of saline solution over Krebs-Henseleit solution control (288 mOsm/L) [p < 0.01 for 1.69 g/dL of saline solution and p < 0.0001 for others]. Mannitol solution, 15 g/dL (1,040 mOsm/L), also significantly increased mucin secretion (n = 4, p < 0.005). There was a 47% and 54% increase in secretion of the serous cell product lysozyme after exposure to 3.69 g/dL (1,192 mOsm/L) and 10.69 g/dL (3,612 mOsm/L) saline solutions, respectively (n = 5, p < 0.05). Secretion was only stimulated when the hyperosmolar exposure was on the luminal side of the epithelium. Mucin secretion was induced within minutes of 3.69 g/dL of saline solution exposure, and this increased mucin secretion quickly peaked. The ratio of mucin to lysozyme secretion was approximately 2. This ratio appeared to be independent of the osmotic concentration of the stimulus and therefore of secretory rate., Conclusions: Mucus secretion is markedly stimulated in response to hyperosmolarity. This may be a protective response. These results also suggest that the therapeutic use of hyperosmolar aerosols should be evaluated with care when used for patients with mucus hypersecretion and impaired mucus clearance.

Chronic obstructive pulmonary disease (COPD) and other inflammatory airway conditions are major causes of morbidity and mortality worldwide. Antibiotics are used to treat acute infectious exacerbations of airway disease. However, for the macrolides, a significant and growing body of evidence indicates that anti-inflammatory effects of these antibiotics, which may be independent of their antibacterial effects, are at least partially responsible for their beneficial effect. In this review, we describe current thinking on the means whereby anti-inflammatory effects of macrolides impact chronic airway disease. The current data indicate that some macrolides have immunomodulatory activity, mediated at least in part by effects on the activation of gene transcription mediated by NF-kappabeta activation that may be separable from their antimicrobial activities, and could explain their surprising efficacy in asthma and viral infections for which the role of bacteria is not established. Other, provocative work indicates that subclinical doses of macrolides may also affect signalling within and between bacterial communities, and thus impact developmental processes such as biofilm formation that are important in the establishment and persistence of chronic infections. The current data clearly suggest that activities beyond antimicrobial effects contribute significantly to the beneficial effect of macrolide therapy on inflammatory conditions.

The effective and efficient delivery of aerosol medications involves physician factors (correct diagnosis and correct prescription of appropriate medications), device factors, and patient factors. For nearly all infants and children, the authors administer asthma medications either using a pMDI with a valved holding chamber or a DPI. Regardless of the device chosen, parent and patient education is critical for the appropriate use of the device, and frequent reinforcement of the educational message will often improve adherence and correct use.

Airway mucus is the secretory product of the mucous cells; it is a variable mixture of water, mucous glycoproteins, low molecular weight ions, proteins, and lipids, whose physical properties are important for airway defense. The factors that contribute to the physical properties of mucus are complex, and there are a number of pharmacological strategies that can potentially serve to improve the clearability of airway mucus. Novel mucoactive approaches include strategies for mucoregulation--decreasing the abnormal volume of mucus secretion--and medications designed to improve the cough clearability of airway secretions. In vitro results suggest potential benefits from the additive effects of selected combinations of mucoactive medications. Further studies are required to confirm these findings, to perform direct assessments of mucus clearability, and to extend the observations to patients with various types of pulmonary diseases where mucoactive treatments are required., (Copyright 2002 Elsevier Science B.V.)

A therapeutic aerosol benefits the patient only if the medication deposits in the airway. Advances in nebulizer design have made them more efficient and "user friendly," but the greatest problem with administering aerosolized medication continues to be educating patients and caregivers to use aerosol devices properly and consistently. Misuse and nonuse are the greatest impediments to effective aerosol delivery. The respiratory pattern and degree of patient cooperation also profoundly affect aerosol deposition, and those effects are greatly magnified in small children. There are many misconceptions about nebulizer use and nebulizer equipment, even in teaching hospitals, and these can have serious consequences when patients do not receive the medication they need. This review discusses how airway physiology, nebulizer technology, and patient education relate to appropriate nebulizer use. Education is critically important, but unfortunately it is often a misunderstood or neglected part of aerosol administration.

We describe a 20-year-old patient with cystic fibrosis who developed acute nonoliguric renal failure associated with inhaled tobramycin. Clinical evaluation and renal biopsy findings were consistent with aminoglycoside-induced changes. Renal failure due to inhaled aminoglycosides has not been previously reported. The incidence may rise, however, with the increased use of this treatment modality. Measurable tobramycin levels due to inhalational therapy with conventional dosing in the reported patient indicate that the drug can be systemically absorbed, and renal tubular toxicity may occur., (Copyright 2002 Wiley-Liss, Inc.)

