Nitric oxide mediates murine cytomegalovirus-associated pneumonitis in lungs that are free of the virus.

Tanaka, Kazuo; Nakazawa, Hiroe; Okada, Kazutake; Umezawa, Kazuo; Fukuyama, Naoto; Koga, Yuichi

doi:10.1172/jci119710

Cited by 36 publications

(38 citation statements)

References 43 publications

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“…The organs, including the salivary gland, lung, and liver, were removed after exsanguination and then fixed in 3.7% formaldehyde at room temperature for 18 h. The sections were stained with hematoxylin-eosin (38). Thin sections of the salivary gland were prepared for a morphological analysis by electron microscopy (JEM-2000EX; JEOL, Tokyo, Japan) according to the method described elsewhere (37).…”

Section: Light Microscopy and Transmission Electron Microscopymentioning

confidence: 99%

Role of Nitric Oxide Synthase Type 2 in Acute Infection with Murine Cytomegalovirus

Noda

Tanaka

Sawamura

et al. 2001

The Journal of Immunology

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Whether or not NO plays a critical role in murine CMV (MCMV) infection has yet to be elucidated. In this study, we examined the role of NO in acute infection with MCMV using NO synthase type 2 (NOS2)-deficient mice. NOS2−/− mice were more susceptible to lethal infection with MCMV than NOS2+/+ mice and generated a much higher peak virus titer in the salivary gland after acute infection. A moderate increase in the MCMV titer was also observed in other organs of NOS2−/− mice such as the spleen, lung, and liver. The immune responses to MCMV infection including NK cell cytotoxicity and CTL response in NOS2−/− mice were comparable with those of NOS2+/+ mice. Moreover, the ability to produce IFN-γ is not impaired in NOS2−/− mice after MCMV infection. The peritoneal macrophages from NOS2−/− mice, however, exhibited a lower antiviral activity than those from NOS2+/+ mice, resulting in an enhanced viral replication in macrophages themselves. Treatment of these cells from NOS2+/+ mice with a selective NOS2 inhibitor decreased the antiviral activity to a level below that obtained with NOS2−/− mice. In addition, the absence of NOS2 and NOS2-mediated antiviral activity of macrophages resulted in not only an enhanced MCMV replication and a high mortality but also a consequent risk of the latency. It was thus concluded that the NOS2-mediated antiviral activity of macrophages via NO plays a protective role against MCMV infection at an early and late stage of the infection.

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Section: Light Microscopy and Transmission Electron Microscopymentioning

confidence: 99%

Role of Nitric Oxide Synthase Type 2 in Acute Infection with Murine Cytomegalovirus

Noda

Tanaka

Sawamura

et al. 2001

The Journal of Immunology

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“…The first site of viral contact with the host and main target of infection and inflammation is the airway mucosal epithelium. Epithelial cells at the airway mucosal surface have a variety of inflammatory and immune defense mechanisms to deal with virus, including expression of cytokines with chemoattractant and proinflammatory functions (4 -7), MHC class II molecules (8), ICAM-1 (9), and NO synthase 2 (NOS2) 3 (6,10).…”

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confidence: 99%

“…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).…”

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confidence: 99%

“…In this context, development of pneumonia in a murine model of influenza infection has been linked to host NOS2 expression (10,17). Although viral infection often activates NOS2 in murine models (6,10), the signaling pathways and effector mechanisms are not known. Viral mechanisms regulating NOS2 expression in human airway epithelial cells have not been studied.…”

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confidence: 99%

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

Uetani

Der

Zamanian-Daryoush

et al. 2000

The Journal of Immunology

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NO synthase 2 (NOS2) is induced in airway epithelium by influenza virus infection. NOS2 induction late in the course of viral infection may occur in response to IFN-γ, but early in infection gene expression may be induced by the viral replicative intermediate dsRNA through the dsRNA-activated protein kinase (PKR). Since PKR activates signaling pathways important in NOS2 gene induction, we determined whether PKR is a component in the signal transduction pathway leading to NOS2 gene expression after viral infection of airway epithelium. We show that NOS2 gene expression in human airway epithelial cells occurs in response to influenza A virus or synthetic dsRNA. Furthermore, dsRNA leads to rapid activation of PKR, followed by activation of signaling components including NF-κB and IFN regulatory factor 1. NOS2 expression is markedly diminished and IFN regulatory factor 1 and NF-κB activation are substantially impaired in PKR null cells. Strikingly, NOS2 induction in response to LPS is abolished in PKR null cells, confirming a central role for PKR in the general signaling pathway to NOS2.

