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Mucociliary Clearance (mucociliary + clearance)
Selected AbstractsSmoke Exposure Exacerbates an Ethanol-Induced Defect in Mucociliary Clearance of Streptococcus pneumoniaeALCOHOLISM, Issue 5 2005Elizabeth A. Vander Top Background: Alcoholics and smokers are particularly susceptible to pulmonary infections caused by Streptococcus pneumoniae, the pneumococcus. Infection begins when pneumococci colonizing the nasopharynx are aspirated into the lower respiratory tract. The major host defense against this movement is the mucociliary clearance apparatus. Both cigarette smoke and ethanol (EtOH) exposure alter ciliary beating and protein kinase activity in the respiratory mucosa in vitro, but their effects on bacterial clearance in the intact animal have not been determined. Methods: Male Sprague Dawley rats were exposed twice daily for 12 weeks to either the smoke generated from 30 cigarettes (smoke,exposed) or room air (sham,exposed). For the last five weeks of smoke exposure, the rats were fed Lieber-DeCarli liquid diets containing 0%, 16%, 26%, or 36% EtOH calories. The rats then were infected intranasally with S. pneumoniae, and movement of the organisms into the lower respiratory tract was quantified by plate counts of the tracheas and lungs 4 hr later. Ciliary beat frequency (CBF) analysis was performed on tracheal ring explants from each animal before and after stimulation with the ,-agonist isoproterenol, and tracheal epithelial cell protein kinase C (PKC) activity was measured. Results: Ingestion of any of the EtOH-containing diets resulted in a dose-dependent increase in movement of S. pneumoniae into the rats' lungs. This EtOH-induced defect was augmented further by concurrent smoke exposure, although smoke exposure alone had little effect on S. pneumoniae movement. Smoke, but not EtOH exposure, activated tracheal epithelial cell PKC. Increased movement of organisms into lungs correlated with a decrease in CBF and loss of the ciliary response to isoproterenol. Conclusion: EtOH ingestion in our model facilitated movement of S. pneumoniae into rats' lungs, a phenomenon exacerbated by concurrent smoke exposure. Furthermore, the organism's movement into the lungs correlated with a blunting of the rats' ciliary response to an established stimulus. Defects in mucociliary clearance thus may be one cause of the increased risk of pneumococcal infections in people who abuse alcohol, particularly if they also smoke. [source] Beta-2 adrenergic receptor genetic polymorphisms and asthmaJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 6 2009N. Hizawa MD Summary Beta-2-Adrenergic receptors (,2AR) participate in the physiologic responses of the lung, including bronchodilation and bronchoprotection, through mechanisms such as mucociliary clearance, fluid accumulation and mediator release from mast cells and basophils. Thus, these receptors may also play an important role in the pathophysiology of asthma. The gene encoding ,2AR (ADRB2) is extremely polymorphic, and studies of this gene improves our understanding of asthma and possibly lead to new methods to prevent, diagnose and treat it. This review summarizes results from various studies on the possible relationship of ADRB2 polymorphisms to asthma and asthma-related phenotypes, including bronchodilator responses to inhaled ,2 -agonists. At present, it appears that, for asthma, ADRB2 polymorphisms are not aetiologically involved. However, they might affect disease severity and clinical response to both acute and chronic administration of ,2 -agonists. The development is that by assessing the ADRB2 genotype, it might be possible to predict the clinical course of asthma as well as responsiveness to chronic administration of ,2 -agonists. Carefully, performed and adequately powered clinical trials continue to be important for achieving those goals. [source] The biopharmaceutical aspects of nasal mucoadhesive drug deliveryJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 1 2001Michael Ikechukwu Ugwoke Nasal drug administration has frequently been proposed as the most feasible alternative to parenteral injections. This is due to the high permeability of the nasal epithelium, allowing a higher molecular mass cut-off at approximately 1000 Da, and the