Respiratory tract secretions consist of mucus, surfactant, and periciliary fluid. The airway surface fluid is present as a bilayer, with a superficial gel or mucous layer and a layer of periciliary fluid interposed between the mucous layer and the epithelium. A thin layer of surfactant separates the mucous and periciliary fluid layers. The mucous layer extends from the intermediate airway to the upper airway and is approximately 2-10 microm thick in the trachea. Airway mucus is the secretory product of the goblet cells and the submucosal glands. It is a nonhomogeneous, adhesive, viscoelastic gel composed of water, carbohydrates, proteins, and lipids. In health, the mucous gel is primarily composed of a 3-dimensional tangled polymer network of mucous glycoproteins or mucin. Mucin macromolecules are 70-80% carbohydrate, 20% protein, and 1-2% sulfate bound to oligosaccharide side chains. The protein backbones of mucins are encoded by mucin genes (MUC genes), at least 8 of which are expressed in the respiratory tract, although MUC5AC and MUC5B are the 2 principal gel-forming mucins secreted in the airway. Mucus is transported from the lower respiratory tract into the pharynx by air flow and mucociliary clearance. Expectorated sputum is composed of lower respiratory tract secretions along with nasopharyngeal and oropharyngeal secretions, cellular debris, and microorganisms. Disruption of normal secretion or mucociliary clearance impairs pulmonary function and lung defense and increases risk of infection. When there is extensive ciliary damage and mucus hypersecretion, airflow-dependent mucus clearance such as cough becomes critically important for airway hygiene.

The airway mucosa responds to infection and inflammation in a variety of ways. This response often includes surface mucous (goblet) cell and submucosal gland hyperplasia and hypertrophy, with mucus hypersecretion. Products of inflammation, including neutrophil-derived deoxyribonucleic acid (DNA) and filamentous actin (F-actin), effete cells, bacteria, and cell debris, all contribute to mucus purulence and, when this mucus is expectorated it is called sputum. Mucoactive medications are intended to serve one of 2 purposes; either to increase the ability to expectorate sputum or to decrease mucus hypersecretion. Mucoactive medications have been classified according to their proposed mechanisms of action. Increased knowledge of the properties of mucus has given us tools to better understand the mechanisms of airway disease and mucoactive therapy. Expectorants are thought to increase the volume or hydration of airway secretions. Systemic hydration and classic expectorants have not been demonstrated to be clinically effective. Modifiers of airway water transport are being clinically investigated as expectorants. Mucolytics degrade polymers in secretions. The classic mucolytics have free thiol groups to degrade mucin. Peptide mucolytics break pathologic filaments of neutrophil-derived DNA and actin in sputum. Nondestructive mucolysis includes mucin dispersion by means of charge shielding. Mucokinetics are medications that increase mucociliary efficiency or cough efficiency. Cough flow can be increased by bronchodilators in patients with airway hyperreactivity. Abhesives such as surfactants decrease mucus attachment to the cilia and epithelium, augmenting both cough and mucociliary clearance. Mucoregulatory agents reduce the volume of airway mucus secretion and appear to be especially effective in hypersecretory states such as bronchorrhea, diffuse panbronchiolitis, and some forms of asthma. Mucoregulatory agents include anti-inflammatory agents (indomethacin, glucocorticosteroids), anticholinergic agents, and some macrolide antibiotics. Classifying mucoactive agents should help us to develop and evaluate new types of therapy and to better direct therapy toward the patients who are most likely to benefit.

Neutrophil-dominated inflammation is prominent in the cystic fibrosis (CF) and chronic bronchitis (CB) airways. We assessed the degree of airway inflammation by measuring the sputum concentrations of interleukin (IL)-8, myeloperoxidase (MPO), and deoxyribonucleic acid (DNA). We determined the relationship among the concentrations of these mediators and investigated methodological problems that may be responsible for reported variability in measurements. Sputa obtained from 31 patients were solubilized with phosphate-buffered saline, dithiothreitol (DTT) (0.1% or 1%), or dornase alfa (0.2 mg/mL). The sputum concentration of IL-8 and MPO was measured by enzyme-linked immunosorbent assay (ELISA), and DNA was measured using microfluorimetry. There was a significant relationship among sputum IL-8, MPO, and DNA. For MPO (means +/- SD), CF was 1,392 +/- 771 vs. CB at 75 +/- 65 mcg/mL; P < 0.0001. For IL-8: CF was 239 +/- 154 vs. CB at 121 +/- 108 ng/mL; P = 0.0002. For DNA, CF was 1.707 +/- 1.25 vs. CB at 0.184 +/- 0.272 mg/mL; P < 0.0001. The MPO concentration in CF sputum was approximately double after in vitro treatment with dornase alfa (P < 0.0001). There is a greater concentration of IL-8, MPO, and DNA in CF than in CB sputa. There is a significant relationship among these inflammatory markers in sputum. DNA polymers bind myeloperoxidase in the sputum, and we speculate that treatment with dornase alfa may remove a source of MPO inhibition., (Copyright 2001 Wiley-Liss, Inc.)

