Viral, not bacterial, symptomatic upper respiratory infections (URI) frequently provoke attacks of asthma. It was previously proposed that a major mechanism in this relationship was an alteration in cell permeability to calcium, a hypothesis subsequently supported by preliminary studies with human leukocytes and the parainfluenza 3 (P-3) infected guinea pigs. It is now proposed to further determine whether or not respiratory viruses, or their symptomatic infection, enhance the rise in cystolic Ca2+ that follows cell activation, the consequence of which would lead to increased secretion of spasmogenic mediators, generation of inflammatory bronchial injury, and contraction of airway smooth muscle. To establish this hypothesis, selected calcium-dependent metabolic activities, estimates of cytoplasmic free Ca2+ by the fluorescent indicator Quin 2 and phosphatidylinosital bisphophate hydrolysis will be evaluated in human polymorphonuclear leukocytes and basophils which have been either incubated in vitro with influenza A virus or isolated from experimentally infected rhinovirus patients showing airway hyperreactivity. Human leukocytes have provided an in vitro model to monitor virus effects on selected metabolic activity. The initial studies will be conducted with PMNs and results from these will serve as guides to selected analysis with isolated human basophils. In P-3 infected guinea pigs, the calcium-dependency of airway smooth muscle and its response to substance P will be determined along with studies of basophils and pulmonary mast cells from the P-3 infected guinea pig to establish abnormalities in calcium metabolism. The P-3 infected guinea pig has shown parallel changes in airway reactivity to humans with viral respiratory infections and provides a unique opportunity to precisely analyze in vivo pulmonary function subsequent isolated airway responsiveness. Furthermore, we have developed methods to isolate from the guinea pig purified peripheral blood basophils and pulmonary mast cells. Because the sequelae of viral respiratory infections is important not only to asthma but other forms of lung disease, these studies are important to our understanding and treatment of various forms of lung disease.
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