rapid drug absorption rate with plasma drug profiles sometimes almost identical to those from intravenous injections. Despite the potential of nasal drug delivery, it has a number of limitations. In this review, the anatomy and physiology of the nasal cavity, as well as ciliary beating and mucociliary clearance as they relate to nasal drug absorption, are introduced. The rationale for nasal drug delivery and its limitations, some factors that influence nasal drug absorption, and the experimental models used in nasal drug delivery research are also reviewed. Nasal mucoadhesion as a promising method of nasal absorption enhancement is discussed, and factors that influence mucoadhesion, as well as safety of nasal mucoadhesive drug delivery systems are reviewed in detail. Nasal drug administration is presently mostly used for local therapies within the nasal cavity. Anti-allergic drugs and nasal decongestants are the most common examples. However, nasal drug administration for systemic effects has been practised since ancient times. Nasally-administered psychotropic drugs by native Americans, the use of tobacco snuffs, and nasal administration of illicit drugs such as cocaine are all well known (Illum & Davis 1992). Nowadays, the nasal cavity is being actively explored for systemic administration of other therapeutic agents, particularly peptides and proteins (Illum 1992; Edman & Bjork 1992), as well as for immunization purposes (Lemoine et al 1998). To better understand the basis for nasal drug absorption and factors that can influence it, a brief review of the anatomy and physiology of the nose is appropriate. [source] Alcohol Stimulates Ciliary Motility of Isolated Airway Axonemes Through a Nitric Oxide, Cyclase, and Cyclic Nucleotide-Dependent Kinase MechanismALCOHOLISM, Issue 4 2009Joseph H. Sisson Background:, Lung mucociliary clearance provides the first line of defense from lung infections and is impaired in individuals who consume heavy amounts of alcohol. Previous studies have demonstrated that this alcohol-induced ciliary dysfunction occurs through impairment of nitric oxide (NO) and cyclic nucleotide-dependent kinase-signaling pathways in lung airway ciliated epithelial cells. Recent studies have established that all key elements of this alcohol-driven signaling pathway co-localize to the apical surface of the ciliated cells with the basal bodies. These findings led us to hypothesize that alcohol activates the cilia stimulation pathway at the organelle level. To test this hypothesis we performed experiments exposing isolated demembranated cilia (isolated axonemes) to alcohol and studied the effect of alcohol-stimulated ciliary motility on the pathways involved with isolated axoneme activation. Methods:, Isolated demembranated cilia were prepared from bovine trachea and activated with adenosine triphosphate. Ciliary beat frequency, NO production, adenylyl and guanylyl cyclase activities, cAMP- and cGMP-dependent kinase activities were measured following exposure to biologically relevant concentrations of alcohol. Results:, Alcohol rapidly stimulated axoneme beating 40% above baseline at very low concentrations of alcohol (1 to 10 mM). This activation was specific to ethanol, required the synthesis of NO, the activation of soluble adenylyl cyclase (sAC), and the activation of both cAMP- and cGMP-dependent kinases (PKA and PKG), all of which were present in the isolated organelle preparation. Conclusions:, Alcohol rapidly and sequentially activates the eNOS,NO,GC,cGMP,PKG and sAC,cAMP, PKA dual signaling pathways in isolated airway axonemes. These findings indicate a direct effect of alcohol on airway cilia organelle function and fully recapitulate the alcohol-driven activation of cilia known to exist in vivo and in intact lung ciliated cells in vitro following brief moderate alcohol exposure. Furthermore, these findings indicate that airway cilia are exquisitely sensitive to the effects of alcohol and substantiate a key role for alcohol in the alterations of mucociliary clearance associated with even low levels of alcohol intake. We speculate that this same axoneme-based alcohol activation pathway is down regulated following long-term high alcohol exposure and that the isolated axoneme preparation provides an excellent model for studying the