Objective: To evaluate the effect of recombinant human deoxyribonuclease I (rhDNase) in shortening the length of the hospitalization and improving the chest radiographs (CXRs) in hospitalized infants with respiratory syncytial virus (RSV) infection as a result of its mucolytic properties., Methods: Randomized, double-blind, placebo-controlled investigation of 75 patients with RSV bronchiolitis. The study was conducted at the University of Michigan Medical Center and St. Joseph Mercy Hospital, both in Ann Arbor, MI., Results: The respiratory rate, wheezing, and retraction difference scores, obtained by subtracting the hospital discharge score from the corresponding hospital admission score, show no difference between the two groups, but the CXR difference scores show that the rhDNase group improved by 0.46 while the placebo group worsened by 0.60 (p < 0.001). Analysis of covariance for the hospital discharge CXR score after adjusting for the hospital admission score for both groups was done. There was a difference in scores between the two groups, with adjusted mean for the study group of 2.03, and 2.76 for the placebo group (p < 0.001). Paired t test statistics in each of the two groups were computed. For the placebo group, the mean increase of 0.60 was significant (p = 0.02), and the mean decrease of 0.46 for the rhDNase group was also significant (p = 0.02). A one-way analysis of covariance with the hospital discharge CXR scores as the dependent variable and the hospital admission score as the covariate showed that there was a significant difference between the groups (p = 0.01)., Conclusion: In patients with RSV bronchiolitis, there was significant improvement in the CXRs with the use of rhDNase compared to significant worsening in the placebo group. To our knowledge, this is the first report of the use of rhDNase to treat RSV bronchiolitis.

Pediatric aerosol therapy encompasses a range of patients from premature neonates with birth weights as low as 500 grams to adult size teenagers. This article focuses on the care of smaller infants and children in whom anatomic differences present substantial challenges for aerosol delivery.

Mucus hypersecretion is an important characteristic of many airway diseases. Mucin is the major component of mucus, and is secreted from surface goblet cells of the airway epithelium and mucous cells of submucosal glands. Lysozyme is an enzyme secreted by serous cells of airway submucosal glands. We hypothesized that secretagogues acting through different pathways would have different effects on tracheal mucin and lysozyme secretion. We used a sandwich enzyme-linked lectin assay (ELLA) to measure mucin-like glycoprotein secretion and a spectrophotometric method to measure lysozyme secretion from isolated ferret tracheal segments. We evaluated the secretory response to four secretagogues; prostaglandin F(2alpha) (PGF(2alpha)), adenosine triphosphate (ATP), methacholine (MCh), and human neutrophil elastase (HNE). Each agent stimulated mucin and lysozyme secretion. The relative potency was PGF(2alpha)< or =ATP

Objective: Anecdotal reports suggest that propofol (Diprivan) may stimulate mucus hypersecretion in patients without pulmonary disease. The purpose of this study was to evaluate the effect of methohexital or propofol anesthesia on the physical and transport properties of airway mucus in spontaneously breathing dogs., Design: Randomized, controlled, crossover laboratory study., Setting: University laboratory., Subjects: Four healthy, purpose-bred female beagle dogs., Interventions: Dogs were anesthetized with 5 mg/kg of propofol by intravenous bolus followed by a maintenance infusion at 0.4 mg x kg(-1) x min(-1) or 4 mg/kg of methohexital followed by an infusion at 0.3 mg x kg(-1) x min(-1). Premedication with 0.05 mg/kg of acepromazine was given, and either atropine (0.2 mg) or saline was given by intravenous bolus at the time of induction. Dogs were intubated but spontaneously breathing throughout the experiment. Tracheal secretions were collected after induction and again after 40 mins., Measurements and Main Results: The volume of secretions collected on the endotracheal tube during the 1.5-hr experiment and on a bronchoscopy brush over 10 mins during the experiment was measured. Tracheal epithelial potential difference was measured bronchoscopically by saturated agar bridges, and tracheal mucus transport velocity was determined by timing particle transport. The dynamic viscoelasticity of collected mucus was assessed by microrheometry, and secretion mucociliary transportability was measured in vitro. There were no differences in any physical or transport properties of airway secretions that could be attributed to the anesthetic agent. Secretion volume was significantly lower (p < .05) and epithelial potential difference was significantly higher (p = .03) with atropine premedication. Despite this, there were no differences in tracheal mucus transport velocity, viscoelasticity, or secretion mucociliary transportability with either anesthetic agent or with atropine., Conclusions: This study suggests that neither methohexital nor propofol significantly affects mucus secretion or clearance in healthy dogs.

