Viral respiratory tract infections commonly provoke acute episodes of wheezing and can lead to more chronic alterations in lung function including increased airways resistance and a state of hyperresponsiveness to nonspecific chemical and physiologic stimuli. Indeed, viral infections are a major triggering factor for childhood asthma resulting in frequent school absenteeism, physician and emergency room visits, and hospitalizations. Corticosteroids, reluctantly used due to potential adverse side effects, are the most potent drugs available for successful treatment of many of the acute and chronic sequelae of virus-induced asthma. Unfortunately, the mechanisms by which viruses induce disease and corticosteroids reverse it are incompletely understood. We have developed a rat animal model that parallels human viral-induced asthma in a number of ways: both lead to acute and chronic airway physiologic changes (airway obstruction, airway hyperresponsiveness, and hypoxemia), both can lead to an enhanced inflammatory response within the airway, and both respond favorably to corticosteroid therapy. Based on preliminary data, we hypothesize that respiratory viral infections, along with the ensuing inflammatory response, alter phospholipid metabolism to favor an increased production of eicosanoids (thromboxanes, prostaglandins, leukotrienes, and platelet activating factor) that subsequently augment airway tone and neural reflexes, resulting in airway obstruction and hyperresponsiveness. We propose to use in vitro biochemical quantitative assays to determine if corticosteroids can attenuate these alterations through their effects on the activity of phospholipase A2 directly, and/or indirectly through the inhibitory effects on lipocortin-1. To identify mechanisms relevant to the development of airway hyperresponsiveness, we will evaluate the effects of eicosanoids and pharmacologic antagonists on neural afferent and efferent reflexes using in vivo physiologic measurements that would not be possible to assess directly in man. Finally, we will evaluate which virus-induced physiologic and biologic alterations can be transiently vs permanently altered by corticosteroid therapy. Due to the multiple parallels between the rat and human model, we anticipate that the results of our experiments will provide new direction for future developments in both the pathogenesis and treatment of this very common and important respiratory tract illness.
