Impaired Mucociliary Clearance Research Articles

Primary Ciliary Dyskinesia in Amish Communities

Primary ciliary dyskinesia is an autosomal recessive multigenic disease that results in impaired mucociliary clearance. We have diagnosed 9 subjects with primary ciliary dyskinesia from geographically dispersed Amish communities, on the basis of clinical characteristics and ciliary ultrastructural defects. Despite consanguinity, affected individuals had evidence of genetic heterogeneity.

Mukoviszidose im Erwachsenenalter

Cystic fibrosis (CF) is a common autosomal-recessive inherited disease, which often results in premature death. Due to treatment advances, life expectancy has however continuously improved in recent years. Currently about half of all patients are adults. There are also "atypical" variants of CF with symptoms occurring in late adulthood. CF is caused by a mutation in the gene coding for a chloride ion channel, known as the cystic fibrosis transmembrane conductance regulator (CFTR). This mutation results in abnormally viscous mucosal secretions, leading to multi-organ disease with particular emphasis in the respiratory and digestive tracts. Impaired mucociliary clearance results in bacterial colonization of the airways (e. g. Pseudomonas aeruginosa) and consequently in chronic pulmonary inflammation, inevitably leading to progressive bronchiectasis and combined ventilatory disorders. Typical acute complications are infective exacerbations - the most frequent cause of death in cystic fibrosis - along with allergic bronchopulmonary aspergillosis, haemoptyses and pneumothoraces. Involvement of the gastrointestinal tract generally manifests as exo- and later endocrine pancreatic insufficiency with diabetes mellitus, malabsorption and sometimes biliary liver cirrhosis. Typical acute complications are pancreatitis and ileus. The article describes epidemiology and pathophysiology of CF and focuses on the signs and symptoms, as well as the diagnostic and multi-modal therapeutic strategies used in adult patients.

Secondhand smoke inhibits both Cl- and K+ conductances in normal human bronchial epithelial cells

Secondhand smoke (SHS) exposure is an independent risk factor for asthma, rhinosinusitis, and more severe respiratory tract infections in children and adults. Impaired mucociliary clearance with subsequent mucus retention contributes to the pathophysiology of each of these diseases, suggesting that altered epithelial salt and water transport may play an etiological role. To test the hypothesis that SHS would alter epithelial ion transport, we designed a system for in vitro exposure of mature, well-differentiated human bronchial epithelial cells to SHS. We show that SHS exposure inhibits cAMP-stimulated, bumetanide-sensitive anion secretion by 25 to 40% in a time-dependent fashion in these cells. Increasing the amount of carbon monoxide to 100 ppm from 5 ppm did not increase the amount of inhibition, and filtering SHS reduced inhibition significantly. It was determined that SHS inhibited cAMP-dependent apical membrane chloride conductance by 25% and Ba2+-sensitive basolateral membrane potassium conductance by 50%. These data confirm previous findings that cigarette smoke inhibits chloride secretion in a novel model of smoke exposure designed to mimic SHS exposure. They also extend previous findings to demonstrate an effect on basolateral K+ conductance. Therefore, pharmacological agents that increase either apical membrane chloride conductance or basolateral membrane potassium conductance might be of therapeutic benefit in patients with diseases related to SHS exposure.

Cardiac tamponade from acute pericarditis associated with a cystic fibrosis (CF) lung infection

Cystic fibrosis (CF) is a genetically inherited autosomal recessive disease characterized by dehydration of the airway surface liquid and impaired mucociliary clearance leading to chronic respiratory infections, bronchiectasis and ultimately death from respiratory causes. Common pulmonary related complications resulting from bronchiectasis include pneumothorax and hemoptysis. A rare, seldom reported complication is acute pericarditis complicating cystic fibrosis. Our review of the literature identified only a single case of culture-proven purulent pericarditis attributed to Pseudomonas aeruginosa in a patient receiving systemic corticosteroids. A second reported case of acute pericarditis in a CF patient was attributed to Mycoplasma pneumoniae which is a known cause of infectious-related pericarditis independent of CF. Both cases required open pericardial drainage with 1 fatality. Here we present a case of cardiac tamponade from a fibrinous pericardial effusion in a 21-year-old female as a complication of CF related parenchymal lung disease. To our knowledge, this is the first reported case of a non-infectious parapneumonic pericardial effusion causing near fatal cardiac tamponade as a complication of CF lung disease.

