While there has been a tremendous advancement in the understanding of the pathophysiology of asthma, both the prevalence and mortality from this disease are increasing. Although asthma is a syndrome comprised of complex interactions of events both externally and internally, airways inflammation plays a prominent role in the overall course. Thus, the specific aims of the two projects presented in this grant focus on interrupting the inflammatory cascade in asthmatic patients. Inhaled glucocorticoids are now suggested to be first line medications in asthma treatment, yet there is not a clear standardized clinical model that can compare one type of inhaled glucocorticoid to another or varying doses to each other.
The specific aim of the first project is to develop a standardized clinical model for inhaled glucocorticoid testing by introducing a """"""""prednisone milligram equivalent"""""""" scale. In doing so, one inhaled agent can be tested against another in regard to beneficial and detrimental effects. Additionally, dosing schedules of different strengths and times can also be adequately compared. This will allow objective measures to be followed by clinicians, regulatory boards and the pharmaceutical industry, thereby improving patient care for all age groups. The second project focuses on """"""""target cell - specific drugs"""""""", initially separately and then in combination. The four novel agents to be investigated are inhaled interleukin-1 receptor antagonist (macrophage), inhaled heparin (eosinophil, mast cell), oral cyclosporin (T-lymphocyte) and erythromycin (neutrophil). Once the individual target cell medication has been evaluated, then the most promising medications will be selected for combination trials. It is postulated that combination low dose regimens will provide comprehensive control of airway inflammation while minimizing adverse effects in moderate to severe asthmatic patients. Using low dose combination regimens may replace the necessity of using oral glucocorticoids in certain asthmatic patients and thereby eliminating the severe glucocorticoid complications that are commonly seen in these patients. Both projects will also use bronchoalveolar lavage/biopsy and/or plasma markers of inflammation to identify the modes of action of these agents; also to determine if these markers can be used to measure the anti-inflammatory effect of these therapeutic interventions. The Asthma Clinical Research Network will provide the opportunity to address these as well as other critical therapeutic issues in the management of asthma.
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| Brehm, John M; Ramratnam, Sima K; Tse, Sze Man et al. (2015) Stress and Bronchodilator Response in Children with Asthma. Am J Respir Crit Care Med 192:47-56 |
| Israel, Elliot; Lasky-Su, Jessica; Markezich, Amy et al. (2015) Genome-wide association study of short-acting ?2-agonists. A novel genome-wide significant locus on chromosome 2 near ASB3. Am J Respir Crit Care Med 191:530-7 |
| Lambert, Allison; Drummond, M Bradley; Wei, Christine et al. (2015) Diagnostic accuracy of FEV1/forced vital capacity ratio z scores in asthmatic patients. J Allergy Clin Immunol 136:649-653.e4 |
| Duan, Q L; Lasky-Su, J; Himes, B E et al. (2014) A genome-wide association study of bronchodilator response in asthmatics. Pharmacogenomics J 14:41-7 |
| Raissy, Hengameh H; Kelly, H William; Harkins, Michelle et al. (2013) Inhaled corticosteroids in lung diseases. Am J Respir Crit Care Med 187:798-803 |
| Szefler, Stanley J (2012) Advances in pediatric asthma in 2011: moving forward. J Allergy Clin Immunol 129:60-8 |
| Szefler, Stanley J; Busse, William W (2012) The long-acting ?-adrenergic agonist controversy in asthma: troublesome times! J Allergy Clin Immunol 130:1256-9 |
| Tantisira, Kelan G; Damask, Amy; Szefler, Stanley J et al. (2012) Genome-wide association identifies the T gene as a novel asthma pharmacogenetic locus. Am J Respir Crit Care Med 185:1286-91 |
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