RESUMO
PURPOSE: Cystic fibrosis (CF) is a multisystem genetic disease caused by dysfunction of the epithelial anionic channel Cystic Fibrosis Transmembrane conductance Regulator (CFTR). Decreased mucociliary clearance because of thickened mucus is part of the pulmonary disease pathophysiology. It is controversial if the thickened airway surface liquid (ASL) is caused by the deficient chloride secretion and excessive sodium (through ENaC) and water hyperabsorption from the periciliar fluid or by the lack of bicarbonate secretion with relative acidification of the ASL. Correlations between the magnitude of in vivo chloride conductance with phenotypic characteristics and CF genotype can help to elucidate these mechanisms and direct to new treatments. METHODS: Nasal potential difference was measured in 28 CF patients (age from 0.3 to 28 year) and correlated with pulmonary function, pancreatic phenotype, pulmonary colonization and genotype severity. RESULTS: The CFTR-chloride conductance was better in older patients (r = 0.40; P = 0.03), in patients with better pulmonary function (r = 0.48; P = 0.01), and was associated with genotype severity. Higher chloride diffusion in the presence of a favorable chemical gradient was associated with Pseudomonas aeruginosa negativity (P < 0.05). More negative NPDmax was associated with pancreatic insufficiency (P < 0.01) as well with genotype severity, but not with the pulmonary function. CONCLUSIONS: The anion permeability through CFTR, mainly chloride, but bicarbonate as well, is the most critical factor in CF airway pathophysiology. Treatments primarily directed to correct CFTR function and/or airway acidity are clearly a priority.
Assuntos
Cloretos/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/fisiopatologia , Insuficiência Pancreática Exócrina/fisiopatologia , Potenciais da Membrana/fisiologia , Mucosa Nasal/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Fibrose Cística/genética , Fibrose Cística/metabolismo , Fibrose Cística/microbiologia , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Feminino , Genótipo , Humanos , Lactente , Masculino , Mutação , Mucosa Nasal/metabolismo , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/fisiopatologia , Pseudomonas aeruginosa , Adulto JovemRESUMO
Although small airways account for the largest fraction of the total conducting airway surfaces, the epithelial fluid and electrolyte transport in small, native airway epithelia has not been well characterized. Investigations have been limited, no doubt, by the complex tissue architecture as well as by its inaccessibility, small dimensions, and lack of applicable assays, especially in human tissues. To better understand how the critically thin layer of airway surface liquid (ASL) is maintained, we applied a "capillary"-Ussing chamber (area ≈1 mm2) to measure ion transport properties of bronchioles with diameters of ~2 mm isolated from resected specimens of excised human lungs. We found that the small human airway, constitutively and concurrently, secretes and absorbs fluid as observed in porcine small airways (50). We found that the human bronchiolar epithelium is also highly anion selective and constitutively secretes bicarbonate ( HCO3- ), which can be enhanced pharmacologically by cAMP as well as Ca2+-mediated agonists. Concurrent secretion and absorption of surface liquid along with HCO3- secretion help explain how the delicate volume of the fluid lining the human small airway is physiologically buffered and maintained in a steady state that avoids desiccating or flooding the small airway with ASL.
Assuntos
Bicarbonatos/metabolismo , Bronquíolos/metabolismo , Líquido Extracelular/metabolismo , Mucosa Respiratória/metabolismo , Animais , Humanos , Transporte de Íons , SuínosRESUMO
The small airways of the lungs are under constant assault from the pathogens and debris in the air that they must conduct to alveoli. Although hygiene is of paramount importance for respiratory health, the underlying principles of airway clearance have not been well integrated or established. Newly emerging concepts of simultaneous absorption and secretion of airway surface liquid (ASL) and the role of [Formula: see text] in the maturation of mucins have advanced from experimental evidence as well as observations from the congenital disease cystic fibrosis (CF) to present a novel model that integrates microanatomy with organ physiology to meet the constant challenge of cleaning small airways.