Erythromycin was first isolated in the 1950s from a Philippine soil sample, and the derivatives of erythromycin A, called the macrolide antibiotics, have been used as effective antibacterial agents ever since. It has long been suspected that the 14-membered macrolides have immunomodulatory activity as demonstrated by their early use as adjunctive therapy for asthma and their astounding effectiveness for the therapy of diffuse panbronchiolitis. It is now clear, that the macrolides and their cousins, the 15-membered azalides, and perhaps the ketolides, have a broad range of biological response modifying effects on inflammation, tumor cells, airway secretions and host defenses. This review highlights some exciting new data, as well as controversies related to understanding the mechanism of action for these diverse effects.

One of the difficulties in assessing mucoactive therapy is selecting clinical outcome variables that reflect the impact of clearing airway secretions on quality of life (QOL). Petty and colleagues developed a questionnaire designed to evaluate the clinical impact of mucoactive therapy in patients with chronic bronchitis (CB). We evaluated this questionnaire in a multicenter study of a mucolytic medication used in patients with CB and hypothesized that spirometry, exercise capacity, and sputum clearability changes would correlate with QOL changes. This was a multicenter trial in 159 patients with stable CB (111 completed the 16-week study). Spirometry, plethysmography, the 6-minute walk test (6MWT), and Petty score as a measure of QOL were assessed at each visit. Sputum was collected at each visit. Cough transportability was measured in a cough machine, and mucociliary transportability was measured on the frog palate. Cohesivity was measured in a filancemeter, interfacial tension by de Noüy ring, and wettability by contact angle analysis. Within the entire data set of 694 evaluations, there was no correlation between pulmonary function and QOL. There was an inverse correlation with distance covered in a 6MWT (R(2) = 0.041, p < 0.0001). Sputum CTR was directly correlated with QOL (R(2) = 0.027, p < 0.0001). Change from baseline (mean of first three visits) was computed and compared the change in the mean of values at the 8- and 12-week visits (n = 108 sets of data pairs). This was analyzed as a percentage of change for continuous measurements, and as QOL is normative, we calculated the absolute change in QOL. There was no relation between QOL and 6MWT changes. There was an inverse relation between change in forced expiratory volume in 1 second and QOL (R(2) = 0.092, p = 0.0021) as well as between forced vital capacity and QOL (R(2) = 0.05, p = 0.024). There was a direct relation between CTR and QOL (R(2) = 0.039, p = 0.048). The relation between QOL and 6-minute walk distance was expected but weak. The consistent relation between CTR and QOL (suggesting that improved CTR of sputum is associated with decreased QOL) is difficult to explain. A change in forced expiratory volume in 1 second and forced vital capacity did correlate with a change in QOL. There is a need for a good QOL tool to evaluate mucus clearance devices or medications. The Petty questionnaire was designed specifically for this task, but the effect on sputum properties by current mucoactive agents may be too small to elicit a significant change in the Petty score.

The aerosol route is attractive for the delivery of mucoactive medications. Mucoactive medications include mucolytics, which depolymerize polymers of mucin (classic mucolytics) or DNA/actin (peptide mucolytics), mucokinetic agents, which increase cough clearance, mucoregulatory medications, which decrease abnormal mucus secretion, and expectorants and ion channel modifiers. Despite the widespread use of these medications, there are few well conducted studies and thus few data clearly supporting (or failing to support) their use. This will change as our understanding of mucociliary physiology and pharmacology increases and as well designed and well powered clinical trials are conducted with appropriate outcome measurements. Effective mucoactive therapy should make a profound impact on the care of patients with chronic bronchitis, asthma, cystic fibrosis, and inflammatory airways disease, and will be essential for the effective delivery of gene therapy vectors and bioactive peptides to the airway epithelium.

These novel and experimental therapies have the potential of drastically altering our understanding of and approach to airway disease. We indeed live in interesting times.

Airway mucus is the secretory product of the mucous cells. The mucus is a variable mixture of water, mucous glycoproteins, low molecular weight ions, proteins, and lipids, the physical properties of which are important for airway defense. The factors that contribute to the physical properties of mucus are complex, and there are several pharmacologic strategies that potentially can serve to improve the clearability of airway mucus. In vitro results suggest potential benefit from the additive effects of selected combinations of mucoactive medications. Further studies are required to confirm these findings, to perform direct assessments of mucus clearability, and to extend the observations to patients with various types of pulmonary diseases for which mucoactive treatments are required.