mechanism of alcohol-mediated cilia dysfunction. [source] Smoke Exposure Exacerbates an Ethanol-Induced Defect in Mucociliary Clearance of Streptococcus pneumoniaeALCOHOLISM, Issue 5 2005Elizabeth A. Vander Top Background: Alcoholics and smokers are particularly susceptible to pulmonary infections caused by Streptococcus pneumoniae, the pneumococcus. Infection begins when pneumococci colonizing the nasopharynx are aspirated into the lower respiratory tract. The major host defense against this movement is the mucociliary clearance apparatus. Both cigarette smoke and ethanol (EtOH) exposure alter ciliary beating and protein kinase activity in the respiratory mucosa in vitro, but their effects on bacterial clearance in the intact animal have not been determined. Methods: Male Sprague Dawley rats were exposed twice daily for 12 weeks to either the smoke generated from 30 cigarettes (smoke,exposed) or room air (sham,exposed). For the last five weeks of smoke exposure, the rats were fed Lieber-DeCarli liquid diets containing 0%, 16%, 26%, or 36% EtOH calories. The rats then were infected intranasally with S. pneumoniae, and movement of the organisms into the lower respiratory tract was quantified by plate counts of the tracheas and lungs 4 hr later. Ciliary beat frequency (CBF) analysis was performed on tracheal ring explants from each animal before and after stimulation with the ,-agonist isoproterenol, and tracheal epithelial cell protein kinase C (PKC) activity was measured. Results: Ingestion of any of the EtOH-containing diets resulted in a dose-dependent increase in movement of S. pneumoniae into the rats' lungs. This EtOH-induced defect was augmented further by concurrent smoke exposure, although smoke exposure alone had little effect on S. pneumoniae movement. Smoke, but not EtOH exposure, activated tracheal epithelial cell PKC. Increased movement of organisms into lungs correlated with a decrease in CBF and loss of the ciliary response to isoproterenol. Conclusion: EtOH ingestion in our model facilitated movement of S. pneumoniae into rats' lungs, a phenomenon exacerbated by concurrent smoke exposure. Furthermore, the organism's movement into the lungs correlated with a blunting of the rats' ciliary response to an established stimulus. Defects in mucociliary clearance thus may be one cause of the increased risk of pneumococcal infections in people who abuse alcohol, particularly if they also smoke. [source] Role of Lung Surfactant in Respiratory Disease: Current Knowledge in Large Animal MedicineJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 2 2009U. Christmann Lung surfactant is produced by type II alveolar cells as a mixture of phospholipids, surfactant proteins, and neutral lipids. Surfactant lowers alveolar surface tension and is crucial for the prevention of alveolar collapse. In addition, surfactant contributes to smaller airway patency and improves mucociliary clearance. Surfactant-specific proteins are part of the innate immune defense mechanisms of the lung. Lung surfactant alterations have been described in a number of respiratory diseases. Surfactant deficiency (quantitative deficit of surfactant) in premature animals causes neonatal respiratory distress syndrome. Surfactant dysfunction (qualitative changes in surfactant) has been implicated in the pathophysiology of acute respiratory distress syndrome and asthma. Analysis of surfactant from amniotic fluid allows assessment of fetal lung maturity (FLM) in the human fetus and exogenous surfactant replacement therapy is part of the standard care in premature human infants. In contrast to human medicine, use and success of FLM testing or surfactant replacement therapy remain limited in veterinary medicine. Lung surfactant has been studied in large animal models of human disease. However, only a few reports exist on lung surfactant alterations in naturally occurring respiratory disease in large animals. This article gives a general review on the role of lung surfactant in respiratory disease followed by an overview of our current knowledge on surfactant in large animal veterinary medicine. [source] Cystic fibrosis lung disease starts in the small airways: Can we treat it more effectively?PEDIATRIC PULMONOLOGY, Issue 2 2010Harm A.W.M. Tiddens MD Abstract The aims of this article