Bronchiectasis: A continuum of ion transport dysfunction or multiple hits?

Bronchiectasis, a syndrome characterized by chronic cough with purulent sputum and bronchial dilation involving more than one lobe on computed tomography scans, remains in many cases a pathophysiological dilemma. Bronchiectasis is often considered to result from a failure of lung defense that leads to chronic airway infection, airway wall damage, and airway ectasia. In this issue of the Journal (pp. 1078–1084), Bienvenu and colleagues investigate the pathogenesis of bronchiectasis in a large cohort of subjects in whom known causes of bronchiectasis were thought to have been excluded

Muco-obstructive lung diseases

A spectrum of lung diseases that affect the airways, including chronic obstructive pulmonary disease (COPD), cystic fibrosis, primary ciliary dyskinesia, and non–cystic fibrosis bronchiectasis, can be characterized as muco-obstructive diseases. These diseases have the clinical features of cough, sputum production, and episodic exacerbations that are often associated with a diagnosis of chronic bronchitis. However, neither “chronic bronchitis” nor “hypersecretory diseases” adequately describes the diffuse mucus obstruction, airway-wall ectasia, chronic inflammation, and bacterial infection that are typical of these conditions; therefore, “muco-obstructive” may be a preferred descriptive term. Although asthma can also be associated with diffuse airway mucus obstruction, its distinct pathophysiological mechanisms preclude discussion in this grouping

Editorial: Idiopathic pulmonary fibrosis - A sticky business

Pulmonary fibrosis comprises a spectrum of disease phenotypes, including familial and idiopathic forms. Current research suggests that pulmonary fibrosis is a “two-hit” disease: a genetic predisposition to abnormal alveolar epithelial-cell regulation of the cell cycle and apoptosis combined with environmental stressors, including exposure to known fibrogenic materials (e.g., asbestos, silica, and cigarette smoke)

On the pathogenesis of acute exacerbations of mucoobstructive lung diseases

Mucoobstructive lung diseases have highlighted the importance of a proper description of the normal mucus clearance system. A useful description of the normal mucus clearance apparatus requires the presence of two gels on the airway surface (i.e., a mucus layer gel and a periciliary gel). Importantly, most mucoobstructive lung diseases are distributed heterogeneously in the lung, and exacerbations may reflect spread of the disease to previously normal areas. The spread may reflect disturbances in the balance of water between the two gel layers, producing heterogeneous mucus adhesion and infection within the lung. Ultimately, spread can produce losses of lung function that may be associated with acute exacerbation frequency

Muco-Obstructive Lung Diseases. Reply

To the Editor: The review article by Boucher (May 16 issue) does not include a discussion of asthma as a muco-obstructive lung disease. In a subgroup of patients with asthma, clinically significant mucus plugging is detected on high resolution computed tomographic imaging. This condition is characterized clinically by severe airflow obstruction and a lack of response to both bronchodilators and systemic glucocorticoids. Mucus-derived obstruction is an important asthma phenotype because it may predict more persistent obstruction than that which is usually encountered and involve a treatment approach that is similar to that for other mucoobstructive diseases

Relationship of airway epithelial ion transport to chronic bronchitis.

Failure to clear mucus normally is a critical event in the pathogenesis of chronic bronchitis (CB). A unifying concept for the failure to clear mucus from airway surfaces has emerged that focuses on an abnormally high mucin-to-airway surface liquid volume ratio. At a certain level, a high mucin-to-volume ratio is associated with loss of the periciliary liquid layer and adhesion of the mucus layer to the cell surface. Adherent mucus becomes a stimulus for irritation and cough and is the nidus for bacterial infection. Therapeutic approaches for clearing mucus from CB airways should focus on restoring the balance of mucin and water. Pharmacologic blockade of the epithelial Na+ channel, which is rate-limiting for volume absorption from airway surfaces, constitutes a novel therapeutic target. Studies of mucus clearance both in sheep models and human subjects demonstrate that blockade of the epithelial Na+ channel is associated with an acceleration of mucus clearance, suggesting that epithelial Na+ channel blockade may indeed constitute a rational form of therapy for CB

Effects of ion composition and tonicity on human neutrophil antibacterial activity

