Rationale: Chronic bronchitis (CB) is characterized by persistent cough and sputum production. Studies were performed to test whether mucus hyperconcentration and increased partial osmotic pressure, in part caused by abnormal purine nucleotide regulation of ion transport, contribute to the pathogenesis of CB.Objectives: We tested the hypothesis that CB is characterized by mucus hyperconcentration, increased mucus partial osmotic pressures, and reduced mucus clearance.Methods: We measured in subjects with CB as compared with normal and asymptomatic smoking control subjects indices of mucus concentration (hydration; i.e., percentage solids) and sputum adenine nucleotide/nucleoside concentrations. In addition, sputum partial osmotic pressures and mucus transport rates were measured in subjects with CB.Measurements and Results: CB secretions were hyperconcentrated as indexed by an increase in percentage solids and total mucins, in part reflecting decreased extracellular nucleotide/nucleoside concentrations. CB mucus generated concentration-dependent increases in partial osmotic pressures into ranges predicted to reduce mucus transport. Mucociliary clearance (MCC) in subjects with CB was negatively correlated with mucus concentration (percentage solids). As a test of relationships between mucus concentration and disease, mucus concentrations and MCC were compared with FEV 1 , and both were significantly correlated.Conclusions: Abnormal regulation of airway surface hydration may slow MCC in CB and contribute to disease pathogenesis.

Transmission of avian influenza viruses from bird to human is a rare event even though avian influenza viruses infect the ciliated epithelium of human airways in vitro and ex vivo. Using an in vitro model of human ciliated airway epithelium (HAE), we demonstrate that while human and avian influenza viruses efficiently infect at temperatures of the human distal airways (37°C), avian, but not human, influenza viruses are restricted for infection at the cooler temperatures of the human proximal airways (32°C). These data support the hypothesis that avian influenza viruses, ordinarily adapted to the temperature of the avian enteric tract (40°C), rarely infect humans, in part due to differences in host airway regional temperatures. Previously, a critical residue at position 627 in the avian influenza virus polymerase subunit, PB2, was identified as conferring temperature-dependency in mammalian cells. Here, we use reverse genetics to show that avianization of residue 627 attenuates a human virus, but does not account for the different infection between 32°C and 37°C. To determine the mechanism of temperature restriction of avian influenza viruses in HAE at 32°C, we generated recombinant human influenza viruses in either the A/Victoria/3/75 (H3N2) or A/PR/8/34 (H1N1) genetic background that contained avian or avian-like glycoproteins. Two of these viruses, A/Victoria/3/75 with L226Q and S228G mutations in hemagglutinin (HA) and neuraminidase (NA) from A/Chick/Italy/1347/99 and A/PR/8/34 containing the H7 and N1 from A/Chick/Italy/1347/99, exhibited temperature restriction approaching that of wholly avian influenza viruses. These data suggest that influenza viruses bearing avian or avian-like surface glycoproteins have a reduced capacity to establish productive infection at the temperature of the human proximal airways. This temperature restriction may limit zoonotic transmission of avian influenza viruses and suggests that adaptation of avian influenza viruses to efficient infection at 32°C may represent a critical evolutionary step enabling human-to-human transmission.

Purinergic signaling pathways regulate airways defense mechanisms, including mucociliary clearance and infl ammatory responses. These pathways are activated by extracellular purines, which include adenosine triphosphate (ATP) and its metabolites adenosine diphosphate, adenosine monophosphate (AMP), and adenosine. Adenosine, in particular, has been linked to infl ammatory airways diseases, 1 including twofold to fourfold elevations in blood 2,3 and BAL fl uid 4 of subjects with asthma. Similarly, adenosine concentrations in exhaled breath condensate (EBC) are elevated in subjects with stable asthma, 5,6 increased with asthma exacerbations, 7 and decreased with successful treatment. Findings from animal models, particularly the adenosine deaminase knockout mouse, 8,9 further support a link between airway infl ammation and lung adenosine.These data suggest that purinergic signaling pathways may be active in infl ammatory lung diseases such as COPD and may be targets for therapeutic intervention. 10 Indeed, elevated airway adenosine concentrations in COPD have been inferred from studies of human airway adenosine receptors, 11 and several reviews have touted potential benefi ts of pharmacologic blockade of adenosine receptors. 10,12 Although these benefi ts are a reasonable extrapolation from the animal 8,13 and human studies, 4,5 a recent investigation suggested that airway adenosine concentrations (as measured in sputum) may actually be lower in COPD. 14 However, adenosine concentrations in respiratory samples such as sputum or BAL can be altered unpredictably by extracellular metabolism during processing or by mechanical and osmotic forces that trigger purine release during collection.

No abstract

No abstract