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Suppression of herpes simplex virus type 1 (HSV-1)-induced pneumonia in mice by inhibition of inducible nitric oxide synthase (iNOS, NOS2).

Adler H, Beland JL, Del-Pan NC, Kobzik L, Brewer JP, Martin TR, Rimm IJ - J. Exp. Med. (1997)

Bottom Line: Manifestations of the disease included: histological pneumonitis, pulmonary influx of lymphocytes, decreased pulmonary compliance, and decreased survival.L-NMMA treatment significantly improved survival and pulmonary compliance of HSV-1-infected mice.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.

View Article: PubMed Central - PubMed

Affiliation: Dana-Farber Cancer Institute, Department of Pediatrics, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

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, 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.

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l-NMMA treatment decreased histological evidence of pneumonia. Mice were infected with HSV-1 and treated with l-NMMA, d-NMMA,  or PBS. Photomicrographs of lung sections stained with H/E show the histopathological changes at day 7 after infection. (A) infected, treated with PBS;  (B) infected, treated with l-NMMA; (C) infected, treated with d-NMMA; (D) uninfected, treated with l-NMMA. Original magnification: (A and C)  ×100; (B and D) ×40.
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Figure 1: l-NMMA treatment decreased histological evidence of pneumonia. Mice were infected with HSV-1 and treated with l-NMMA, d-NMMA, or PBS. Photomicrographs of lung sections stained with H/E show the histopathological changes at day 7 after infection. (A) infected, treated with PBS; (B) infected, treated with l-NMMA; (C) infected, treated with d-NMMA; (D) uninfected, treated with l-NMMA. Original magnification: (A and C) ×100; (B and D) ×40.

Mentions: Intranasal infection of mice with HSV-1 led to the development of pneumonia. Histopathological changes in infected animals were most evident at day 7 after infection. The pneumonia was characterized histologically by mononuclear infiltrates (Fig. 1, compare A with D), an increase in the histology score (Fig. 2, compare uninfected/ l-NMMA with infected/PBS), an increase in the number of cells recovered by BAL (Fig. 3, A and B, compare uninfected/l-NMMA with infected/PBS), a change in the CD4/ CD8 ratio (Table 1, compare uninfected/untreated with infected/PBS), and by a decrease in lung compliance (see below).


Suppression of herpes simplex virus type 1 (HSV-1)-induced pneumonia in mice by inhibition of inducible nitric oxide synthase (iNOS, NOS2).

Adler H, Beland JL, Del-Pan NC, Kobzik L, Brewer JP, Martin TR, Rimm IJ - J. Exp. Med. (1997)

l-NMMA treatment decreased histological evidence of pneumonia. Mice were infected with HSV-1 and treated with l-NMMA, d-NMMA,  or PBS. Photomicrographs of lung sections stained with H/E show the histopathological changes at day 7 after infection. (A) infected, treated with PBS;  (B) infected, treated with l-NMMA; (C) infected, treated with d-NMMA; (D) uninfected, treated with l-NMMA. Original magnification: (A and C)  ×100; (B and D) ×40.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196291&req=5

Figure 1: l-NMMA treatment decreased histological evidence of pneumonia. Mice were infected with HSV-1 and treated with l-NMMA, d-NMMA, or PBS. Photomicrographs of lung sections stained with H/E show the histopathological changes at day 7 after infection. (A) infected, treated with PBS; (B) infected, treated with l-NMMA; (C) infected, treated with d-NMMA; (D) uninfected, treated with l-NMMA. Original magnification: (A and C) ×100; (B and D) ×40.
Mentions: Intranasal infection of mice with HSV-1 led to the development of pneumonia. Histopathological changes in infected animals were most evident at day 7 after infection. The pneumonia was characterized histologically by mononuclear infiltrates (Fig. 1, compare A with D), an increase in the histology score (Fig. 2, compare uninfected/ l-NMMA with infected/PBS), an increase in the number of cells recovered by BAL (Fig. 3, A and B, compare uninfected/l-NMMA with infected/PBS), a change in the CD4/ CD8 ratio (Table 1, compare uninfected/untreated with infected/PBS), and by a decrease in lung compliance (see below).

Bottom Line: Manifestations of the disease included: histological pneumonitis, pulmonary influx of lymphocytes, decreased pulmonary compliance, and decreased survival.L-NMMA treatment significantly improved survival and pulmonary compliance of HSV-1-infected mice.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.

View Article: PubMed Central - PubMed

Affiliation: Dana-Farber Cancer Institute, Department of Pediatrics, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

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, 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.

Show MeSH
Related in: MedlinePlus