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Effect of Gamma Tocopherol Enriched Supplementation on Response to Inhaled LPS

(funded by NIH)

Allergic asthma (AA) is the most commonly encountered respiratory disease in the United States and is a leading cause of morbidity worldwide The goals of this project are to undertake phase IIa studies of a gamma tocopherol enriched mixed tocopherol (γT-mT) preparation on chronic eosinophilic inflammation and acute increases in neutrophilic inflammation in allergic asthmatics (AAs) associated with LPS and O3 challenge. Endotoxin (lipopolysaccharide or LPS) is a component of coarse and fine mode PM, bioaerosols, tobacco and biomass smoke. Ozone (O3) is the most commonly encountered ambient air pollutant in the US. Epidemiological studies have shown that both LPS and O3 are important asthma triggers. In challenge studies of AAs, we have shown that LPS and O3 induces influx of neutrophils (PMNs) and eosinophils in AAs as well as augmenting response to inhaled allergens. O3 is also an oxidant, and both O3 and LPS increase radical production by airway cells, with both nutritional and genetically defined antioxidant deficiencies (such as the GSTM1 null genotype) being associated with increased risk for pollutant-induced asthma exacerbation. In challenge studies, we have reported that LPS and O3 PMN responses are increased in GSTM1 null volunteers. Gamma tocopherol has known antioxidant and anti-inflammatory actions. We have shown that γT prevents allergen, O3 and LPS-induced respiratory tract inflammation in rodents. Our phase I human studies with γT-mT established a dose which maintains γT and its anti-inflammatory metabolites, decreases monocyte responses to LPS and IgE-mediated basophil response to allergen. Data from our initial double-blinded, placebo controlled phase IIa study in healthy volunteers demonstrates that γT-mT inhibits LPS-induced granulocyte influx. Successful completion of this phase IIa study in AAs will guide development of a phase III efficacy study of this low cost nutriceutical intervention for prevention of pollutant-induced asthma exacerbations.

Pharmacodynamics of Hypertonic Saline on MCC in CF

(funded by CF Foundation)

A reduction in epithelial lining fluid height in cystic fibrosis (CF) as a consequence of decreased function of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) chloride channel and related increased activity of the epithelial sodium (Na) Channel (ENaC) results in impaired mucociliary clearance (MCC), mucus stasis, inflammation, infection, and ultimately progressive bronchiectasis. Inhalation of hypertonic saline (HS), through a direct osmotic effect on the airways, results in an increase in epithelial lining fluid height in vitro and a sustained increase in MCC in vivo as measured following inhalation of a radiotracer with gamma scintigraphy, following repetitive dosing. Clinically, these effects translate into a marked reduction in pulmonary exacerbation frequency in patients with established lung disease.

Based in large part on these studies, HS has gained acceptance in the CF community, with 60% of patients being treated with this therapy. However, in a recent trial in CF infants/toddlers, HS failed to yield an effect on exacerbation frequency. The question that arises, is whether HS is less effective in young children with CF, or whether the trial design and outcome measures were simply inadequate to demonstrate benefit. We set out to address the first possibility by measuring the duration of MCC effects in different populations. Interestingly, a single dose of HS had only short term effects on MCC in healthy volunteers (<1 hour), and was similarly short acting in CF children with preserved lung function. In contrast, preliminary data in adults with established CF lung disease suggest that HS results in a prolonged improvement in MCC (>4 hours), even after only a single dose. We recently proposed that the burden of airways mucus could be an important determinant of HS effects on MCC, which could explain these findings. In this proposed study, we wish to confirm the observation that HS has a prolonged effect in CF adults with established lung disease. Because the clinical benefits from HS likely rely upon having a sufficiently long duration of action, these data could provide important clues on the disease populations most likely to benefit from this therapeutic.

Novel Therapies for Muco-Obstructive Lung Diseases: Sustained Effects of Hypertonic Saline on Mucociliary Clearance and Clinical Tolerability in Subjects with Chronic Bronchitis

(funded by NIH)

Defective mucociliary clearance (MCC) is central to the pathogenesis of prevalent lung diseases, including COPD/chronic bronchitis (CB) and cystic fibrosis (CF). Our long term goals are to reach an in-depth understanding of MCC in health and disease and to develop effective therapies that support and/or restore MCC in patients with these diseases.

Our previous studies have shown that the administration of inhaled hypertonic saline (HS) acutely accelerates MCC in CF, and that repetitive use “resets” the baseline rate of MCC within 2 weeks (link to pdf download Donaldson et al, N Eng J Med 354:241-50, 2006). It is likely that the sustained effect of HS on MCC was responsible for the ~60% reduction in the frequency of pulmonary disease exacerbations, reduced antibiotic use and improved lung function in a long-term study of HS in CF. As a result, HS has now become a standard therapy for CF lung disease and its success raises optimism that similar benefits might be observed in patients with CB.