Recombinant human DNase in children with airway malacia and lower respiratory tract infection

Children with airway malacia often have protracted courses of airway infections, because dynamic airway collapse during coughing results in impaired mucociliary clearance. The aim of this study was to determine the effect of the mucolytic drug recombinant human deoxyribonuclease (rhDNase) on the recovery of respiratory symptoms in children with airway malacia and lower respiratory tract infection (LRTI). In a randomized double-blind controlled clinical trial, 40 children with airway malacia and LRTI were randomly assigned to receive either 2.5 mg nebulized rhDNase or placebo twice daily for 2 weeks. The primary endpoint was the change in the cough diary score (CDS) (scale 0-5) from baseline to the second week of treatment. Secondary endpoints were VAS symptom scores for cough, dyspnea, and difficulty in expectorating sputum, need for an antibiotic course, and lung function data (FVC, FEV(1), FEF(75), R(int(e))). There was no significant difference in the mean change in CDSs from baseline between the rhDNase group and the placebo group (mean difference for daytime 0.19 (95% CI -0.53 to 0.90); for nighttime 0.38 (95% CI -0.30 to 1.05). Proportions of patients requiring antibiotics, and the mean changes in symptom scores and lung function from baseline did not significantly differ between both groups. Treatment with 2 weeks of nebulized rhDNase does not enhance recovery or reduce the need for antibiotics in children with airway malacia and LRTI. (Controlled-trials.com number, ISRCTN85366144).

Lung dosimetry for inhaled radon progeny in smokers

Cigarette smoking may change the morphological and physiological parameters of the lung. Thus the primary objective of the present study was to investigate to what extent these smoke-induced changes can modify deposition, clearance and resulting doses of inhaled radon progeny relative to healthy non-smokers (NSs). Doses to sensitive bronchial target cells were computed for four categories of smokers: (1) Light, short-term (LST) smokers, (2) light, long-term (LLT) smokers, (3) heavy, short-term (HST) smokers and (4) heavy, long-term (HLT) smokers. Because of only small changes of morphological and physiological parameters, doses for the LST smokers hardly differed from those for NSs. For LLT and HST smokers, even a protective effect could be observed, caused by a thicker mucus layer and increased mucus velocities. Only in the case of HLT smokers were doses higher by about a factor of 2 than those for NSs, caused primarily by impaired mucociliary clearance, higher breathing frequency, reduced lung volume and airway obstructions. These higher doses suggest that the contribution of inhaled radon progeny to the risk of lung cancer in smokers may be higher than currently assumed on the basis of NS doses.

Treatment strategies for cystic fibrosis: what's in the pipeline?

Cystic fibrosis (CF) is an inherited disease, characterised by pancreatic malabsorption (with poor growth) and impaired mucociliary clearance (leading to recurrent pulmonary infection). The prognosis has markedly improved over the last 40 years. This was achieved initially by improving pancreatic enzyme supplements and more recently through drugs designed to treat pulmonary infection, reduce inflammation and enhance mucociliary clearance. The CF gene has been sequenced, allowing new therapeutic targets to be identified. Currently the greatest therapeutic challenges are to correct the biochemical defect of CF and to identify effective treatments for chronic respiratory infection. This review provides an overview of CF, the treatment strategies currently used, and new drugs undergoing clinical trials.

Nebulised hypertonic saline for cystic fibrosis

Impaired mucociliary clearance characterises lung disease in cystic fibrosis (CF). Hypertonic saline (HS) enhances mucociliary clearance in vitro and may lessen the destructive inflammatory process in the airways. To investigate the effects of nebulised HS in CF compared to placebo or other treatments for mucociliary clearance. We searched the Cochrane CF and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings.Most recent search: 31 July 2008. Controlled trials assessing HS compared to placebo or other mucolytic therapy, for any duration or dose regimen in people with CF (any age or disease severity). Two authors independently reviewed all identified trials and data; and assessed trial quality. Twelve trials (442 participants, aged 6 to 46 years) were included; five excluded and two await classification.In two placebo-controlled trials, HS (3% to 7%, 10 ml twice-a-day) significantly increased forced expiratory volume at one second (FEV1) at four weeks, mean difference (MD) 4.15 (95% CI 1.14 to 7.16); but not significantly after 48 weeks, MD 2.31 (95% CI -2.72 to 7.34). Two trials compared a similar dose of HS to recombinant deoxyribonuclease (RhDNAse). One three-week trial showed a non-significant difference, MD 1.60 (95% CI -7.96 to 11.16). However, in the second trial, after 12 weeks, RhDNAse led to a greater increase in FEV1 than HS (5 ml twice-daily), in participants with moderate to severe lung disease, MD 8.00 (95% CI 2.00 to 14.00).One 48-week placebo-controlled trial showed significant improvements in frequency of antibiotic use and quality of life; also that HS did not increase the concentration of Pseudomonas aeruginosa or Staphylococcus aureus. Treatment with 7% HS for 48 weeks showed a small improvement in FEV1 at four weeks; however, this was not sustained at 48 weeks (primary outcome measure of the only long-term trial). Unlike RhDNAse, HS can't, in the long term, be said to improve lung function. However, it did improve quality of life and reduce pulmonary exacerbations. Delivered following a bronchodilator, HS appears inexpensive and safe with no increased infection risk.We believe there is sufficient evidence to recommend using HS in CF; qualifying this we highlight that the only long-term trial failed to demonstrate a significant difference in its primary outcome (lung function) with improvements only in secondary outcomes.

