This application proposes a series of studies in healthy and asthmatic volunteer subjects to examine possible mechanisms by which viral upper respiratory infections (URIs) precipitate asthma exacerbations. The association of infection with the common viral causes of URIs - rhinovirus, parainfluenza, influenza, respiratory synctial virus, and adenovirus - and asthma exacerbations is well established. Infection with the rhinovirus appears to be responsible for up to 50% of all severe asthma exacerbations. The mechanisms of this association are unknown. In a previous study of patients presenting to the emergency department with attacks of asthma, the investigators noted that the cellular and chemical content of the sputum produced differed from what would be predicted from the prevailing conceptual model of asthma's pathogenesis. In brief, the investigators propose that viral infection stimulates airway epithelial cells and lymphocytes to produce pro-inflammatory cytokines that differ from those produced by mast cells and Th2 lymphocytes stimulated by antigen inhalation, and that the difference in the pattern of cytokine production leads to different functional consequences, perhaps in part due to the attraction and activation of a different pattern of inflammatory cells. While the dramatic bronchial responses to allergen inhalation in people with asthma can be related to the presence of mechanisms of response that are thought to be unique to people with allergic disease, the dramatic bronchial response to viral respiratory infection in people with asthma cannot be so easily explained. The mechanisms activated by viral respiratory infection are not known to be different in asthmatic and healthy people., despite the remarkable difference in the resulting disturbances in airway function. To begin examination of possible differences in the mechanisms of response, these studies propose to use recently developed methods for comparing the airway effects of viral infection in healthy and asthmatic subjects, and for comparing the airway responses to antigen inhalation, viral infection, and antigen inhalation in the immediate post-infectious period in asthmatic subjects. The methods to be used include inoculation with rhinovirus 16, sputum induction to obtain samples of airway secretions, and quantitative RT-PCR as well as ELlSA and RIA for detection of cytokines, mast cell tryptase and chymase, mucin-like glycoproteins, and other products of interest. In addition to study of the effects of controlled, experimentally-induced infection with rhinovirus, these studies will examine possible relationships between specific viral pathogens and the magnitude and nature of airway responses by following prospectively 30 healthy and 30 asthmatic subjects for a year or longer. The airway function and inflammatory content of airway secretions of these subjects will be characterized in the baseline state and immediately after the appearance of symptoms of a community acquired URI. In this study, the method of PCR for viral primers will be used in addition to standard culture techniques to establish viral etiologies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL056385-04
Application #
6202485
Study Section
Project Start
1999-09-30
Project End
2000-08-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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