This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.(from CRISP website)Viral respiratory tract infections are an important cause of asthma exacerbations. Rhinoviruses (RV) are the most common type detected in these patients. We have evidence that RV infect the lower airway, and stimulate the generation of proinflammatory mediators leading to recruitment of neutrophils which then cause airway injury including epithelial damage and increased mucus secretion. These changes result in airway obstruction, hyper-responsiveness and increased asthma symptoms. Since asthma exacerbations develop only in a subset of asthma patients who suffer a viral respiratory tract infection, host susceptibility factors including decreased generation of antiviral factors or increased release of proinflammatory mediators have been suspected to play a role in the pathogenesis of these attacks. We therefore, hypothesize that virus-induced asthma exacerbation (VIAX) with RV infections are the result of enhanced neutrophil recruitment and activation in the lower airway with subsequent intraluminal airway obstruction and airway parenchymal uncoupling. We further propose that this enhanced neutrophilic inflammatory response is seen in a subset of asthma patients with altered antiviral responses and increased generation of proinflammatory responses to RV. To test this hypothesis we will determine the physiological consequences of VIAX on lung function including intraluminal bronchial obstruction and airway-parenchymal uncoupling. We will also use radiological imaging with CT scans, 3He-MRI, and 18FDG PET to determine the functional and structural changes in the lung during VIAX and to determine the relationship of these changes to observed pulmonary physiology. Finally we will determine the mechanisms of lower airway inflammation associated with the VIAX by analysis of sputum and bronchial lavage cells and mucosal biopsies, determine the relationship of these virus-induced effects to airflow obstruction and lung structure, and begin to determine the genetic host susceptibility factors that may regulate these processes. From these observations, we will be able to better define the mechanisms of VIAX and hopefully help develop improved treatment.
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