Autonomic cardiorespiratory control changes with sleep-wake states and is influenced by sleep-related breathing disorders. Power spectrum (PS) analysis of instantaneous fluctuations in heart rate (HR) is used to investigate the role of the autonomic nervous system (ANS) in cardiorespiratory control. The two spectral regions of interest are the low frequency component (LF) and high frequency component (HF). The aim of the present study was to investigate the autonomic cardiorespiratory control in children with obstructive sleep apnea (OSA) syndrome. We studied 10 children with OSA versus 10 normal children. All subjects underwent whole night polysomnography. Spectral analysis of the HR and breathing signals was performed for 256 second long, artifact-free epochs in each sleep-wake state. The LF power was higher in the OSA group compared with control subjects for all states, reflecting enhanced sympathetic activity in OSA subjects. The results indicated sympathetic predominance during REM sleep in all subjects and parasympathetic predominance in slow wave sleep only in controls. The autonomic balance (LF/HF) was significantly higher in OSA patients than in control subjects, at all stages during night sleep, and while awake before sleep onset. An index of overall autonomic balance (ABI) was computed for each subject and correlated well with the measured respiratory disturbance index (RDI).

Study Objective: The mechanism of action of potential mucoactive agents could relate to effects on the mucociliary apparatus or to direct effects on the secretions. The purpose of this study was to determine the in vitro effects of several agents on the properties of mucus simulants and sputum collected from 30 adults with stable chronic bronchitis., Design: Sputum or simulants were analyzed untreated and after the addition of the test agent at 1:5 volume to volume ratio for a contact period of 60 s. The concentrations of the agents were as follows: guaifenesin, 20 mg/mL; iodinated glycerol, 3 mg/mL; surfactant (Exosurf; Glaxo Wellcome; Research Triangle Park, NC) containing 13.5 mg of phospholipid per milliliter; albuterol, 5 mg/mL; and amphibian Ringer's solution (ARS) as a control. Dynamic viscoelasticity and surface mechanical impedance were measured in a magnetic microrheometer. Cohesiveness was measured using a filancemeter. The wettability of a hydrophilic surface was measured using an image processing system. The mucociliary transportability of sputum was timed on the frog palate, and cough transportability (CTR) was measured in a cough machine., Results: When compared to sputum that had no test agent or ARS added, all agents reduced sputum elasticity G', with surfactant, albuterol, and guaifenesin significant at p < 0.001. As well, guaifenesin (p = 0.006), albuterol (p = 0.003), and surfactant (p = 0.02) decreased surface mechanical impedance (frictional adhesiveness) compared to untreated sputum. However, there were no significant changes in wettability, hydration, cohesiveness, or CTR with any agent, and there were no significant changes in the properties of sputum or simulants treated with test agents when compared to those treated with ARS. Guaifenesin irreversibly disrupted mucociliary transport when applied directly to the frog palate., Conclusions: These agents appear to have a minimal direct action on sputum in vitro, suggesting that at the concentrations studied, these agents do not have a significant beneficial effect on either the mucociliary transportability or CTR of chronic bronchitis sputum. However, there could be an effect of some of these agents after oral administration, especially if there is a secondary effect of the agent on an effector cell.

Objective: To compare the biophysical properties of mucus from the left and right mainstem bronchi in patients undergoing diagnostic bronchoscopy because of a unilateral radiological abnormality. It was hypothesized that abnormalities in the properties of mucus would be greater on the side with the lesion and that this would be most obvious in patients with unilateral lung cancer., Patients and Methods: Bilateral paired samples of bronchial mucus were taken from 38 nonatopic patients (aged 59.8+/-12.6 years) including 16 nonsmokers, 14 current smokers and eight exsmokers (more than one year). Twenty of the 38 patients had a radiologically defined unilateral abnormality. Eight of these 20, including one nonsmoker, had lung cancer. The viscoelastic properties of the collected mucus were determined by magnetic microrheometry, and the analysis was carried out without knowledge of the histological diagnosis or source., Results: The rheological properties of mucus strongly suggested which was the abnormal side. Within the group of 20 patients with a unilateral radiological abnormality, mucus from the side of the lesion had a lower value of the loss tangent, tan d100 (P=0.004), indicating greater mucus recoil. This is consistent with poor mucus cough clearability on the lesion side. All eight cancer patients fit this mucus rheological pattern with a lower value of tan d100 on the affected side (P=0.007). Four of the five other patients with a similar mucus abnormality were categorized as high cancer risk by other criteria, while six of seven patients with mucus that did not have this abnormality were considered to be lower risk. Based on the mucus analysis done at the time of the bronchoscopy, two of the 'noncancer' patients initially designated as high risk had cancer detected after several months of follow- up. Only two of the 18 patients without a defined unilateral lesion fit the mucus 'cancer pattern'., Conclusions: These findings are consistent with the hypothesis that either abnormalities in mucus properties may represent a risk factor for the development of lung cancer or that bronchial mucus abnormalities may be associated with products secreted by the tumours that, in turn, may suppress mucus clearance.