Assuntos
Bronquíolos/fisiologia , Animais , Bronquíolos/metabolismo , Fibrose Cística/metabolismo , Fibrose Cística/fisiopatologia , Humanos , Mucinas/metabolismo , Mucosa Respiratória/metabolismo , Mucosa Respiratória/fisiologiaRESUMO
The secretion and management of readily transportable airway surface liquid (ASL) along the respiratory tract is crucial for the clearance of debris and pathogens from the lungs. In proximal large airways, submucosal glands (SMGs) can produce ASL. However, in distal small airways, SMGs are absent, although the lumens of these airways are, uniquely, highly plicated. Little is known about the production and maintenance of ASL in small airways, but using electrophysiology, we recently found that native porcine small airways simultaneously secrete and absorb. How these airways can concurrently transport ASL in opposite directions is puzzling. Using high expression of the Na-K-2Cl cotransport (NKCC) 1 protein (SLC12a2) as a phenotypic marker for fluid secretory cells, immunofluorescence microscopy of porcine small airways revealed two morphologically separated sets of luminal epithelial cells. NKCC1 was abundantly expressed by most cells in the contraluminal regions of the pleats but highly expressed very infrequently by cells in the luminal folds of the epithelial plications. In larger proximal airways, the acini of SMGs expressed NKCC1 prominently, but cells expressing NKCC1 in the surface epithelium were sparse. Our findings indicate that, in the small airway, cells in the pleats of the epithelium secrete ASL, whereas, in the larger proximal airways, SMGs mainly secrete ASL. We propose a mechanism in which the locations of secretory cells in the base of pleats and of absorptive cells in luminal folds physically help maintain a constant volume of ASL in small airways.
Assuntos
Líquidos Corporais/metabolismo , Brônquios/metabolismo , Células Epiteliais/metabolismo , Mucosa Respiratória/metabolismo , Animais , Biomarcadores/metabolismo , Brônquios/citologia , Modelos Animais , Fenótipo , Mucosa Respiratória/citologia , Membro 2 da Família 12 de Carreador de Soluto/metabolismo , Sus scrofaRESUMO
Since the discovery of Cl(-) impermeability in cystic fibrosis (CF) and the cloning of the responsible channel, CF pathology has been widely attributed to a defect in epithelial Cl(-) transport. However, loss of bicarbonate (HCO3(-)) transport also plays a major, possibly more critical role in CF pathogenesis. Even though HCO3(-) transport is severely affected in the native pancreas, liver, and intestines in CF, we know very little about HCO3(-) secretion in small airways, the principle site of morbidity in CF. We used a novel, mini-Ussing chamber system to investigate the properties of HCO3(-) transport in native porcine small airways (â¼ 1 mm φ). We assayed HCO3(-) transport across small airway epithelia as reflected by the transepithelial voltage, conductance, and equivalent short-circuit current with bilateral 25-mM HCO3(-) plus 125-mM NaGlu Ringer's solution in the presence of luminal amiloride (10 µM). Under these conditions, because no major transportable anions other than HCO3(-) were present, we took the equivalent short-circuit current to be a direct measure of active HCO3(-) secretion. Applying selective agonists and inhibitors, we show constitutive HCO3(-) secretion in small airways, which can be stimulated significantly by ß-adrenergic- (cAMP) and purinergic (Ca(2+)) -mediated agonists, independently. These results indicate that two separate components for HCO3(-) secretion, likely via CFTR- and calcium-activated chloride channel-dependent processes, are physiologically regulated for likely roles in mucus clearance and antimicrobial innate defenses of small airways.
Assuntos
Bicarbonatos/metabolismo , Pulmão/anatomia & histologia , Pulmão/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Animais , Cálcio/metabolismo , Canais de Cloreto/metabolismo , AMP Cíclico/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Condutividade Elétrica , Feminino , Transporte de Íons , Pulmão/efeitos dos fármacos , Masculino , Agonistas Purinérgicos/farmacologia , Suínos , Fatores de TempoRESUMO
Evidence from the pathology in cystic fibrosis (CF) and recent results in vitro indicate that HCO3- is required for gel-forming mucins to form the mucus that protects epithelial surfaces. Mucus formation and release is a complex process that begins with an initial intracellular phase of synthesis, packaging and apical granule exocytosis that is followed by an extracellular phase of mucin swelling, transport and discharge into a lumen. Exactly where HCO3- becomes crucial in these processes is unknown, but we observed that in the presence of HCO3-, stimulating dissected segments of native mouse intestine with 5-hydroxytryptamine (5-HT) and prostaglandin E2 (PGE2) induced goblet cell exocytosis followed by normal mucin discharge in wild-type (WT) intestines. CF intestines that inherently lack cystic fibrosis transmembrane conductance regulator (CFTR)-dependent HCO3- secretion also demonstrated apparently normal goblet cell exocytosis, but in contrast, this was not followed by similar mucin discharge. Moreover, we found that even in the presence of HCO3-, when WT intestines were stimulated only with a Ca2+-mediated agonist (carbachol), exocytosis was followed by poor discharge as with CF intestines. However, when the Ca2+-mediated agonist was combined with a cAMP-mediated agonist (isoproterenol (isoprenaline) or vasoactive intestinal peptide) in the presence of HCO3- both normal exocytosis and normal discharge was observed. These results indicate that normal mucus formation requires concurrent activation of a Ca2+-mediated exocytosis of mucin granules and an independent cAMP-mediated, CFTR-dependent, HCO3- secretion that appears to mainly enhance the extracellular phases of mucus excretion.
