SUPPRESSION OF HERPES-SIMPLEX VIRUS TYPE-1 (HSV-1)-INDUCED PNEUMONIA IN MICE BY INHIBITION OF INDUCIBLE NITRIC-OXIDE SYNTHASE (INOS, NOS2)

Intranasal Herpes simplex virus type 1 (HSV-1) infection of mice cause d pneumonia. Manifestations of the disease included: histological pneu monitis, pulmonary influx of lymphocytes, decreased pulmonary complian ce, and decreased survival. Immunohistochemical staining demonstrated iNOS induction and the nitrotyrosine antigen in the lungs of infected, but not uninfected mice, suggesting that nitric oxide contributes to the development of pneumonia. To elucidate the role of nitric oxide in the pathogenesis of HSV-1 pneumonia, infected mice were treated eithe r with the inhibitor of nitric oxide synthase activity, N-G-monomethyl -L-arginine (L-NMMA), or, as a control, with PBS or D-NMMA. L-NMMA tre atment decreased the histological evidence of pneumonia and reduced th e bronchoalveolar lavage lymphocyte number to one-quarter of the total measured in control-treated mice. L-NMMA treatment significantly impr oved survival and pulmonary compliance of HSV-l-infected mice. Strikin gly, the L-NMMA-mediated suppression of pneumonia occurred despite the presence of a 17-fold higher pulmonary viral titer. Taken together, t hese data demonstrated a previously unrecognized role of nitric oxide in HSV-l-induced pneumonia. Of note, suppression of pneumonia occurred despite higher pulmonary virus content; therefore, our data suggest t hat HSV-1 pneumonia is due to aspects of the inflammatory response rat her than to direct viral cytopathic effects.