Primary ciliary dyskinesia: when to suspect the diagnosis and how to confirm it

Primary ciliary dyskinesia (PCD) is a rare, autosomal recessive condition. The signs and symptoms are due to congenital abnormalities of ciliary structure and function, resulting in impaired mucociliary clearance. This affects the ciliated epithelium lining the nose, sinuses, Eustachian tube and airways. As a consequence, the patient typically presents with a range of features, including recurrent upper and lower respiratory tract infections, persistent glue ear and possible hearing deficit. Around half of all patients will have situs anomalies, most typically situs inversus totalis. The most significant morbidity results from the development of bronchiectasis. Access to early diagnosis and effective treatment is essential to reduce disease progression and to alleviate the burden of symptoms. This review aims to provide a clinical guide to what to look for and when to suspect the diagnosis. Recent advances in the screening and diagnostic tests available will be outlined, as well as some future directions that aim to enhance the current diagnostic techniques.

Primary ciliary dyskinesia: prospects for new therapies, building on the experience in cystic fibrosis

Primary ciliary dyskinesia (PCD) is a genetic disease associated with abnormal ciliary structure and function, leading to impaired mucociliary clearance, an important primary innate defense mechanism that protects the lungs. Drugs that can effectively treat PCD should overcome the defect in ciliary function and increase the mucociliary clearance. However, there are currently no therapeutic strategies that correct the inborn error of ciliary dysfunction to restore mucociliary clearance. It is unclear if osmolar agents like hypertonic saline or mannitol, therapies that increase the respiratory surface hydration like ion-channel regulators, or therapies aimed at reducing inflammation or mucus production, or softening the mucus will be effective in PCD. Many of these modalities are used in cystic fibrosis, yet no evidence exists to support their routine use in PCD. Newer genetic modifiers show an exciting potential for personalized medication, combining selection of patients with a common genetic mutation and a drug treatment that has been specifically designed to overcome that mutation, and will greatly enhance the therapeutic arsenal for PCD. This review summarizes current and future prospects for these therapeutic options.

Camostat Attenuates Airway Epithelial Sodium Channel Function in Vivo through the Inhibition of a Channel-Activating Protease

Inhibition of airway epithelial sodium channel (ENaC) function enhances mucociliary clearance (MCC). ENaC is positively regulated by channel-activating proteases (CAPs), and CAP inhibitors are therefore predicted to be beneficial in diseases associated with impaired MCC. The aims of the present study were to 1) identify low-molecular-weight inhibitors of airway CAPs and 2) to establish whether such CAP inhibitors would translate into a negative regulation of ENaC function in vivo, with a consequent enhancement of MCC. To this end, camostat, a trypsin-like protease inhibitor, provided a potent (IC(50) approximately 50 nM) and prolonged attenuation of ENaC function in human airway epithelial cell models that was reversible upon the addition of excess trypsin. In primary human bronchial epithelial cells, a potency order of placental bikunin > camostat > 4-guanidinobenzoic acid 4-carboxymethyl-phenyl ester > aprotinin >> soybean trypsin inhibitor = alpha1-antitrypsin, was largely consistent with that observed for inhibition of prostasin, a molecular candidate for the airway CAP. In vivo, topical airway administration of camostat induced a potent and prolonged attenuation of ENaC activity in the guinea pig trachea (ED(50) = 3 microg/kg). When administered by aerosol inhalation in conscious sheep, camostat enhanced MCC out to at least 5 h after inhaled dosing. In summary, camostat attenuates ENaC function and enhances MCC, providing an opportunity for this approach toward the negative regulation of ENaC function to be tested therapeutically.