are to summarize existing knowledge regarding the pathophysiology of small airways disease in cystic fibrosis (CF), to speculate about additional mechanisms that might play a role, and to consider the available or potential options to treat it. In the first section, we review the evidence provided by pathologic, physiologic, and imaging studies suggesting that obstruction of small airways begins early in life and is progressive. In the second section we discuss how the relationships between CF transmembrane conductance regulator (CFTR), ion transport, the volume of the periciliary liquid layer and airway mucus might lead to defective mucociliary clearance in small airways. In addition, we discuss how chronic endobronchial bacterial infection and a chronic neutrophilic inflammatory response increase the viscosity of CF secretions and exacerbate the clearance problem. Next, we discuss how the mechanical properties of small airways could be altered early in the disease process and how remodeling can contribute to small airways disease. In the final section, we discuss how established therapies impact small airways disease and new directions that may lead to improvement in the treatment of small airways disease. We conclude that there are many reasons to believe that small airways play an important role in the pathophysiology of (early) CF lung disease. Therapy should be aimed to target the small airways more efficiently, especially with drugs that can correct the basic defect at an early stage of disease. Pediatr Pulmonol. 2010; 45:107,117. © 2010 Wiley-Liss, Inc. [source] Pharmacotherapy of impaired mucociliary clearance in non-CF pediatric lung disease.PEDIATRIC PULMONOLOGY, Issue 11 2007A review of the literature Abstract 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. 2007;42:989,1001. © 2007 Wiley-Liss, Inc. [source] Clinical and Subclinical Endometritis in the Mare: Both Threats to FertilityREPRODUCTION IN DOMESTIC ANIMALS, Issue 2009MM LeBlanc Contents Endometritis, a major cause of mare infertility arising from failure to remove bacteria, spermatozoa and inflammatory exudate post-breeding, is often undiagnosed. Defects in genital anatomy, myometrial contractions, lymphatic drainage, mucociliary clearance, cervical function, plus vascular degeneration and inflamm-ageing underlie susceptibility to endometritis. Diagnosis is made through detecting uterine fluid, vaginitis, vaginal discharge, short inter-oestrous intervals, inflammatory uterine cytology and positive uterine culture. However, these signs may be absent in subclinical cases. Hypersecretion of an irritating, watery, neutrophilic exudate underlies classic, easy-to-detect streptococcal endometritis. In contrast, biofilm production, tenacious exudate and focal infection may characterize subclinical endometritis, commonly caused by Gram-negative organisms, fungi and staphylococci. Signs of subclinical endometritis include excessive oedema post-mating and a white line between endometrial folds on ultrasound. In addition, cultures of uterine biopsy tissue or of small volume uterine lavage are twice as sensitive as guarded swabs in detecting Gram-negative organisms, while uterine cytology is twice as sensitive as culture in detecting endometritis. Uterine biopsy may detect deep inflammatory and degenerative changes, such as disruption of the elastic fibres of uterine vessels (elastosis), while endoscopy reveals focal lesions invisible on ultrasound. Mares with subclinical endometritis require careful monitoring by ultrasound post-breeding. Treatments that may be added to traditional therapies, such as post-breeding uterine lavage, oxytocin and intrauterine antibiotics, include lavage 1-h before mating, carbetocin, cloprostenol, cervical dilators, systemic antibiotics, intrauterine chelators (EDTA,Tris), mucolytics (DMSO, kerosene, N -acetylcysteine), corticosteroids (prednisolone, dexamethasone) and immunomodulators (cell wall extracts of Mycobacterium phlei and Propionibacterium acnes). [source] The bioflavonoid compound, sinupret, stimulates transepithelial chloride transport in vitro and in vivo,,§THE LARYNGOSCOPE, Issue 5 2010Frank Virgin MD Abstract Objectives/Hypothesis: Dehydration of airway surface liquid (ASL) disrupts normal mucociliary clearance in sinonasal epithelium