Assuntos
Bicarbonatos/metabolismo , Cálcio/metabolismo , AMP Cíclico/metabolismo , Exocitose , Células Caliciformes/metabolismo , Mucinas/metabolismo , Animais , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Dinoprostona/farmacologia , Células Caliciformes/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CFTR , Serotonina/farmacologiaRESUMO
This study was designed to assess the relative importance of Cl(-) and HCO(3)(-) secretion to mucociliary transport rate (MCT) in ex vivo porcine tracheas. MCT was measured in one group of tissues that was exposed to adventitial HCO(3)(-)-free solution while a parallel group was exposed to adventitial HCO(3)(-)-replete solution. After measurement of baseline MCT rates, acetylcholine (ACh) was added to stimulate submucosal gland mucous liquid secretion, and MCT rates were again measured. Before ACh addition, the mean MCT was higher in the HCO(3)(-)-free group (4.2 ± 0.9 mm/min) than in the HCO(3)(-)-replete group (2.3 ± 0.3 mm/min), but this difference was not statistically significant. ACh addition significantly increased MCT in both groups, but ACh-stimulated MCT was significantly lower in the HCO(3)(-)-free group (11.0 ± 1.5 mm/min) than in the HCO(3)(-)-replete group (17.0 ± 2.0 mm/min). A second series of experiments examined the effect on MCT of blocking Cl(-) secretion with 100 µM bumetanide. Before adding ACh, MCT in the bumetanide-treated group (1.0 ± 0.2 mm/min) was significantly lower than in the control group (3.8 ± 1.1 mm/min). ACh addition significantly increased MCT in both groups, but there was no significant difference between the bumetanide-treated group (21.4 ± 1.7 mm/min) and control group (19.5 ± 3.4 mm/min). These results indicate that ACh-stimulated MCT has greater dependence on HCO(3)(-) secretion, whereas the basal MCT rate has greater dependence on Cl(-) secretion.
Assuntos
Bicarbonatos/metabolismo , Cloretos/metabolismo , Depuração Mucociliar/efeitos dos fármacos , Traqueia/efeitos dos fármacos , Acetilcolina/farmacologia , Animais , Bicarbonatos/antagonistas & inibidores , Bumetanida/farmacologia , Cloretos/antagonistas & inibidores , Agonistas Colinérgicos/farmacologia , Muco/efeitos dos fármacos , Muco/fisiologia , Técnicas de Cultura de Órgãos , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacologia , Suínos , Traqueia/fisiologiaRESUMO
RATIONALE: ß-Adrenergically induced sweat secretion offers an expedient method to assess native cystic fibrosis transmembrane conductance regulator (CFTR) secretory function in vivo. OBJECTIVES: To evaluate the sensitivity, specificity, and reliability of a test based on the activity and secretory function of CFTR in the sweat gland. METHODS: Primary and validation trials with prospectively ascertained healthy control subjects, obligate heterozygotes, and patients with a CFTR-related disorder and CF (pancreatic sufficient and insufficient). MEASUREMENTS AND MAIN RESULTS: Diagnostic accuracy and reliability of ß-adrenergic sweat secretory rates using an evaporimeter was assessed and compared with sweat chloride concentrations. The cholinergically stimulated mean sweat rate did not differ among groups. The mean maximal ß-adrenergically stimulated sweat rate in heterozygotes was about half the rate of healthy control subjects, and completely absent in pancreatic-insufficient patients with CF and pancreatic-sufficient patients with CF (P < 0.0001). Subjects with a CFTR-related disorder showed reduced or absent ß-adrenergic sweat secretion. The ß-adrenergic secretory response demonstrated high diagnostic accuracy (area under a characteristic receiver-operator curve = 0.99; 95% confidence interval, 0.97-1.00) and reliability (intraclass correlation, 0.90; 95% confidence interval, 0.81-0.95). The diagnostic cutoff level for CF, derived from the primary trial, correctly identified all control subjects, heterozygotes, and patients with CF in the validation cohort, whereas concurrent sweat chloride measurements misclassified one heterozygote and five subjects with CF. The cholinergic and ß-adrenergic sweat secretion rates were lower in women compared with men (P < 0.001). CONCLUSIONS: ß-Adrenergic sweat secretion rate determined by evaporimetry is an accurate and reliable technique to assess different levels of CFTR function and to identify patients with CF.