An unusual presentation of immotile-cilia syndrome with azoospermia: Case report and literature review

Immotile-cilia syndrome is a rare disorder characterized by chronic recurrent sino-pulmonary infection, impaired tracheobronchial clearance, situs inversus in about 50% of cases, and living but immotile spermatozoa of normal morphology in semen analysis. In this report, we describe an unusual presentation of immotile-cilia syndrome with azoospermia in a 32-year-old male patient. The diagnosis was based on history of recurrent respiratory tract infection, bronchiectasis, maxillary sinusitis, hypoplasia of frontal sinuses, dextrocardia with situs inversus, impaired nasal mucociliary clearance, etc. Semen analysis revealed azoospermia without any evidence of obstruction in epididymides or vas deference. Normal spermatogenesis was seen on testicular biopsy.

Diagnostik der primären Ziliendyskinesie

Primary ciliary dyskinesia (PCD) is an autosomal recessive inherited disease characterized by abnormal ciliary motion and impaired mucociliary clearance. The prevalence of PCD is approximately 1 : 15 000 - 1 : 20 000 in live births. Cilia dysfunction is also implicated in a wider spectrum of diseases due to impaired organ genesis and body symmetry. Cilia are highly conserved in animals and show complex structures containing more than 250 proteins for their formation. Recent studies have begun to locate the PCD genes in the genome and characterize functional mutations. Specific diagnosis of the ciliary dysfunction requires physiological measurements as well as light- and electron microscopy. Abnormalities in ciliary motion and ultrastructural studies can be performed with nasal mucosal epithelium.

Impact of isotonic and hypertonic saline solutions on mucociliary activity in various nasal pathologies: clinical study

To investigate the impact of nasal irrigation with isotonic or hypertonic sodium chloride solution on mucociliary clearance time in patients with allergic rhinitis, acute sinusitis and chronic sinusitis. Mucociliary clearance time was measured using the saccharine clearance test on 132 adults before and after 10 days' application of intranasal isotonic or hypertonic saline. Patient numbers were as follows: controls, 45; allergic rhinitis, 21; acute sinusitis, 24; and chronic sinusitis, 42. The results before and after irrigation were compared using the Wilcoxon t-test. Before application of saline solutions, mucociliary clearance times in the three patient treatment groups were found to be significantly delayed, compared with the control group. Irrigation with hypertonic saline restored impaired mucociliary clearance in chronic sinusitis patients (p < 0.05), while isotonic saline improved mucociliary clearance times significantly in allergic rhinitis and acute sinusitis patients (p < 0.05). Nasal irrigation with isotonic or hypertonic saline can improve mucociliary clearance time in various nasal pathologies. However, these solutions should be selectively prescribed rather than used based on anecdotal evidence. Further studies should be conducted to develop a protocol for standardised use of saline solution irrigation in various nasal pathologies.

Microbiological study of role of fungi in primary atrophic rhinitis

Fungal rhinosinusitis has gained much attention in recent years. To our knowledge, no previous studies have addressed the role of fungus in primary atrophic rhinitis. Prospective case study. All cases of primary atrophic rhinitis presenting to the out-patient department at El-Sahel Teaching Hospital over a five-month period were included in the study. Crusts and purulent secretions removed from patients' nasal cavities underwent microbiological analysis at the Medical Microbiology and Immunology department of the Cairo University Faculty of Medicine. Special emphasis was placed on fungal isolation. Fourteen consecutive cases of primary atrophic rhinitis were studied in the five-month period starting 26 November 2007. Patients comprised eight females and six males, with an age range of 12 to 65 years (mean 37 years). Microscopy of the crusts and purulent secretions showed pus cells in most of the samples. Klebsiella species were isolated from nine patients (65 per cent), and other bacterial species were isolated in most of the remainder. Fungal elements, most commonly aspergillus species, were isolated in 13 patients (93 per cent). It is proposed that the initial trigger for primary atrophic rhinitis is a virulent bacterial infection of the nasal lining, which leads to damage of the ciliated epithelium. This initiates the cascade of events leading to inflammation of the mucosa and submucosa, with secondary pyogenic osteomyelitis of the turbinate bone. The persistence of purulent secretion, within the setting of impaired mucociliary clearance, leads to saprophytic fungal colonisation which contributes greatly to the clinical picture.

Update in Cystic Fibrosis 2007

Cystic fibrosis (CF) is a chronic condition involving several organ systems that results in life-long morbidity and premature mortality (1). CF is caused by abnormalities in the gene that codes for the CF transmembrane conductance regulator (CFTR), a membrane glycoprotein found in secretory and absorptive epithelial surfaces. CFTR is a chloride channel, but also participates in regulating ion flux through interactions with other proteins. Lung disease in CF, believed to be caused by dehydration of airway surface liquid layers, is the major killer through a complex process involving impairment of mucociliary clearance, infection, inflammation, and structural injury. This update of studies reported during 2007 focuses on issues in clinical care and clinical research relating to CF, but with some attention to basic investigations through model systems.

