Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis.

Nicholson, Susan; Bonecini-Almeida, Maria da Glória; Silva, José Roberto Lapa e; Nathan, Carl; Xie, Qiao-wen; Mumford, Richard A.; Weidner, Jeffrey R.; Calaycay, Jimmy; Geng, Juan; Boéchat, Neio; Linhares, Cristiane; Rom, William N.; Ho, John L.

doi:10.1084/jem.183.5.2293

Cited by 449 publications

(332 citation statements)

References 53 publications

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“…are obligate intracellular parasites residing primarily in host macrophages. One of the most important antimicrobial effector molecules in murine macrophages is NO ⅐ (9, 10, 34), and a role for NO ⅐ in human macrophage microbicidal function has been documented in a few instances (29,35,36). NO ⅐ is produced from arginine by iNOS, the product of the NOS2 gene.…”

Section: Discussionmentioning

confidence: 99%

An Effect of Parasite-Encoded Arginase on the Outcome of Murine Cutaneous Leishmaniasis

Gaur¹,

Roberts

Dalvi³

et al. 2007

The Journal of Immunology

112

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Classical activation of macrophages infected with Leishmania species results in expression and activation of inducible NO synthase (iNOS) leading to intracellular parasite killing. Macrophages can contrastingly undergo alternative activation with increased arginase activity, metabolism of arginine along the polyamine pathway, and consequent parasite survival. An active role for parasite-encoded arginase in host microbicidal responses has not previously been documented. To test the hypothesis that parasite-encoded arginase can influence macrophage responses to intracellular Leishmania, a comparative genetic approach featuring arginase-deficient mutants of L. mexicana lacking both alleles of the gene encoding arginase (Δarg), as well as wild-type and complemented Δarg controls (Δarg[pArg]), was implemented. The studies showed: 1) the absence of parasite arginase resulted in a significantly attenuated infection of mice (p < 0.05); 2) poorer survival of Δarg in mouse macrophages than controls correlated with greater NO generation; 3) the difference between Δarg or control intracellular survival was abrogated in iNOS-deficient macrophages, suggesting iNOS activity was responsible for increased Δarg killing; 4) consistently, immunohistochemistry showed enhanced nitrotyrosine modifications in tissues of mice infected with Δarg compared with control parasites. Furthermore, 5) in the face of decreased parasite survival, lymph node cells draining cutaneous lesions of Δarg parasites produced more IFN-γ and less IL-4 and IL-10 than controls. These data intimate that parasite-encoded arginase of Leishmania mexicana subverts macrophage microbicidal activity by diverting arginine away from iNOS.

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Section: Discussionmentioning

confidence: 99%

An Effect of Parasite-Encoded Arginase on the Outcome of Murine Cutaneous Leishmaniasis

Gaur¹,

Roberts

Dalvi³

et al. 2007

The Journal of Immunology

112

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“…Furthermore, it has been reported that human macrophages do not produce as much NO in response to IFN-␥ as murine macrophages. 24,25 Therefore, transfection or introduction directly into the peritoneal cavity of the iNOS gene should generate higher levels of NO and result in a more direct and enhanced therapeutic modality. To make the treatment better, we are also actively investigating ways to enhance NO production and a synergistic tumor cytotoxicity of NO with TNF-␣ for the treatment of drug-resistant human ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide-mediated tumor cell killing of cisplatin-based interferon-γ gene therapy in murine ovarian carcinoma

Son

Hall

2000

Cancer Gene Ther

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We have determined the role of nitric oxide (NO)-mediated tumor cell killing in the treatment of an animal model of murine ovarian carcinoma grown in the peritoneum with a combination of cisplatin and cationic liposomes containing an expression vector for interferon-␥ (IFN-␥). The approach was to determine whether the therapy was effective in mice homozygous for a disrupted inducible NO synthase (iNOS) allele; these mice were unable to produce NO in response to IFN-␥. iNOS (Ϫ/Ϫ) mice treated with both cisplatin and liposomal IFN-␥ gene did not produce a significant amount of NO in ascites (12.1 Ϯ 4.5 M), although they expressed a high level of IFN-␥ (9002 Ϯ 723 U/mL of ascitic fluid). As a result, mice died of tumors within 11-62 days. However, wild-type mice treated with both cisplatin and liposomal IFN-␥ gene produced a significant amount of NO in ascites (113.7 Ϯ 17.9 M) with a high level of IFN-␥ gene expression (9350 Ϯ 1254 U/mL of ascitic fluid) and were free of tumors for at least 80 days. This result confirmed that NO was a direct mediator of IFN-␥ cytotoxicity.