Assuntos
Agonistas Adrenérgicos beta , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Fibrose Cística/diagnóstico , Suor/metabolismo , Adolescente , Adulto , Idoso , Biomarcadores/análise , Estudos de Casos e Controles , Cloretos/análise , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Feminino , Triagem de Portadores Genéticos , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Suor/química , Perda Insensível de ÁguaRESUMO
There is increasing international interest in the use of police drug diversion schemes that offer people suspected of minor drug-related offences an educative or therapeutic intervention as an alternative to criminalisation. While there have been randomised trials of some such schemes for their effects on reducing offending, with generally positive results, less is known about the health outcomes, and what works, for whom, in what circumstances and why. This protocol reports on a realist evaluation of police drug diversion in England that has been coproduced by a team of academic, policing, health, and service user partners. The overall study design combines a qualitative assessment of the implementation, contexts, mechanisms, moderators and outcomes of schemes in Durham, Thames Valley and the West Midlands with a quantitative, quasi-experimental analysis of administrative data on the effects of being exposed to the presence of police drug diversion on reoffending and health outcomes. These will be supplemented with analysis of the cost-consequences of the evaluated schemes, an analysis of the equity of their implementation and effects, and a realist synthesis of the various findings from these different methods.
RESUMO
OBJECTIVE: To determine the early and long-term outcomes of conventional aortic root (ARR) and valve-sparing root replacement (VSRR) using a standard perioperative and operative approach. METHODS: We present prospectively collected data of 609 consecutive patients undergoing elective and urgent aortic root surgery (470 ARR, 139 VSRR) between 2006 and 2020. Primary outcomes were operative mortality and incidence of postoperative complications. Secondary outcomes were long-term survival and requirement for reintervention. Median follow-up was 7.6 years (range 0.5-14.5). RESULTS: 189 patients (31%) had bicuspid aortic valves and 17 (6.9%) underwent redo procedures. Median cross-clamp time was 88 (range 54-208) min with cardiopulmonary bypass of 108 (range 75-296) min. In-hospital mortality was 10 (1.6%), with transient ischaemic attacks/strokes occurring in 1.1%. In-hospital mortality for VSRR was 0.7%. 12 patients (2.0%) required a resternotomy for bleeding and 14 (2.3%) received haemofiltration. Intensive care unit and hospital stay were 1.7 and 7.0 days, respectively. During follow-up, redo surgery for native aortic valve replacement was required in 1.4% of the VSRR group. Overall survival was 95.1% at 3 years, 93.1% at 5 years, 91.2% at 7 years and 88.6% at 10 years. CONCLUSIONS: ARR and VSRR can be performed with low mortality and morbidity as well as a low rate of reintervention during the period of long-term follow-up, if performed by an experienced team with a consistent perioperative approach. This series provides contemporary evidence to balance the risks of aortic aneurysms and their rupture at diameters of <5.5 cm against the risks and benefits of surgery.
