Suppression of Herpes Simplex Virus Type 1 (HSV-1)–induced Pneumonia in Mice by Inhibition of Inducible Nitric Oxide Synthase (iNOS, NOS2)

Abstract

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, NG-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.

Herpes simplex type 2 pneumonia

“…In a study of secondary diffuse interstitial pneumonia, Oda [12], observed that classical herpetic inclusion bodies in lungs are not always associated with viral infection, which confirms the experimental studies of Adler et al (1997) [13].…”

Respiratory syncytial virus infection of human respiratory epithelial cells enhances inducible nitric oxide synthase gene expression

“…Alternatively, NO has been implicated in the pathogenesis of infection with several neurotropic viruses [26,27], influenza virus [17], and HSV-1 [32]. The NOS inhibitor, L-NMMA, in experimental pneumonia in mice with either influenza virus [17] or HSV-1 infections [32] significantly improved pulmonary function and survival rates.…”

“…iNOS gene expression has been demonstrated in various viral infection models [16,18,19,[27][28][29][30][31][32][33][34][35] and iNOS induction is now being considered as a possible universal event in all viral infections, although almost all of these investigations have been done in animals. In this study the in vitro induction of the iNOS gene by RSV infection is demonstrated for the first time in human cells.…”

“…In vitro, for most viruses studied, pre-infection activation of cellular NOS activity is associated with inhibition of viral replication [18, 29-31, 33, 34]. The treatment of infected hosts with an inhibitor of NOS is associated with increased viral replication in the VSV [31], HSV-1 [32] infection models.…”

Central Role of Double-Stranded RNA-Activated Protein Kinase in Microbial Induction of Nitric Oxide Synthase

“…However, NO also contributes to inflammation and injury through formation of toxic reactive nitrogen intermediates (6,10,16). In this context, development of pneumonia in a murine model of influenza infection has been linked to host NOS2 expression (10,17).…”