Nitric oxide targets bronchiolar epithelial cells in murine cytomegalovirus-associated disease in lungs that are free of the virus.
At 4 weeks after intraperitoneal (i.p.) injection of 0.2LD50 (50% lethal dose) of murine cytomegalovirus (MCMV) in adult BALB/c mice, productive virus and the viral DNA were detected only in the salivary glands, but not in the lungs. A single i.p. injection of anti-CD3 mAb to these mice provoked pulmonary lesions, which included a thickening of the interstitium and peribronchiolar areas, accompanied with a cellular infiltration in those areas. As a result, half of the mice died. In a histochemical analysis with anti-nitrotyrosine polyclonal Ab, bronchiolar epithelial cells were stained with this Ab, thus demonstrating that peroxynitrite, which was biochemically derived from nitric oxide (NO), injured those cells. Similarly, when T cells of iNOS+/+ mice, which had been infected with MCMV 4 weeks before, were activated by a single injection of anti-CD3 mAb, 37.5% of the mice died. Nitrotyrosine was also detected in the bronchiolar epithelial cells in these mice. In contrast, none of MCMV-infected iNOS-/- mice died after the anti-CD3 injection. No pathological changes were noted in the histological findings of the lungs of those mice. An intranasal injection of bacterial superantigen, staphylococcal enterotoxin B (SEB), demonstrated the same histopathological changes in the lungs and mortality in BALB/c mice as those in mice i.p. injected with anti-CD3. Therefore, T-cell responsiveness to stimulation with anti-CD3 or a superantigen was presumably modified by MCMV infection. MCMV-associated pneumonitis in the present study was thus mediated not by a direct viral attack but by iNOS-derived NO, which can be induced by the cytokines from the T cells. In addition, it was demonstrated that the NO produced by the cytokine-mediated pathway targeted bronchiolar epithelial cells.
Tanaka
K
K
Department of Infectious Diseases, Tokai University School of Medicine, Kanagawa, Japan. tanakaka@is.icc.u-tokai.ac.jp
Noda
S
S
Sawamura
S
S
Kabir
A M
AM
Koga
Y
Y
D000818:Animals; D000906:Antibodies / Q000276:immunology; D001980:Bronchi / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D017252:CD3 Complex / Q000276:immunology; D006566:Herpesviridae Infections / Q000473:pathology* / Q000503:physiopathology / Q000821:virology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018146:Muromegalovirus; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011024:Pneumonia, Viral / Q000473:pathology* / Q000503:physiopathology / Q000821:virology; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D000906:Antibodies; D017252:CD3 Complex; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse