Functional and immune response to respiratory syncytial virus infection in aged BALB/c mice: a search for genes determining disease severity.

BACKGROUND: Recent studies have demonstrated that respiratory syncytial virus (RSV) is a significant cause of morbidity and mortality in the elderly. The cellular mechanisms that determine the host's susceptibility and severity of the disease are not well understood. In this study, we sought a mouse model of human respiratory disease by studying the functional and cellular response to RSV in aged animals. METHODS: Aged BALB/c mice (>10 months of age) were infected with human RSV (strain A2) and compared with sham-infected mice. Clinical progress of the illness was monitored by daily assessment of weight changes and mortality. The animals were sacrificed four days postinfection. Lung pathology was obtained and viral titers were measured by plaque assay. Gene expression profiles were studied from lung tissue RNA using gene array. RESULTS: RSV produced significant clinical illness in aged mice as evidenced by a 15% weight loss and a 10% mortality rate. Lung pathology revealed inflammatory changes with a predominance of neutrophils and diffuse alveolar damage. Microarray analysis revealed variable profiles of gene activation/downregulation at day 4 postinfection. RSV infection resulted in a proinflammatory response. Surprisingly, some of the genes involved in antigen-processing pathway were downregulated, specifically, genes implicated in the major histocompatibility complex (MHC) class II pathway. CONCLUSIONS: Our findings indicate that RSV infection produces profound functional and cellular changes in aged mice thus resembling the human disease described in the elderly. Further studies will be needed to understand the cellular mechanisms involved in the host response to RSV in aged mice.

Meconium enhances the release of nitric oxide in human airway epithelial cells.

Meconium aspiration syndrome (MAS) is a cause of significant morbidity and mortality in the perinatal period. Despite the clinical relevance of MAS, its pathogenesis is poorly understood and the role played by epithelial-derived metabolites not well defined. In this study, we evaluated whether exposure to meconium affects the release of nitric oxide production in human airway epithelial cells. Monolayers of A549 cells, a transformed human epithelial cell line, were incubated with various concentrations of meconium. Control cells were incubated with serum-free medium in a similar manner. The supernatant fluid was removed at various time points and assayed for nitrite production. In selected experiments, the effects of dexamethasone (10(-6) M), L-nitroarginine methyl ester (L-NAME, 10(-6) M) and indomethacin (10(-6) M) on nitrite release were evaluated. Results were obtained in terms of pmol/mg protein and expressed as % control (mean +/- SE). We found exposure to meconium produced a significant release of nitrite from A549 cells. Dexamethasone, L-NAME and indomethacin inhibited meconium-induced release of nitrite. Our findings demonstrate meconium enhances the production of nitric oxide from A549 cells suggesting that airway epithelial cells and their metabolic products may play an important role in the pathogenesis of MAS.