Airway mucus hypersecretion is in part a response to infection and inflammation. Pseudomonas aeruginosa infection is nearly universal in advanced cystic fibrosis (CF) lung disease. Mucoid strains of P. aeruginosa produce an exopolysaccharide product called alginate. The purpose of this study was to determine whether P. aeruginosa alginate stimulates secretion from mucous or serous cells in the ferret trachea exposed to alginate at concentrations reported to be present in the CF airway. We used a sandwich enzyme-linked lectin assay (ELLA) to measure mucin secretion and spectrophotometry to measure lysozyme secretion from isolated ferret tracheal segments. Purified Pseudomonas aeruginosa alginate stimulated mucin and lysozyme secretion in a dose-dependent fashion (mucin = +111%: P = 0.003; lysozyme = +20%: P = 0.024 at 200 microg/mL). This stimulated secretion was not due to proteolytic activity, and alginate exposure did not produce ultrastructural damage to the trachea. We conclude that alginate may contribute to mucus hypersecretion and respiratory morbidity associated with P. aeruginosa infection in patients with CF.

Objectives: Partial liquid ventilation with perfluorooctyl bromide (perflubron) has been shown to be safe and effective in animal models with respiratory failure. However, airway mucus accumulation has been reported to be a problem in human trials. We hypothesized that this might be because perflubron directly affects mucociliary clearance or stimulates mucus secretion., Methods and Results: We first measured the mucociliary transportability of secretions on the mucus-depleted frog palate exposed to perflubron and demonstrated that the ciliated epithelium remained intact with preservation of mucociliary transport. We then measured mucin and lysozyme secretion from isolated ferret tracheal segments to evaluate the secretagogue potential of perflubron. There was an 86% increase in mucin secretion with perflubron incubation at 40 min (n = 19; p < 0.01) and a 52% increase after 4 h of exposure followed by evaporation of perflubron (n = 19; p < 0.01). There was no significant difference in lysozyme secretion at any time between perflubron-exposed or buffer-exposed tissue (n = 4). The secretagogue effect was completely blocked by nordihydroguaiaretic acid, an inhibitor of arachidonic acid (AA) metabolism., Conclusion: These data suggest that although perflubron does not seem to be harmful to the airway, it induces mucus secretion in a noninflamed airway, and that this can be modulated by inhibitors of AA metabolism.

Background: There is indirect evidence implicating viral respiratory tract infections in the pathogenesis of fatal asthma. However, it is unknown whether viruses are present within the lower respiratory tract in fatal asthma., Objectives: To apply a nine-virus polymerase chain reaction (PCR) panel to postmortem specimens of lower airway secretions and compare the prevalence of viral nucleic acid among patients who died of asthma, asthmatic patients who died of other causes and persons who died without lung disease., Patients and Methods: Postmortem specimens of lower airway secretions from patients who died of asthma (fatal asthma [n=10]), asthmatic patients who died of other causes (n=4) and nonasthma controls (n=6) underwent PCR for nine common respiratory viruses. The prevalence of each virus was compared among the three groups., Results: PCR was positive for at least one virus in 19 of 20 cases, and multiple viruses were detected in 14 of 20 cases. The prevalence of each virus was similar in the three groups studied., Conclusions: In fatal asthma, lower airway secretions do not show a specific pattern of viral nucleic acid. Intriguingly, these results suggest that the lower respiratory tract may act as a potential reservoir for common respiratory viruses.

Although the activity of nitric oxide (NO) synthases are increased in lung tissue of patients with cystic fibrosis, the concentrations of nasal and exhaled NO have recently been found to be decreased in cystic fibrosis. This could either be due to reduced NO formation or metabolism of NO within airway fluids. In this study, the stable NO metabolites, nitrate and nitrite, were determined in the saliva and sputum of 18 stable cystic fibrosis patients, 21 cystic fibrosis patients during a pulmonary exacerbation, and in saliva and endotracheal secretions of normal controls. Median saliva concentrations of NO metabolites (nitrate plus nitrite) were 704 mumol/l (95% confidence interval (CI) 419 to 1477) in stable cystic fibrosis patients, 629 mumol/l (95% CI 382 to 1392) in cystic fibrosis patients presenting with pulmonary exacerbation, and 313 mumol/l (95% CI 312 to 454) in controls. Median sputum NO metabolite concentration in stable cystic fibrosis was 346 mumol/l (95% CI 311 to 504). This was not significantly different from cystic fibrosis patients presenting with pulmonary exacerbation (median 184 mumol/l, 95% CI 249 to 572), but significantly higher than in endotracheal secretions of controls (median 144 mumol/l, 95% CI 96 to 260). Sputum NO metabolite concentration in cystic fibrosis pulmonary exacerbation significantly increased during antibiotic treatment. A positive correlation was observed between sputum NO metabolites and lung function in stable cystic fibrosis, suggesting less airway NO formation in cystic fibrosis patients with more severe lung disease. These data indicate that decreased exhaled NO concentrations in cystic fibrosis patients may be due to retention and metabolism of NO within the airway secretions. However, sputum NO metabolites are not a useful marker of airway inflammation in cystic fibrosis lung disease.