Infants with cystic fibrosis (CF) often are infected with Staphylococcus aureus (S. aur.), which is followed by colonization with Pseudomonas aeruginosa (P. aerug.). In spite of an excessive, neutrophil-dominated inflammatory response in the respiratory tract, patients with CF often succumb to pulmonary infections with P. aerug. Because peripheral blood neutrophils of these patients have normal functions, we examined whether hypothesized alterations of the airway surface liquids (ASL) in these patients significantly impair neutrophil bactericidal activity in the microenvironment of the CF lung. The ionic composition of CF ASL is still not entirely defined and has been speculated to be abnormally high or abnormally low in Na+ and Cl- concentrations; estimates of osmolarities have ranged from 200 (hypo-osmolar) to 285 (iso-osmolar) to > 300 meq/L (hyper-osmolar). Our data indicate that bacterial killing activity of human peripheral blood neutrophils against P. aerug. or S. aur. is not decreased in buffers in which NaCI was replaced with equimolar concentrations of choline Cl. KC1, or N-methyl-D-glucamine chloride to maintain isotonicity. Amiloride or benzamil, known modulators of Na+ transport in neutrophils, did not interfere with this neutrophil function. Deviations from isotonicity of ± 50% also failed to diminish bactericidal activity of neutrophils significantly. In contrast, superoxide production and enzyme secretion in response to the chemotactic peptide N-formylmethionylleucylphenylalanine appeared to be sensitive to the ionic milieu of the assay buffers. Our results suggest that the postulated alterations in the ionic composition of ASL in CF lungs are insufficient to explain why neutrophils fail to clear infections with P. aerug. in these patients

Biochemical evidence for an ecto alkaline phosphodiesterase I in human airways

Because dinucleotides are signaling molecules that can interact with cell surface receptors and regulate the rate of mucociliary clearance in lungs, we studied their metabolism by using human airway epithelial cells. A membrane-bound enzyme was detected on the mucosal surface of polarized epithelia that metabolized dinucleotides with a broad substrate specificity (diadenosine polyphosphates and diuridine polyphosphates [Up(n)U], n = 2 to 6). The enzymatic reaction yielded nucleoside monophosphates (NMP) and Np(n-1) (N = A or U), and was inhibited by nucleoside 5'-triphosphates (α,βmet adenosine triphosphate [ATP] > ATP ≥ uridine triphosphate > guanidine triphosphate > cytidine triphosphate). The apparent Michaelis constant (K(m,app)) and apparent maximal velocity (V(max,app)) for [3H]Up4U were 22 ± 4 μM and 0.24 ± 0.05 nmoles · min-1 ·cm-2, respectively. Thymidine 5'-monophosphate p-nitrophenyl ester and adenosine diphosphate (ADP)-ribose, substrates of ecto alkaline phosphodiesterase I (PDE I) activities, were also hydrolyzed by the apical surface of airway epithelia. ADP-ribose competed with [3H]Up4U, with a K(i) of 23 ± 3 μM. The metabolism of ADP-ribose and Ap4A was not affected by inhibitors of cyclic nucleotide phosphodiesterases (3-isobutyl-1-methylxanthine, Ro 20-1724, and 1,3-dipropyl-8-p-sulfophenylxanthine), but similarly inhibited by fluoride and N-ethylmaleimide. These results suggest that a PDE I is responsible for the hydrolysis of extracellular dinucleotides in human airways. The wide substrate specificity of PDE I suggests that it may be involved in several signaling events on the luminal surface of airway epithelia, including purinoceptor activation and cell surface protein ribosylation

D--branes and Spinning Black Holes

We obtain a new class of spinning charged extremal black holes in five dimensions, considered both as classical configurations and in the Dirichlet(D)--brane representation. The degeneracy of states is computed from the D--brane side and the entropy agrees perfectly with that obtained from the black hole side.Comment: 10 pages, harvmac ``b'' mode (minor changes

Rationale for hypertonic saline therapy for cystic fibrosis lung disease

Cystic fibrosis (CF) is caused by alterations in the CF transmembrane conductance regulator (CFTCR) gene. More than 1400 mutations in the CFTCR gene have been described, but the most common mutation (noted in 70% of CF chromosomes) is ΔF508. Alterations in the CFTCR gene result in deranged sodium and chloride ion transport channels. This leads to failure of airway epithelia to hydrate their surfaces normally, particularly in response to infectious or toxic insults. Additional effects include mucus adhesion to airway surface, chronic inflammation, and infections. The concept that airway surface dehydration can cause CF-like lung disease is supported by in vitro data and in vivo animal models. Rehydrating airway surfaces may reduce or prevent lung injury and damage. Short- and longer term studies have shown that inhalation of hypertonic saline is well tolerated and improves lung function, reduces exacerbations, and improves quality of life in CF patients. This review discusses the importance of airway epithelial sodium and chloride channels in the pathogenesis of CF, and strategies (particularly the use of inhaled hypertonic saline) to reverse or minimize lung inflammation and injury in this disease