Role of p38 and inducible nitric oxide synthase in the in vivo dopaminergic cells’ degeneration induced by inflammatory processes after lipopolysaccharide injection

The role of nitric oxide in the immune response to allogeneic tissue was explored in an in vivo cardiac transplant model in the rat. Nitric oxide production during organ rejection was demonstrated by elevations in systemic serum nitrite/nitrate levels and by electron paramagnetic resonance spectroscopy. Messenger RNA for the inducible nitric oxide synthase enzyme was detected in the rejecting allografted heart, but not in the nonrejecting isografted heart. The enzyme was demonstrated to be biologically active by the in vitro conversion of L-arginine to L-citrulline and was immunohistochemically localized to the infiltrating inflammatory cells. Treatment with aminoguanidine, a preferential inhibitor of the inducible nitric oxide synthase isoform, prevented the increased nitric oxide production in the transplanted organ and significantly attenuated the pathogenesis of acute rejection. Aminoguanidine treatment prolonged graft survival, improved graft contractile function, and significantly reduced the histologic grade of rejection. These results suggest an important role for nitric oxide in mediating the immune response to allogeneic tissue. Inhibition of inducible nitric oxide synthase may provide a novel therapeutic modality in the management of acute transplant rejection and of other immune-mediated processes.

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Geldanamycin inhibits hemorrhage-induced increases in caspase-3 activity: role of inducible nitric oxide synthase

Journal of Applied Physiology ◽

10.1152/japplphysiol.00100.2007 ◽

2007 ◽

Vol 103 (3) ◽

pp. 1045-1055 ◽

Cited By ~ 13

Author(s):

Juliann G. Kiang ◽

Phillip D. Bowman ◽

Xinyue Lu ◽

Yansong Li ◽

Brian W. Wu ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Inducible Nitric Oxide Synthase ◽

Caspase 3 ◽

Gene Transfection ◽

Organ Injury ◽

Molecular Events ◽

Oxide Synthase ◽

Inducible Nitric Oxide

Hemorrhage has been shown to increase inducible nitric oxide synthase (iNOS) and deplete ATP levels in tissues and geldanamycin limits both processes. Moreover, it is evident that inhibition of iNOS reduces caspase-3 and increases survival. Thus we sought to identify the molecular events responsible for the beneficial effect of geldanamycin. Hemorrhage in mice significantly increased caspase-3 activity and protein while treatment with geldanamycin significantly limited these increases. Similarly, geldanamycin inhibited increases in proteins forming the apoptosome (a complex of caspase-9, cytochrome c, and Apaf-1). Modulation of the expression of iNOS by iNOS gene transfection or siRNA treatment demonstrated that the level of iNOS correlates with caspase-3 activity. Our data indicate that geldanamycin limits caspase-3 expression and protects from organ injury by suppressing iNOS expression and apoptosome formation. Geldanamycin, therefore, may prove useful as an adjuvant in fluids used to treat patients suffering blood loss.

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A Novel Role of Lactosylceramide in the Regulation of Lipopolysaccharide/Interferon- -Mediated Inducible Nitric Oxide Synthase Gene Expression: Implications for Neuroinflammatory Diseases

Journal of Neuroscience ◽

10.1523/jneurosci.1271-04.2004 ◽

2004 ◽

Vol 24 (26) ◽

pp. 5942-5954 ◽

Cited By ~ 43

Author(s):

R. Pannu

Keyword(s):

Gene Expression ◽

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Inducible Nitric Oxide Synthase ◽

Oxide Synthase ◽

Inducible Nitric Oxide

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