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“…NO can be synthesized by different kinds of cells. Among these cells, macrophages play a pivotal role in the inflammatory infiltrate and, in patients with tubercolosis, iNOS is expressed in alveolar macrophages [6]. Inflammatory cells produce reactive oxygen species (ROS) that, reacting with NO, form tissue-damaging NO-derived inflammatory oxidants.…”

Section: Introductionmentioning

confidence: 99%

Effect of N-acetyl-l-cysteine on peroxynitrite and superoxide anion production of lung alveolar macrophages in systemic sclerosis

et al. 2002

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Lung macrophages may play a relevant role in oxidative processes producing both superoxide anion ðO À 2 Þ and NO. In this view, an antioxidant therapy can be useful in the treatment of systemic sclerosis (SSc) patients. N-Acetylcysteine (NAC) is able to expand natural antioxidant defenses by increasing intracellular gluthatione concentration and it has been proposed as an antioxidant therapy in respiratory distress syndromes. The aim of our study was to determine whether lung macrophages obtained from SSc patient bronchoalveolar lavage (BAL) express the inducible form of nitric oxide synthase (iNOS) and whether NAC can reduce the peroxynitrite ðONOO À Þ and O À 2 production of these cells. Alveolar macrophages were isolated from BAL of 32 patients and used for the immunocytochemical determination of iNOS, and the production of ONOO À and O À 2 was measured by fluorimetric or spectrophotometric methods, respectively. Lung macrophages obtained from SSc patients expressed a higher level of iNOS compared to healthy subject cells. NAC preincubation (5 Â 10 À5 M, 24 h) significantly reduced ()21%) the ONOO À production in formyl Met-Leu-Phe (fMLP)-activated cells and slightly reduced it under resting conditions, whereas NAC preincubation was unable to modify the release of O À 2 both in basal condition and in fMLP-stimulated cells. We conclude that since SSc lung macrophages express high levels of iNOS and produce a significant quantity of ONOO À , NAC administration reduces ONOO À production and can be an useful treatment to alleviate SSc symptoms. Ó 2002 Elsevier Science (USA). All rights reserved.Keywords: Systemic sclerosis; Inducible nitric oxide synthase; N-acetylcysteine; Peroxynitrite; Superoxide anion; Alveolar macrophages Nitric oxide (NO) 1 is physiologically produced by constitutive nitric oxide synthase isoforms (cNOS) and in several pathophysiological conditions by an inducible nitric oxide synthase isoform (iNOS). In systemic sclerosis (SSc) patients, NO is increased in exhaled air [1,2] while it is decreased in those patients with pulmonary hypertension [2,3]. Moreover, serum NO levels are enhanced [4], iNOS is highly expressed in mononuclear cells infiltrating the skin [4] and peripheral blood mononuclear cells produce increased NO levels when stimulated with IL-1 [5]. NO can be synthesized by different kinds of cells. Among these cells, macrophages play a pivotal role in the inflammatory infiltrate and, in patients with tubercolosis, iNOS is expressed in alveolar macrophages [6]. Inflammatory cells produce reactive oxygen species (ROS) that, reacting with NO, form tissue-damaging NO-derived inflammatory oxidants. ROS

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Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis.

Cited by 449 publications

References 53 publications

An Effect of Parasite-Encoded Arginase on the Outcome of Murine Cutaneous Leishmaniasis

An Effect of Parasite-Encoded Arginase on the Outcome of Murine Cutaneous Leishmaniasis

Nitric oxide-mediated tumor cell killing of cisplatin-based interferon-γ gene therapy in murine ovarian carcinoma

Effect of N-acetyl-l-cysteine on peroxynitrite and superoxide anion production of lung alveolar macrophages in systemic sclerosis

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