Assuntos
Aneurisma Aórtico , Implante de Prótese de Valva Cardíaca , Humanos , Valva Aórtica/cirurgia , Implante de Prótese de Valva Cardíaca/métodos , Resultado do Tratamento , Aorta/cirurgia , Aneurisma Aórtico/cirurgia , Estudos RetrospectivosAssuntos
Aminofenóis/economia , Aminopiridinas/economia , Benzodioxóis/economia , Fibrose Cística/tratamento farmacológico , Medicina de Precisão/economia , Quinolonas/economia , Medicamentos para o Sistema Respiratório/economia , Aminofenóis/uso terapêutico , Aminopiridinas/uso terapêutico , Benzodioxóis/uso terapêutico , Análise Custo-Benefício , Fibrose Cística/economia , Fibrose Cística/genética , Combinação de Medicamentos , Humanos , Quinolonas/uso terapêutico , Medicamentos para o Sistema Respiratório/uso terapêutico , Estados UnidosRESUMO
The invitation to present the 2010 Hans Ussing lecture for the Epithelial Transport Group of the American Physiological Society offered me a unique, special, and very surprising opportunity to join in saluting a man whom I met only once, but whose work was the basis, not only for my career, but also for finding the molecular defect in the inherited disease cystic fibrosis (CF). In this context, I will venture to make the tribute with a new explanation of why a mutation in a single gene that codes for an anion channel can cause devastation of multiple epithelial systems with pathogenic mucus. In so doing, I hope to raise awareness of a new role for that peculiar anion around which so much physiology revolves, HCO(3)(-). I begin by introducing CF pathology as I question the name of the disease as well as the prevalent view of the basis of its pathology by considering: 1) mucus, 2) salt, and 3) HCO(3)(-). I then present recent data showing that HCO(3)(-) is required for normal mucus discharge, and I will close with conjecture as to how HCO(3)(-) may support mucus discharge and why the failure to transport this electrolyte is pathogenic in CF.
Assuntos
Bicarbonatos/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/fisiologia , Fibrose Cística/metabolismo , Mucinas/metabolismo , Animais , Fibrose Cística/genética , Fibrose Cística/patologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Feminino , Humanos , Transporte de Íons/genética , Transporte de Íons/fisiologia , Pulmão/patologia , Pulmão/fisiopatologia , Masculino , Camundongos , Muco/metabolismo , Cloreto de Sódio/metabolismo , Glândulas Sudoríparas/metabolismo , Glândulas Sudoríparas/patologia , Glândulas Sudoríparas/fisiopatologiaRESUMO
Cervical mucus thinning and release during the female reproductive cycle is thought to rely mainly on fluid secretion. However, we now find that mucus released from the murine reproductive tract critically depends upon concurrent bicarbonate (HCO(3)(-)) secretion. Prostaglandin E(2) (PGE(2))- and carbachol-stimulated mucus release was severely inhibited in the absence of serosal HCO(3)(-), HCO(3)(-) transport, or functional cystic fibrosis transmembrane conductance regulator (CFTR). In contrast to mucus release, PGE(2)- and carbachol-stimulated fluid secretion was not dependent on bicarbonate or on CFTR, but was completely blocked by niflumic acid. We found stimulated mucus release was severely impaired in the cystic fibrosis F508 reproductive tract, even though stimulated fluid secretion was preserved. Thus, CFTR mutations and/or poor bicarbonate secretion may be associated with reduced female fertility associated with abnormal mucus and specifically, may account for the increased viscosity and lack of cyclical changes in cervical mucus long noted in women with cystic fibrosis.
Assuntos
Bicarbonatos/metabolismo , Colo do Útero/metabolismo , Muco/metabolismo , Útero/metabolismo , Animais , Líquidos Corporais/metabolismo , Carbacol/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Dinoprostona/farmacologia , Feminino , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Mucinas/metabolismo , Muco/química , Ocitócicos/farmacologia , Soluções , Estimulação QuímicaRESUMO
The impact of small anions on the physical properties of gel-forming mucin has been almost overlooked relative to that of cations. Recently, based on the coincident abnormalities in HCO(3)(-) secretion and abnormal mucus formed in the hereditary disease cystic fibrosis (CF), HCO(3)(-) was hypothesized to be critical in the formation of normal mucus by virtue of its ability to sequester Ca(2+) from condensed mucins being discharged from cells. However, direct evidence of the impact of HCO(3)(-) on mucus properties is lacking. Herein, we demonstrate for the first time that mucin diffusivity (â¼1/viscosity) increases as a function of [HCO(3)(-)]. Direct measurements of exocytosed mucin-swelling kinetics from airway cells showed that mucin diffusivity increases by â¼300% with 20 mM extracellular HCO(3)(-) concentration. Supporting data indicate that HCO(3)(-) reduces free Ca(2+) concentration and decreases the amount of Ca(2+) that remains associated with mucins. The results demonstrate that HCO(3)(-) enhances mucin swelling and hydration by reducing Ca(2+) cross-linking in mucins, thereby decreasing its viscosity and likely increasing its transportability. In addition, HCO(3)(-) can function as a Ca(2+) chelator like EGTA to disperse mucin aggregates. This study indicates that poor HCO(3)(-) availability in CF may explain why secreted mucus remains aggregated and more viscous in affected organs. These insights bear on not only the fundamental pathogenesis in CF, but also on the process of gel mucus formation and release in general.
