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 caused pneumonia. Manifestations of the disease included: histological pneumonitis, pulmonary influx of lymphocytes, decreased pulmonary compliance, 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 either 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 treatment decreased the histological evidence of pneumonia and reduced the bronchoalveolar lavage lymphocyte number to one-quarter of the total measured in control-treated mice. l-NMMA treatment significantly improved survival and pulmonary compliance of HSV-1–infected mice. Strikingly, the l-NMMA–mediated suppression of pneumonia occurred despite the presence of a 17-fold higher pulmonary viral titer. Taken together, these data demonstrated a previously unrecognized role of nitric oxide in HSV-1–induced pneumonia. Of note, suppression of pneumonia occurred despite higher pulmonary virus content; therefore, our data suggest that HSV-1 pneumonia is due to aspects of the inflammatory response rather than to direct viral cytopathic effects.