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Am J Physiol Lung Cell Mol Physiol 281: L922-L930, 2001;
1040-0605/01 $5.00
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Vol. 281, Issue 4, L922-L930, October 2001

Effects of oxidant stress on inflammation and survival of iNOS knockout mice after marrow transplantation

Shuxia Yang1, Valerie A. Porter1, David N. Cornfield1,2, Carlos Milla1, Angela Panoskaltsis-Mortari2, Bruce R. Blazar2, and Imad Y. Haddad1,2

1 Division of Pulmonary and Critical Care, Department of Pediatrics, and 2 Division of Bone Marrow Transplantation, Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455

In a model of idiopathic pneumonia syndrome after bone marrow transplantation (BMT), injection of allogeneic T cells induces nitric oxide (·NO), and the addition of cyclophosphamide (Cy) generates superoxide (O<UP><SUB>2</SUB><SUP>−</SUP></UP>·) and a tissue-damaging nitrating oxidant. We hypothesized that ·NO and O<UP><SUB>2</SUB><SUP>−</SUP></UP>· balance are major determinants of post-BMT survival and inflammation. Inducible nitric oxide synthase (iNOS) deletional mutant mice (-/-) given donor bone marrow and spleen T cells (BMS) exhibited improved survival compared with matched BMS controls. Bronchoalveolar lavage fluids obtained on day 7 post-BMT from iNOS(-/-) BMS mice contained less tumor necrosis factor-alpha and interferon-gamma , indicating that ·NO stimulated the production of proinflammatory cytokines. However, despite suppressed inflammation and decreased nitrotyrosine staining, iNOS(-/-) mice given both donor T cells and Cy (BMS + Cy) died earlier than iNOS-sufficient BMS + Cy mice. Alveolar macrophages from iNOS(-/-) BMS + Cy mice did not produce ·NO but persisted to generate strong oxidants as assessed by the oxidation of the intracellular fluorescent probe 2',7'-dichlorofluorescin. We concluded that ·NO amplifies T cell-dependent inflammation and addition of Cy exacerbates ·NO-dependent mortality. However, the lack of ·NO during Cy-induced oxidant stress decreases survival of T cell-recipient mice, most likely by generation of ·NO-independent toxic oxidants.

nitric oxide; peroxynitrite; lymphocytes; macrophages; tumor necrosis factor-alpha ; idiopathic pneumonia syndrome


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