leading to chronic rhinosinusitis. Abnormal chloride (Cl,) transport is one mechanism that contributes to this disorder, as demonstrated by the disease cystic fibrosis. Identifying safe compounds that stimulate transepithelial Cl, transport is critical to improving hydration of the ASL and promoting mucociliary transport. Sinupret (Bionorica, LLC, San Clemente, CA), a combination of naturally occurring bioflavonoids, is a widely used treatment for respiratory ailments in Europe. However, the effects of Sinupret on target respiratory epithelium have yet to be fully investigated. The present study evaluated the mechanisms underlying this bioflavonoid therapeutic on transepithelial Cl, transport in respiratory epithelium. Study Design: In vitro and in vivo investigation. Methods: Well characterized murine nasal septal epithelial (MNSE) cultures, and murine nasal potential difference (NPD) techniques were used to evaluate the effects of Sinupret on Cl, secretion. Results: The change in Sinupret-stimulated current (, ISC expressed as ,A/cm2) in MNSE, representing Cl, secretion, was significantly increased when compared to controls (19.04 ± 1.67 ,A/cm2 vs. 1.8 ± 0.35 ,A/cm2, respectively; P = .00005). Transepithelial Cl, transport measured in the murine NPD in vivo assay (n = 42) was also significantly enhanced when compared to controls (,0.8 mV vs. ,0.9 mV; P = .0004). Importantly, Sinupret-stimulated Cl, transport was substantially more robust in vivo than forskolin, a compound among the strongest known cystic fibrosis transmembrane conductance regulator activators (,3.8 mV vs. ,1.65 mV; P = .01). Conclusions: Sinupret strongly activates transepithelial Cl, secretion through a mechanism known to hydrate the ASL of respiratory epithelium. This is one means by which the medication is likely to exert therapeutic benefit. Laryngoscope, 2010 [source] Connexin 26 and 30 Genes Mutations in Patients with Chronic Rhinosinusitis,THE LARYNGOSCOPE, Issue 2 2008FACS, Nicolas Y. BuSaba MD Abstract Objectives: Connexin proteins play an important role in cell-to-cell communication. Mutations in the genes that encode for these connexins may potentially lead to dysfunction in mucociliary clearance predisposing to chronic rhinosinusitis (CRS) or recurrent acute rhinosinusitis (RARS). The objective of this study was to assess for the presence of connexin 26 and 30 gene mutations in patients with CRS and RARS. Study Design: Prospective case series. Methods: Forty-six consecutive patients who were diagnosed with CRS or RARS at a single tertiary care facility were included in the study. Patients with known dysfunction in mucociliary clearance were excluded. The following clinical data were collected: age, gender, duration of disease and age at onset, personal history of otitis media and/or sensorineural hearing loss (SNHL), and family history of paranasal sinus disease and SNHL. Buccal swab deoxyribonucleic acid (DNA) specimens were sequenced for connexin 26 and 30 genes. Results: The study group consisted of 32 females and 14 males, 8 children and 38 adults. Adequate sequencing of connexin 30 gene was possible in all 46 specimens, but in only 19 specimens for connexin 26 gene. Connexin 30 gene mutations were not detected in any of the 46 specimens. Two of the 19 specimens had heterozygous mutations in the connexin 26 gene; there was one V371 mutation and one 35dG mutation. Both patients were adults; the patient with 35dG mutation had SNHL. Conclusion: Mutations in connexin 26 and 30 genes are rare in patients with CRS or RARS and do not seem to play a contributory role in the pathogensis of these disorders. [source] Hyperthermic, Supersaturated Humidification in the Treatment of Xerostomia,THE LARYNGOSCOPE, Issue 6 2001Mark A. Criswell MD Abstract Objectives To investigate the role of hyperthermic, supersaturated humidification in the treatment of radiation-induced xerostomia. Study Design A randomized, controlled, crossover pilot study of patients with symptomatic xerostomia following radiotherapy for head and neck cancer. Patients compared a standard bedside humidifier with a new device delivering hyperthermic, supersaturated humidification through a nasal cannula. Methods The patients were randomized to a 2-week course of standard, cool air bedside humidification or