Chronic wet cough: Protracted bronchitis, chronic suppurative lung disease and bronchiectasis

The role of persistent and recurrent bacterial infection of the conducting airways (endobronchial infection) in the causation of chronic respiratory symptoms, particularly chronic wet cough, has received very little attention over recent decades other than in the context of cystic fibrosis (CF). This is probably related (at least in part) to the (a) reduction in non-CF bronchiectasis in affluent countries and, (b) intense focus on asthma. In addition failure to characterize endobronchial infections has led to under-recognition and lack of research. The following article describes our current perspective of inter-related endobronchial infections causing chronic wet cough; persistent bacterial bronchitis (PBB), chronic suppurative lung disease (CSLD) and bronchiectasis. In all three conditions, impaired muco-ciliary clearance seems to be the common risk factor that provides organisms the opportunity to colonize the lower airway. Respiratory infections in early childhood would appear to be the most common initiating event but other conditions (e.g., tracheobronchomalacia, neuromuscular disease) increases the risk of bacterial colonization. Clinically these conditions overlap and the eventual diagnosis is evident only with further investigations and long term follow up. However whether these conditions are different conditions or reflect severity as part of a spectrum is yet to be determined. Also misdiagnosis of asthma is common and the diagnostic process is further complicated by the fact that the co-existence of asthma is not uncommon. The principles of managing PBB, CSLD and bronchiectasis are the same. Further work is required to improve recognition, diagnosis and management of these causes of chronic wet cough in children.

Heat Shock Transcription Factor 1 Is Required for Maintenance of Ciliary Beating in Mice

Heat shock transcription factors (HSFs) maintain protein homeostasis through regulating expression of heat shock proteins, especially in stressed conditions. In addition, HSFs are involved in cellular differentiation and development by regulating development-related genes, as well as heat shock genes. Here, we showed chronic sinusitis and mild hydrocephalus in postnatal HSF1-null mice, which are associated with impaired mucociliary clearance and cerebrospinal flow, respectively. Analysis of ciliary beating revealed that the amplitude of the beating was significantly reduced, and ciliary beat frequencies were lower in the respiratory epithelium, ependymal cells, oviduct, and trachea of HSF1-null mice than those of wild-type mice. Cilia possess a common axonema structure composed of microtubules of alpha- and beta-tubulin. We found a marked reduction in alpha- and ciliary betaiv-tubulin in the HSF1-null cilia, which is developmentally associated with reduced Hsp90 expression in HSF1-null mice. Treatment of the respiratory epithelium with geldanamycin resulted in rapid reduction of ciliary beating in a dose-dependent manner. Furthermore, Hsp90 was physically associated with ciliary betaiv-tubulin, and Hsp90 stabilizes tubulin polymerization in vitro. These results indicate that HSF1 is required to maintain ciliary beating in postnatal mice, probably by regulating constitutive expression of Hsp90 that is important for tubulin polymerization.

Allergic bronchopulmonary aspergillosis complicating chronic obstructive pulmonary disease

Allergic bronchopulmonary aspergillosis (ABPA) is a well recognised entity which complicates the course of 1-2% of patients with asthma and 2-15% of cystic fibrosis. Also, current criteria generally require the presence of asthma or cystic fibrosis for recognition of ABPA. The occurrence of ABPA in conditions other than cystic fibrosis or bronchial asthma is rare. Patients with chronic obstructive pulmonary disease (COPD) have mucus hypersecretion and impaired mucociliary clearance but are not reported to develop ABPA. Herein, we report a 50-year-old male who presented with an exacerbation of COPD due to co-existent ABPA. To our knowledge, this is the first report of such an association. We also speculate on mechanisms of causality and impact of ABPA on disease progression in COPD.

Pharmacotherapy of impaired mucociliary clearance in non‐CF pediatric lung disease. A review of the literature

Mucoactive agents are used to treat a variety of lung diseases involving impaired mucociliary clearance or mucus hypersecretion. The mucoactive agents studied most frequently are N-acetylcysteine (NAC), recombinant human DNase (rhDNase), and hypertonic saline. Studies on the efficacy of these have been mainly conducted in adults, and in patients with cystic fibrosis (CF). The exact role of mucoactive agents in children with non-CF lung disease is not well established. We present an overview of the current literature reporting clinical outcome measures of treatment with NAC, rhDNase, and hypertonic saline in children.