Acute respiratory infections in humans are associated with the development of bronchiolitis, airway hyperresponsiveness, asthma, increased viral specific IgE, and persistent pulmonary function abnormalities but the mechanisms are unknown. Our beagle puppies develop acute bronchiolitis and histamine hyperresponsiveness with acute canine parainfluenza type 2 (CPI2) or canine adenovirus type 2 (CAV2) infections. These effects, lasting 9-14 days, parallel the clinical illness in duration and severity. Pathologically, CPI2 and CAV2 produce a uniformily patchy bronchiolitis in all lung segments which is reflected accurately by cytologic changes in bronchoalveolar lavage fluid (BALF). In other studies we have identified the target cells of CAV2 airway infections: pulmonary alveolar macrophage (PAM), nonciliated airway epithelial cells, alveolar epithelial type 2 cells, and airway neutrophils. Neither airway smooth muscle nor airway neural tissue, tissues suggested to play a role as possible mechanisms of hyperresponsiveness contained CAV2 when histamine hyperresponsiveness was prominent. Thus, we suggest that acute viral respiratory infections alter vagal tone and airway smooth muscle function indirectly through mediator release from infected cells. We also known that individual PAM are activated and produce superoxide radicals (O2-). Furthermore, substance P (SP), a neuropeptide released from sensory neurons with airway epithelial injury, is present in airways as detected by histochemical stains. Thromboxane B2 and SP are increased in BALF during acute CPI2 or CAV2 infections. In preliminary studies we successfully sensitized neonatal beagle puppies to ragweed antigen as indicated by increased serum anti- ragweed IgE concentrations and bronchoconstriction to ragweed aerosol challenge. Our proposed studies will determine if ragweed sensitized puppies have more severe CAV2 induced bronchiolitis and histamine hyperresponsiveness than nonsensitized puppies. We also will determine if activated PAM with eicosanoids or platelet activing factor (PAF) release and if airway epithelial injury with SP release are important mechanisms of CAV2 induced airway injury and histamine hyperresponsiveness and normal and ragweed sensitized puppies. The time course of mediator release as well as humoral and cellular immune responses in the lung will be determined. We also will study the effects of pharmacologic interventions on the natural history of these changes. In other studies we will determine if passive smoke exposure in utero and in early life enhance anti-ragweed and anti-viral IgE production leading to the development of chronic CAV2 induced obstructive airways disease.
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