Effects of oxidant stress on inflammation and survival of iNOS knockout mice after marrow transplantation.
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.) and a tissue-damaging nitrating oxidant. We hypothesized that.NO and O. 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.
Yang
S
S
Division of Pulmonary and Critical Care, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Porter
V A
VA
Cornfield
D N
DN
Milla
C
C
Panoskaltsis-Mortari
A
A
Blazar
B R
BR
Haddad
I Y
IY
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D003520:Cyclophosphamide / Q000494:pharmacology; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000032:analysis; D008264:Macrophages / Q000276:immunology; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D009566:Nitrates / Q000032:analysis / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000032:analysis; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology*; D011014:Pneumonia / Q000209:etiology / Q000276:immunology* / Q000401:mortality; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism
D007166:Immunosuppressive Agents; D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; C039642:peroxynitric acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D007371:Interferon-gamma; D003520:Cyclophosphamide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse