Respiratory syncytial virus (RSV)-induced acute wheezing syndromes produce great morbidity among children. Inflammation is probably a key factor in the pathogenesis of wheezing, but the inflammatory pathways resulting in virus-induced wheezing are unknown. RSV induces production of the chemokines IL-8 and RANTES by respiratory epithelial cells in culture. These chemokines are potent chemotactic or priming agents for leukocytes which may cause bronchospasm, edema, and airway hyperreactivity. We hypothesize that individuals who wheeze during RSV infection have greater respiratory epithelia chemokine production than those who do not wheeze during viral infections. Nasal epithelium is susceptible to RSV infection and can be sampled noninvasively in children, and available evidence suggests that nasal inflammation reflects or influences the lower airway in humans. We therefore propose a series of studies which will determine nasal epithelial chemokine responses to RSV and their relationship to inflammation, memory T cell responses, and wheezing.
The specific aims of this proposal are to determine (1) the time course of, cellular sources of, and effects of antiinflammatory agents on epithelial chemokine production during human RSV respiratory illnesses; (2) the nasal epithelial subtypes and infection status of the cells producing chemokines during RSV infections; (3) if the nasal chemokine and/or memory T lymphocyte cytokine responses to RSV differ between children who do vs. Do not manifest wheezing with RSV infection; and (4) if RSV-induced chemokine responses by nasal epithelial cells are greater in cells cultured from subjects with vs. Without recurrent wheezing. Studies will include serial nasal lavage and mucosal biopsies obtained from children with naturally-acquired RSV infections and from adults with experimental RSV infections. Chemokine production and cell types of origin in respiratory mucosa will be determined using a combination of ELISA, RT-PCR, and immunohistochemistry. In experimental RSV infections of adults, the effects of topical antiinflammatory agents on nasal inflammation and chemokine production will be determined. Production of cytokines by cultured T lymphocytes stimulated with RSV antigens will be measured by RT-PCR, in situ hybridization, and ELISA. Nasal epithelial cell cultures established from subjects with and without recurrent wheezing will be infected with RSV for comparison of chemokine induction responses. These studies will establish the kinetics of RSV-induced epithelial chemokine induction in the upper respiratory tract, its relationship to common acute childhood wheezing syndromes, and the relative degree to which epithelial and T lymphocyte cytokine responses correlate with susceptibility for wheezing with acute RSV infection. Definition of specific epithelium-driven inflammatory pathways triggered by RSV infections should lead to identification of future therapies or preventive strategies for RSV-induced respiratory illnesses.
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