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“…The mechanism by which CMV infection leads to CMV-IP is thought to be as follows: the lungs are the site of virus entry and also a site for the production of cytokines such as TNF-␣. 16 Thus, the stimulation of TNF-␣ production by CMV may lead to an increase of various cytokines and mediators, resulting in CMV-IP. The present study showed that patients with HLA-B51 or HLA-B52 had a significantly higher risk of CMV-IP than those without these HLA types.…”

Section: Discussionmentioning

confidence: 99%

Association of cytomegalovirus interstitial pneumonitis with HLA-type following allogeneic bone marrow transplantation

Yamada

Takatsuka

Takemoto

et al. 2000

Bone Marrow Transplant

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Summary:Certain human leukocyte antigens may increase the risk of cytomegalovirus interstitial pneumonitis, an important complication of bone marrow transplantation. The prevalence of this pneumonitis was compared between patients possessing either HLA-B51 or HLA-B52 and patients without either antigen. The role of tumor necrosis factor-␣ in cytomegalovirus interstitial pneumonitis was also studied. Among 72 patients undergoing allogeneic bone marrow transplantation at our institution during the past 5 years, HLA-B51 or -B52 was detected in 29. Among these 29 patients, 13 (45%) developed cytomegalovirus interstitial pneumonitis, a significantly higher rate (P Ͻ 0.001) than among patients without these HLA types (4/43, 9%). In the preconditioning and stable phases, tumor necrosis factor-␣ levels were higher in patients with HLA-B51 or HLA-B52 than in patients without (P Ͻ 0.05; t-test). Throughout the period from pre-conditioning to around day 40, except on day 0, tumor necrosis factor-␣ levels were also significantly higher (P Ͻ 0.05 to P Ͻ 0.001) in patients developing cytomegalovirus infection than in those without it. These results suggest that HLA-B51 and HLA-B52 may be risk factors for cytomegalovirus interstitial pneumonitis after bone marrow transplantation, with an increase of tumor necrosis factor-␣ also being involved. Bone Marrow Transplantation (2000) 25, 861-865. Keywords: cytomegalovirus interstitial pneumonitis; human leukocyte antigen; bone marrow transplantation; tumor necrosis factor-␣ Cytomegalovirus interstitial pneumonitis (CMV-IP) is a very important and common complication of bone marrow transplantation (BMT), which can influence the outcome of this procedure. There have been many reports on the risk factors, preventive measures, and treatment of CMV-IP. [1][2][3][4] We focused on the influence of human leukocyte antigen (HLA) status, investigating HLA-B51 and HLA-B52, for which an association with CMV-IP has not yet been reported. The frequency of HLA-B51 is significantly increased in patients with Behçet's disease, 5 and the same is true for HLA-B52. 6 Neutrophil dysfunction, 5,7 immunological abnormalities, 7,8 and microvascular inflammation, 9,10 caused by an increase of tumor necrosis factor (TNF)-␣ are generally accepted to occur in Behçet's disease. In the present study, the influence of HLA-B51 and HLA-B52 was assessed in patients with CMV-IP diagnosed at our institution over the past 5 years since the establishment of preventative therapy for this disease. In addition, changes of the TNF-␣ level were studied in an attempt to clarify the role of this cytokine in CMV-IP. Materials and methods PatientsThe subjects were 72 consecutive patients who were seropositive for CMV or whose donors were seropositive and who underwent allogeneic BMT at our department between April 1994 and March 1999. Before bone marrow transplantation, all patients were in good condition without any signs of infection. HLA typingA serological method was used for HLA typing. Two controls were provided for each o...

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Nitric oxide mediates murine cytomegalovirus-associated pneumonitis in lungs that are free of the virus.

Cited by 36 publications

References 43 publications

Role of Nitric Oxide Synthase Type 2 in Acute Infection with Murine Cytomegalovirus

Role of Nitric Oxide Synthase Type 2 in Acute Infection with Murine Cytomegalovirus

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

Association of cytomegalovirus interstitial pneumonitis with HLA-type following allogeneic bone marrow transplantation

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