The rhinovirus (RV) common cold often provokes wheezing in patients with asthma. Although the consequences of such infections are often substantial, the precise mechanism by which RV upper respiratory illnesses increase asthma have yet to be fully established. The overall objective of this proposal is to establish the links among RV infections and alterations in biologic and physiologic events which present clinically as asthma. To accomplish this goal, we developed an in vivo human model which allows assessment and correlation of airway physiology and biology during an experimental RV16 infection. Using this approach, we have established that intranasal inoculation with live RV16 of allergic subjects causes a significant increase in airway responsiveness and in probability for the development of a late allergic reaction to inhaled antigen. Based upon these observations, we hypothesize that a principal mechanism for RV- provoked asthma is viral activation of airway cells to secret pro- inflammatory cytokines, which amplify allergic bronchial inflammation by: (1) increasing the local expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), (2) promoting greater recruitment of inflammatory cells, and (3) by directly potentiating inflammatory cell function. Furthermore, we propose that RV infects cells in the lower airways to cause these changes in the lung, and thus leads to a more persistent increase in bronchial inflammation and responsiveness after the acute illness. To confirm these hypotheses and thereby establish mechanisms for RV-provoked asthma, patients with allergic rhinitis and asthma will be given an experimental intranasal RV16 infection and then undergo bronchoscopy, segmental bronchoprovocation with antigen, lavage and biopsy. Using this approach, the effect of RV16 illness on selected cytokine mRNA will be determined by solution and in situ hybridization; further, bronchoalveolar lavage fluid, obtained immediately and 48 hrs after segmental antigen challenge, will be analyzed by ELISA techniques for cytokines. The effect of RV16 illness on ICAM-1 expression will be determined by flow cytometry of airway eosinophils, lymphocytes, and epithelial cells, quantitation of soluble ICAM-1 in lavage fluid, and in situ hybridization of biopsy tissue and lavage cells. Finally, nasal and bronchial fluid, cells, and tissues will be evaluated for RV16 infection by culture and in situ hybridization with an RV16 oligonucleotide probe. These findings will be correlated with concomitant changes in airway inflammatory mediator release, cellular components of inflammation, and pulmonary physiology. From these experiments we will understand and establish, more specifically, the immunobiology of the airway response to RV and mechanisms of virus-induced bronchial inflammation, hyperresponsiveness, and asthma.
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