Assuntos
Bicarbonatos/metabolismo , Cálcio/metabolismo , Exocitose/fisiologia , Muco/metabolismo , Mucosa Respiratória/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Mucinas/metabolismo , Alvéolos Pulmonares/metabolismo , Vesículas Secretórias/metabolismo , Células Tumorais Cultivadas , ViscosidadeRESUMO
BACKGROUND: Among the many consequences of loss of CFTR protein function, a significant reduction of the secretion of bicarbonate (HCO3-) in cystic fibrosis (CF) is a major pathogenic feature. Loss of HCO3- leads to abnormally low pH and impaired mucus clearance in airways and other exocrine organs, which suggests that NaHCO3 inhalation may be a low-cost, easily accessible therapy for CF. OBJECTIVE: To evaluate the safety, tolerability, and effects of inhaled aerosols of NaHCO3 solutions (4.2% and 8.4%). METHODS: An experimental, prospective, open-label, pilot, clinical study was conducted with 12 CF volunteer participants over 18 years of age with bronchiectasis and pulmonary functions classified as mildly to severely depressed. Sputum rheology, pH, and microbiology were examined as well as spirometry, exercise performance, quality-of-life assessments, dyspnea, blood count, and venous blood gas levels. RESULTS: Sputum pH increased immediately after inhalation of NaHCO3 at each clinical visit and was inversely correlated with rheology when all parameters were evaluated: [G' (elasticity of the mucus) = - 0.241; Gâ³ (viscosity of the mucus) = - 0.287; G* (viscoelasticity of the mucus) = - 0.275]. G* and G' were slightly correlated with peak flow, forced expiratory volume in 1 s (FEV1), and quality of life; Gâ³ was correlated with quality of life; sputum pH was correlated with oxygen consumption (VO2) and vitality score in quality of life. No changes were observed in blood count, venous blood gas, respiratory rate, heart rate, peripheral oxygen saturation of hemoglobin (SpO2), body temperature, or incidence of dyspnea. No adverse events associated with the study were observed. CONCLUSION: Nebulized NaHCO3 inhalation appears to be a safe and well tolerated potential therapeutic agent in the management of CF. Nebulized NaHCO3 inhalation temporarily elevates airway liquid pH and reduces sputum viscosity and viscoelasticity.
Assuntos
Fibrose Cística/tratamento farmacológico , Bicarbonato de Sódio/administração & dosagem , Administração por Inalação , Adolescente , Adulto , Fibrose Cística/fisiopatologia , Fibrose Cística/psicologia , Elasticidade , Feminino , Humanos , Masculino , Projetos Piloto , Estudos Prospectivos , Qualidade de Vida , Bicarbonato de Sódio/efeitos adversos , Escarro/metabolismo , ViscosidadeRESUMO
For more than 20 years, the abnormally thick mucus (mucoviscidosis) in cystic fibrosis has been widely shown to be linked to a genetic defect in the cystic fibrosis transmembrane conductance regulator Cl(-) channel. The defect is widely thought to cause mucus to become dehydrated as a result of basic defects in Cl(-) dependent fluid transport. However, this widely held explanation is inconsistent with the known physiological properties and functions of organs affected by cystic fibrosis. During the process of releasing highly condensed mucins from intracellular granules, Ca(2+) and H(+) cations must be removed to enable the mucins to expand by as much as 1000 times, forming extracellular mucus-gel networks. Over the past few years, that HCO(3)(-) transport is also defective in patients with cystic fibrosis has become apparent. I propose that HCO(3)(-) is crucial to normal mucin expansion because it forms complexes with these cations. Thus, because HCO(3)(-) secretion is defective in cystic fibrosis, mucins in organs affected by cystic fibrosis tend to remain aggregated, poorly solubilised, and less transportable. If the hypothesis is valid, pathogenesis in cystic fibrosis could be due as much to defective transport of HCO(3)(-) as to defective Cl(-) transport.