Context: Chronic bronchitis, estimated to affect more than 13 million adults in the United States, is characterized in part by retention of airway secretions, but no approved or effective therapy for airway mucus retention in patients with chronic bronchitis has been established. Surfactant reduces sputum adhesiveness, which contributes to difficulty in clearing secretions, but surfactant has not been tested in patients with chronic bronchitis., Objective: To examine the effects of exogenous surfactant on sputum clearance and pulmonary function in patients with stable chronic bronchitis., Design: A prospective, multicenter, randomized, double-blind, parallel-group, placebo-controlled comparison of the effects of 2 weeks of treatment with 3 doses of aerosolized surfactant (palmitoylphosphadidylcholine [DPPC]) or saline (placebo)., Setting: Four US teaching hospitals., Participants: A total of 87 adult patients with the diagnosis of stable chronic bronchitis., Main Outcome Measures: Pulmonary function, respiratory symptoms, and sputum properties before treatment (day 0), after 2 weeks of treatment (day 14), and 7 days after stopping treatment (day 21)., Results: A total of 66 patients were randomized to surfactant treatment and 21 to saline treatment. Patient demographic characteristics between groups were similar at baseline. In patients who received a DPPC dose of 607.5 mg/d for 2 weeks, prebronchodilator forced expiratory volume in 1 second (FEV1) increased from 1.22 L (SEM, 0.08 L) at day 0 to 1.33 L (SEM, 0.09 L) at day 21 (P=.05), an improvement of 11.4%; postbronchodilator FEV1 improved 10.4% by days 14 and 21 (P=.02); and the ratio of residual volume to total lung capacity, a measure of thoracic gas trapping, decreased 6.2% by day 21 (P=.009). In the surfactant groups, there was a dose-dependent increase in the ability of sputum to be transported by cilia in vitro., Conclusion: Aerosolized surfactant improved pulmonary function and resulted in a dose-related improvement in sputum transport by cilia in patients with stable chronic bronchitis.

Mucin is the major component of mucus and can be used as a marker for mucus secretion. The purpose of this study was to develop an in vitro method to evaluate the regulation of mucin secretion. To do this, we used a sandwiched enzyme-linked lectin assay to measure mucin secretion from isolated ferret tracheal segments. This assay entailed coating microtiter plate wells with dolichos biflorus agglutinin and detecting the bound mucin that was secreted into a buffer solution by the tracheal segments. We used this method to evaluate the secretory response to four secretagogues: prostaglandin F2alpha (PGF2alpha), adenosine triphosphate (ATP), methacholine, and human neutrophil elastase (HNE). Each agent stimulated mucin secretion above baseline secretion (ATP (p = 0.022), PGF2alpha (p = 0.009), and HNE (p < 0.05)), and the relative potency of these secretagogues was PGF2alpha < or = ATP < MCh < HNE. We also demonstrated that there is an anatomic gradient for both constitutive and stimulated mucin secretion, with the distal tracheal segments secreting more mucin per gram of weight than the proximal segments. This fairly simple and reproducible technique can be used to evaluate the regulation of mucin secretion in the airway and to assess the efficacy of agents that might alter the secretory response.

