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1.  Gene transfer of the Na+,K+-ATPase β1 subunit using electroporation increases lung liquid clearance in rats 
The development of non-viral methods for efficient gene transfer to the lung is highly desired for the treatment of a number of pulmonary diseases. We have developed a non-invasive procedure using electroporation to transfer genes to the lungs of rats. Purified plasmid (100 to 600 μg) was delivered to the lungs of anesthetized rats through an endotracheal tube and a series of square wave pulses were delivered via electrodes placed on the chest. Relatively uniform gene expression was observed in multiple cell types and layers throughout the lung, including airway and alveolar epithelial cells, airway smooth muscle cells, and vascular endothelial cells and was dose- and pulse length-dependent. Most importantly, no inflammatory response was detected. To demonstrate efficacy of this approach, the β1 subunit of the Na+,K+-ATPase was transferred to the lungs of rats with or without electroporation, and three days later, alveolar fluid clearance was measured. Animals electroporated with the β1 subunit plasmid showed a two-fold increase in alveolar fluid clearance and Na+,K+-ATPase activity as compared to animals receiving all other plasmids, with or without electroporation. These results demonstrate that electroporation is an effective method to increase clearance by introducing therapeutic genes (Na+,K+-ATPase) into the rat lung.
doi:10.1164/rccm.200403-313OC
PMCID: PMC4152914  PMID: 15516538
plasmid; electroporation; acute lung injury; edema
2.  Immunostimulatory Oligonucleotides Attenuate Airways Remodeling in Allergic Monkeys 
To determine whether inhaled immunostimulatory DNA sequence oligonucleotides containing CpG motifs mitigate the pathophysiologic manifestation of the asthmatic phenotype (airways hyperresponsiveness and airways remodeling), rhesus monkeys with experimentally induced allergic airways disease were treated seven times with inhaled immunostimulatory oligonucleotides (or sham) periodically for 33 weeks. Airways hyperresponsiveness was reduced twofold in immunostimulatory DNA sequence–treated compared with sham-treated monkeys. Airways from immunostimulatory oligonucleotide-treated monkeys had thinner reticular basement membranes, fewer mucous cells, fewer eosinophils, and fewer mast cells than sham-treated allergic monkeys. We conclude that inhaled immunostimulatory oligonucleotides can attenuate the magnitude of airway hyperreactivity and airways remodeling produced in nonhuman primates with experimentally induced allergic airways disease.
doi:10.1164/rccm.200404-533OC
PMCID: PMC3927836  PMID: 15306532
airway wall alterations; allergic asthma; immunostimulatory DNA sequence oligonucleotides; nonhuman primate
3.  Ventilatory Control and Airway Anatomy in Obstructive Sleep Apnea 
American journal of respiratory and critical care medicine  2004;170(11):10.1164/rccm.200404-510OC.
Ventilatory instability may play an important role in the pathogenesis of obstructive sleep apnea. We hypothesized that the influence of ventilatory instability in this disorder would vary depending on the underlying collapsibility of the upper airway. To test this hypothesis, we correlated loop gain with apnea–hypopnea index during supine, nonrapid eye movement sleep in three groups of patients with obstructive sleep apnea based on pharyngeal closing pressure: negative pressure group (pharyngeal closing pressure less than –1 cm H2O), atmospheric pressure group (between –1 and +1 cm H2O), and positive pressure group (greater than +1 cm H2O). Loop gain was measured by sequentially increasing proportional assist ventilation until periodic breathing developed, which occurred in 24 of 25 subjects. Mean loop gain for all three groups was 0.37 ± 0.11. A significant correlation was found between loop gain and apnea–hypopnea index in the atmospheric group only (r = 0.88, p = 0.0016). We conclude that loop gain has a substantial impact on apnea severity in certain patients with sleep apnea, particularly those with a pharyngeal closing pressure near atmospheric.
doi:10.1164/rccm.200404-510OC
PMCID: PMC3861244  PMID: 15317668
control of breathing; loop gain; pharyngeal closing pressure; pharyngeal collapsibility; ventilatory stability
4.  Airway Responses to Aerosolized Brevetoxins in an Animal Model of Asthma 
Florida red tide brevetoxins are sodium channel neurotoxins produced by the dinoflagellate Karenia brevis. When aerosolized, the toxin causes airway symptoms in normal individuals and patients with airway disease, but systematic exposures to define the pulmonary consequences and putative mechanisms are lacking. Here we report the effects of airway challenges with lysed cultures of Karenia brevis (crude brevetoxin), pure brevetoxin-2, brevetoxin-3, and brevetoxin-tbm (brevetoxin-2 minus the side chain) on pulmonary resistance and tracheal mucus velocity, a marker of mucociliary clearance, in allergic and nonallergic sheep. Picogram concentrations of toxin caused bronchoconstriction in both groups of sheep. Brevetoxin-tbm was the least potent, indicating the importance of the side chain for maximum effect. Both histamine H1– and cholinergic-mediated pathways contributed to the bronchoconstriction. A synthetic antagonist, β-naphthoyl-brevetoxin-3, and brevenal, a natural antagonist, inhibited the bronchoconstriction. Only crude brevetoxin and brevetoxin-3 decreased tracheal mucus velocity; both antagonists prevented this. More importantly, picomolar concentrations of the antagonists alone improved tracheal mucus velocity to the degree seen with mM concentrations of the sodium channel blocker amiloride. Thus, Karenia brevis, in addition to producing toxins that adversely affect the airways, may be a source of agents for treating mucociliary dysfunction.
doi:10.1164/rccm.200406-735OC
PMCID: PMC2650266  PMID: 15447946
bronchoconstriction; mucus transport; natural therapies

Results 1-4 (4)