Assuntos
Bicarbonatos/metabolismo , Fibrose Cística , Mucinas/metabolismo , Muco/metabolismo , Pâncreas/fisiologia , Fibrose Cística/metabolismo , Fibrose Cística/fisiopatologia , Humanos , Mucinas/fisiologiaRESUMO
We investigated the effects of bicarbonate on the growth of several different bacteria as well as its effects on biofilm formation and intracellular cAMP concentration in Pseudomonas aeruginosa. Biofilm formation was examined in 96-well plates, with or without bicarbonate. The cAMP production of bacteria was measured by a commercial assay kit. We found that NaHCO3 (100 mmol l-1) significantly inhibited, whereas NaCl (100 mmol l-1) did not influence the growth of planktonic bacteria. MIC and MBC measurements indicated that the effect of HCO 3 - is bacteriostatic rather than bactericidal. Moreover, NaHCO3 prevented biofilm formation as a function of concentration. Bicarbonate and alkalinization of external pH induced a significant increase in intracellular cAMP levels. In conclusion, HCO 3 - impedes the planktonic growth of different bacteria and impedes biofilm formation by P. aeruginosa that is associated with increased intracellular cAMP production. These findings suggest that aerosol inhalation therapy with HCO 3 - solutions may help improve respiratory hygiene in patients with cystic fibrosis and possibly other chronically infected lung diseases.
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Cystic fibrosis (CF) of the pancreas is the most widely accepted name of the most common fatal inherited single gene defect disease among Caucasians. Its incidence among other races is thought to be significantly less, but mutations in the gene have been reported in most, if not all, major populations. This review is intended to give general concepts of the molecular as well as physiological basis of the pathology that develops in the disease. First, an overview of the organ pathology and genetics is presented, followed by the molecular structure of the gene product (cystic fibrosis transmembrane conductance regulator, CFTR), its properties, functions, and controls as currently understood. Second, since mutations appear to be expressed primarily as a defect in electrolyte transport, effects and mechanisms of pathology are presented for two characteristically affected organs where the etiology is best described: the sweat gland, which excretes far too much NaCl ("salt") and the pancreas, which excretes far too little HCO3(- )("soda"). Unfortunately, morbidity and mortality in CF develop principally from refractory airway infections, the basis of which remains controversial. Consequently, we conclude by considering possible mechanisms by which defects in anion transport might predispose the CF lung to chronic infections.
Assuntos
Ânions/metabolismo , Fibrose Cística/fisiopatologia , Transporte de Íons , Bicarbonatos , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Humanos , Pâncreas/fisiopatologia , Cloreto de Sódio , Glândulas Sudoríparas/fisiopatologiaRESUMO
ß-adrenergically stimulated sweat secretion depends on the function of the cystic fibrosis transmembrane conductance regulator (CFTR) and discriminates between cystic fibrosis (CF) patients and healthy controls. Therefore, we sought to determine the feasibility, safety, and efficacy of assaying ß-adrenergic sweating in children identified by CF newborn screening to help determine prognoses for individuals with CFTR-related metabolic syndrome (CRMS). Preschool age children with a positive newborn screening test for CF participated in this cross-sectional study. Sweat rates were measured by evaporimetery (cyberDERM, inc.) as transepidermal water losses (g H2O/m2/h) before and after selectively stimulating sweat glands either cholinergically or ß-adrenergically. Net peak sweat responses assayed as evaporation rates were compared between CF and CRMS cohorts. After a pilot test in adults, children between 4 and 6 years of age were evaluated (CF, n = 16; CRMS, n = 10). The test protocol was well tolerated; electrocardiograms and vital signs were within normal range for all subjects. The mean evaporative sweat rates in both groups in response to cholinergic stimulation were similar (CF, 60.3 ± 23.8; CRMS, 57.7 ± 13.9; p = 0.72) as well as to ß-adrenergic stimulation (CF, 1.1 ± 1.7; CRMS, 2.0 ± 2.0; p = 0.14). The ß-adrenergic sweat test is safe and well tolerated by young children. However, the ß-adrenergic sweat secretion rates as measured by evaporimetery did not discriminate between CF and CRMS cohorts.