To investigate the role of high frequency oscillation (HFO) in promoting meconium clearance from the airway, we used a commercially available ventilator configured with maximal expiratory flow exceeding inspiratory flow (asymmetric HFO or AHFO). We hypothesized that AHFO would move meconium in an expiratory direction (toward the ventilator). We first tested our hypothesis in vitro and, later, in vivo using the neonatal piglet. In vitro experiments using a Plexiglas airway confirmed meconium movement in an expiratory direction when bias ratio was > or = 2. For in vivo experiments, each piglet received a 3 mL/kg intratracheal bolus of a 44 g/100 mL meconium mixture followed by 45 min of mechanical ventilation. Then, in part 1, the piglet was placed in a 15 degree head down tilt position and randomized to either AHFO [ratio of inspiratory time/expiratory time (I:E) of 70:30] or HFO (I:E ratio of 30:70). After 30 min of either AHFO or HFO, the piglet was crossed over to the alternate strategy for an additional 30 min. For part 2, we maintained the piglet on either AHFO or HFO continuously for 4 h. Results demonstrate that, although there was a tendency for larger volumes of meconium to be aspirated from the airway during AHFO in part 1 experiments, there was no difference found in part 2. We also found no significant differences in blood gases or hemodynamic measurements between AHFO and HFO during the prolonged observation period in part 2 of our study. We conclude that AHFO is of no benefit in the treatment of meconium aspiration syndrome.

Erythromycin inhibits mucus glycoconjugate secretion from airway cells in vitro and may increase mucus clearance in patients with asthma or diffuse panbronchiolitis. Because mucus hypersecretion is common in purulent rhinitis, we questioned whether clarithromycin would change the properties of nasal mucus from subjects without sinus disease and from patients with acute purulent rhinitis. Nasal secretions were collected before and after nasal methacholine challenge from 10 adults without nasal symptoms and without methacholine from 10 patients with purulent rhinitis. After 2 wk of oral clarithromycin (500 mg twice daily), secretions were again collected from both groups. Secretions were analyzed for viscoelasticity, cohesion, hydration, and ciliary and airflow (sneeze) transportability. Compared with secretions from healthy subjects, rhinitis secretions had decreased wettability (contact angle on Teflon 100 degrees versus 84.67 degrees; p = 0.001), increased cohesion (36.8 versus 24.3 mm; p = 0.003), decreased sneeze clearability (20.6 versus 32 mm; p = 0.04), and increased percent solids (4.61 versus 2.82%; p = 0.04). After clarithromycin, the rheology, hydration, cohesion, and transportability of the rhinitis secretions were similar to those of the postclarithromycin secretions from the healthy subjects. Secretion volume also decreased (500.1 versus 28.3 mg; p = 0.01), and mucociliary transportability increased by 30% (0.76 versus 0.99; p = 0.005). Although clarithromycin reduced mucus secretion in both rhinitis patients and normal subjects, it did not alter the secretory response to methacholine.

Study Objective: Nebulizer systems used to generate therapeutic aerosols vary in their ability to deliver medication to the airway. In a recent study in 17 adults with stable asthma, albuterol given using an ultrasonic nebulizer (UN) appeared to produce greater bronchodilatation than the same dose of albuterol given by a jet nebulizer (JN). The purpose of this study was to determine if the UN used in that study would produce a better bronchodilator response in children with acute asthma than the JN system that has been in use at Cardinal Glennon Children's Hospital., Design: Randomized, prospective, unblinded study., Setting: An urban university children's hospital emergency department., Participants: One hundred thirteen children, aged 7 to 16 years, who presented for treatment of acute moderately severe asthma completed this study., Interventions: After randomization and exclusion of dropouts, 46 children received albuterol by UN and 67 were treated by JN., Measurements: Pulmonary function tests (PFTs) by spirometry, pulse oximetry, and symptom score at baseline and at 15 and 30 min following a single prescribed treatment., Results: PFT on entry to the study was the same in both groups (FEV1; p>0.97). The change in FEV1 after therapy (UN+0.22 L vs JN+0.37 L) was significant (p<0.05) and favored JN. There was no difference in the improvement in pulmonary function between JN and UN therapy in children with an initial FEV1/FVC > 75% predicted but when FEV1/FVC < 75%, the improvement in FEV1 again favored the JN (UN+0.2 vs JN+0.47; p<0.05)., Conclusion: For the treatment of acute exacerbations of asthma in children, there is no greater bronchodilator response when albuterol is administered by a UN than by a JN.

Passage of meconium in utero and subsequent pulmonary aspiration of meconium admixed with amniotic fluid is a major cause of neonatal respiratory distress. Airway clearance is the first defense of the lung, and clearance is dependent on the bulk physical (rheologic) as well as the surface properties of airway material. We therefore evaluated the surface adhesive properties and the transport properties of freshly passed meconium and of two dilutions of reconstituted, blended, meconium as used to mimic the effect of meconium passage into the amniotic fluid in animal models of meconium aspiration syndrome. Reconstituted and fresh meconium had similar physical and transport properties, including an extremely high interfacial (adhesion) tension and very poor transportability by either airflow or cilia. The similarities between the freshly passed and reconstituted meconium suggest that the latter is an adequate substitute for use in animal models of meconium aspiration syndrome. The high adhesiveness of meconium suggests a potential role for surfactant administration as an adhesive to improve airway clearance after meconium aspiration.