Nitric oxide modulates MCP-1 expression in endothelial cells: implications for the pathogenesis of pulmonary granulomatous vasculitis.

Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0602, USA.
Inflammation (Impact Factor: 1.92). 09/2003; 27(4):213-23. DOI: 10.1023/A:1025036530605
Source: PubMed

ABSTRACT Monocyte chemoattractant protein-1 (MCP-1) is a pivotal mediator of angiocentric granuloma formation in glucan-induced pulmonary granulomatous vasculitis. Based on the rationale that mononuclear phagocytes retrieved from granulomas are rich sources of nitric oxide (NO) and that the recruitment of mononuclear phagocytes into lesions abates as granuloma formation slows, we tested the hypothesis that MCP-1 gene expression is regulated by a NO-sensitive mechanism. Preexposure of endothelial cell (EC) monolayers to NO donor compounds markedly reduced cytokine-induced MCP-1 expression and cytosolic-to-nuclear translocation of nuclear factor-kappa B (NF-kappaB), reversed fluctuations in endothelial reduced glutathione (GSH) pools but did not affect cGMP concentrations. The lungs of mice bearing targeted disruptions of the inducible nitric oxide synthase (iNOS) gene exhibited significantly higher concentrations of MCP-1 following glucan infusion than did those of wild-type mice. Cumulatively, these data suggest that NO suppresses MCP-1 expression by blunting the redox changes associated with cytokine-induced EC activation.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Vasculitis refers to a number of distinct disease entities characterized by cellular inflammation within and adjacent to the blood vessel wall.1 Typically, there is destruction of the vessel but leukocytoclastic vasculitis exhibits only leukocytic infiltrates within the vessel wall. Multiple classification schemes have been proposed to categorize this group of diseases (Table 59.1). Lung involvement is most common in primary idiopathic, small vessel, or antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides of Wegener’s granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome.2 However, medium vessel vasculitis of classic polyarteritis nodosa, large and medium vessel vasculitis of Takayasu’s arteritis (causing associated pulmonary hypertension), primary immune complex-mediated vasculitis of Goodpasture’s syndrome, and lupus erythematosus can all affect the lungs. The pulmonary circulation is characterized by low perfusion pressure, and large- and medium-sized pulmonary arteries are shorter in length and contain less elastin than in the systemic circulation; these factors apparently limit involvement of the larger pulmonary vessels by vasculitis. Table 59.1. Classification of pulmonary vasculitides based on size of the vessel involved.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective Many different genes or mediators have been implicated in promoting the development of vasculitis, although little is known regarding the mechanisms that normally act to suppress lesion formation. Endothelial nitric oxide synthase (eNOS) has been shown to inhibit vascular inflammation in many different model systems, but its roles in the pathogenesis of vasculitis have not been elucidated. This study was undertaken to determine the functions of eNOS in the initiation and progression of vasculitic lesion formation. MethodsMRL/MpJ-Faslpr mice lacking the gene for eNOS (Nos3−/−) were generated and comprehensively evaluated and compared to controls with regard to the development of autoimmune disease, including vasculitic lesion formation and glomerulonephritis. ResultsNos3−/− MRL/MpJ-Faslpr mice exhibited accelerated onset and increased incidence of renal vasculitis compared to Nos3+/+ controls. In contrast, no significant differences in severity of glomerulonephritis were observed between groups. Vasculitis was also observed in other organs of eNOS-deficient mice, including in the lungs of several of these animals. Ultrastructural analyses of renal lesions revealed the presence of electron-dense deposits in affected arteries, and IgG, IgA, and C3 deposition was observed in some vessels in the kidneys of Nos3−/− mice. In addition, Nos3−/− MRL/MpJ-Faslp mice showed increased levels of circulating IgG–IgA immune complexes at 20 weeks of age, compared to Nos3+/+ MRL/MpJ-Faslpr and Nos3−/− C57BL/6 mice. Conclusion These findings strongly indicate that eNOS serves as a negative regulator of vasculitis in MRL/MpJ-Faslpr mice and further suggest that NO produced by this enzyme may be critical for inhibiting lesion formation and vascular damage in human vasculitic diseases.
    Arthritis & Rheumatology 12/2012; 64(12). DOI:10.1002/art.37683 · 7.87 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hydrogen sulfide is an inflammatory mediator and is produced by the activity of the enzyme cystathionine γ-lyase (CSE) in macrophages. Previously, pharmacological inhibition of CSE has been reported to have conflicting results, and this may be due to the lack of specificity of the pharmacological agents. Therefore, this study used a very specific approach of small interfering RNA (siRNA) to inhibit the production of the CSE in an in vitro setting. We found that the activation of macrophages by lipopolysaccharide (LPS) resulted in higher levels of CSE mRNA and protein as well as the increased production of proinflammatory cytokines and nitric oxide (NO). We successfully used siRNA to specifically reduce the levels of CSE mRNA and protein in activated macrophages. Furthermore, the levels of proinflammatory cytokines in LPS-activated macrophages were significantly lower in siRNA-transfected cells compared to those in untransfected controls. However, the production levels of NO by the transfected cells were higher, suggesting that CSE activity has an inhibitory effect on NO production. These findings suggest that the CSE enzyme has a crucial role in the activation of macrophages, and its activity has an inhibitory effect on NO production by these cells.
    Applied Microbiology and Biotechnology 07/2013; DOI:10.1007/s00253-013-5080-x · 3.81 Impact Factor


Available from