| The goal of this research was to investigate the role of the host response in the pathogenesis of viral respiratory disease, using influenza A viral pneumonia in mice as a model system. This study evaluated changes in cellular immunity parameters, changes in T cell populations within the lung, as well as their ability to express and secrete the proinflammatory cytokine TNF{dollar}alpha{dollar}. Splenic natural killer cell activity was significantly enhanced on days 3 and 5 postinfection (p.i.). The ability of splenocytes to proliferate and produce IL-2 was severely reduced. An increased number of cells within the lung secreted TNF{dollar}alpha{dollar} and/or expressed it on the cell membrane. Profound circulating lymphopenia, reduced lymphocyte numbers in the spleen, and increased numbers of pulmonary lymphocytes were noted as early as 24 hours p.i.; The kinetic expression of proinflammatory and immunoregulatory cytokines in lung homogenate was determined during the development of viral pneumonia. TNF{dollar}alpha{dollar}, IFN{dollar}gamma{dollar} and IL-6, were elevated by day 1 p.i. and continued to increase throughout the test period. IL-1{dollar}alpha{dollar} reached maximum levels on day 1 p.i. and decreased to baseline levels by day 4 p.i. IL-10 rapidly reached maximal levels within 24 hours of infection and remained elevated. IL-2 and IL-4 levels in the homogenate did not change from baseline levels throughout the course of infection.; This study established that levels of NO increase in the lung during the development of influenza pneumonia. The rise and peak levels of NO mirror those of IFN{dollar}gamma{dollar}, TNF{dollar}alpha{dollar}, and IL-6, measured in lung homogenate and lavage during lethal influenza virus-infections, but not those of IL-1.; Treatment with TNF{dollar}alpha{dollar}-neutralizing antibody on virus titer, TNF{dollar}alpha{dollar} levels, morbidity, mortality, and on pathologic lung lesions were compared with sham-treated controls. Severity of gross and histologic lung lesions positively correlated with peak bronchoalveolar TNF{dollar}alpha{dollar} levels and was ameliorated with anti-TNF{dollar}alpha{dollar} treatment. Survivorship was prolonged in mice by treatment with TNF-{dollar}alpha{dollar} neutralizing antibodies. Reduction of TNF{dollar}alpha{dollar} levels did not affect virus titers in the lung. |