to hyperthermic, supersaturated humidification through a nasal cannula (Vapotherm Inc., Annapolis, MD). After a 1-week washout period, patients were crossed over to the opposite device for another 2 weeks. The patients underwent physical examination initially and after each trial period using an objective xerostomia scale, and then completed a questionnaire quantifying their symptoms. Patients additionally rated their symptoms at home, twice daily, using a visual analogue scale. Results Using the Oral Assessment Guide, lip scores went from 1.67 initially to 1.67 after control and 1.67 after Vapotherm. Tongue scores were 1.67, 1.5, and 1.83, respectively. Saliva scores were 1.67, 1.5, and 1.5, respectively. Mucous membranes scores were 1.5, 1.67, and 1.5, respectively. The physical examination scores at these four sites were not significantly different between control and Vapotherm (P = .78, .78, .72, and .37, respectively). The patient symptom questionnaire and visual analogue scores also revealed no significant difference between the two devices. Conclusion The Vapotherm MT-3000 device appears to provide minimal or no additional relief from radiation xerostomia over standard bedside humidifiers. Further investigation may be warranted with newer models of the device and with disorders of mucociliary clearance. [source] Interleukin-12 induces salivary gland dysfunction in transgenic mice, providing a new model of Sjögren's syndromeARTHRITIS & RHEUMATISM, Issue 12 2009Jelle L. Vosters Objective Interleukin-12 (IL-12) is a pleiotropic cytokine that is elevated in the affected organs of patients with Sjögren's syndrome (SS). We have previously reported that overexpression of IL-12 in CBA mice leads to mononuclear infiltration of salivary and lacrimal glands, as well as to expansion of bronchial lymphoid tissue and decreased mucociliary clearance. Because xerostomia is one of the most important clinical features in SS patients, our main objective in the current study was to evaluate salivary gland function in IL-12,transgenic mice. Our secondary objective was to further characterize this animal model and to determine if the changes observed in these mice are representative of those observed in patients with SS overall. Methods Pilocarpine-stimulated salivary flow was used to address salivary gland function in a large group of IL-12,transgenic mice bred onto the autoimmune-prone SJL background. Furthermore, salivary glands were removed to assess the formation of infiltrates in the glands and gland morphology. Serum was also collected from these animals to investigate the formation of autoantibodies. Results Pilocarpine-stimulated salivary flow was significantly lower in IL-12,transgenic mice than in wild-type controls. Salivary glands from transgenic mice exhibited an increase in both the number and the size of lymphocytic foci, versus glands from age-matched controls. Furthermore, the acini in transgenic mice were fewer in number and larger in size compared with acini in controls. An age-dependent increase in anti-SSB/La antibodies was observed in IL-12,transgenic mice and was accompanied by an increase in antinuclear antibodies. Conclusion Our findings indicate that a number of conditions associated with SS are exhibited by IL-12,transgenic SJL mice and that this model might be useful in researching multiple aspects of the disease. [source] The effect of hypertonicity on nasal mucociliary clearanceCLINICAL OTOLARYNGOLOGY, Issue 6 2000J.J. Homer The effect of the tonicity of saline nasal douching solutions on mucociliary clearance was studied in order to ascertain whether hypertonicity conferred any advantage. Thirty-eight normal subjects were included in a randomised double-blind crossover trial. Saline douching solutions of 0.9%, 3% and 5% tonicity were used and mucociliary clearance was measured by the saccharin clearance time (SCT). The resultant SCT after administration of 5% saline was significantly reduced compared to both 0.9% (P = 0.005) and 3% saline (P = 0.04). There was no difference between 0.9% and 3% saline administration. Thus hypertonic saline solutions improve mucociliary clearance, although this was only observed with solutions of 5% tonicity. The effect is probably brought about by changes in mucus rheology. [source] | ||||||||||