Endogenous nitric oxide protects against T cell-dependent lethality during graft-versus-host disease and idiopathic pneumonia syndrome.
The pathogenesis of idiopathic pneumonia syndrome (IPS), a noninfectious pulmonary complication of allogeneic bone marrow transplantation (BMT), has not been fully elucidated. However, several contributing factors have been proposed, including lung injury caused by reactive oxygen and nitrogen intermediates during preconditioning and development of graft-vs-host disease (GVHD). Studies on the role of reactive oxygen and nitrogen intermediates in IPS have yielded conflicting results. We have described a murine model of IPS, in which the onset of lung inflammation was delayed by several weeks relative to GVHD. This study evaluated whether the delay in onset of IPS was due to slow turnover of NO-producing, immunosuppressive alveolar macrophages (AM) following BMT. The results indicated that AM were immunosuppressive due to synthesis of NO. However, NO production and immunosuppressive activity by AM did not decline after BMT, but rather remained elevated throughout the 12-wk development of GVHD and IPS. In a 14-day model of IPS, continuous inhibition of NO with aminoguanidine (AG) reduced signs of IPS/GVHD, but also led to higher mortality. When AG treatment was initiated after onset of IPS/GVHD, rapid mortality occurred that depended on the severity of IPS/GVHD. AG-enhanced mortality was not due to inhibition of marrow engraftment, elevated serum TNF-alpha, liver injury, or hypertensive responses. In contrast, T cells were involved, because depletion of CD4(+) lymphocytes 24 h before AG treatment prevented mortality. Thus, NO production following allogeneic BMT affords a protective effect that helps down-regulate injury caused by T cells during GVHD and IPS.
Hongo
David
D
Department of Microbiology, Immunology, and Molecular Genetics, College of Medicine, University of Kentucky, Lexington, 40536, USA.
Bryson
J Scott
JS
Kaplan
Alan M
AM
Cohen
Donald A
DA
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D006086:Graft vs Host Disease / Q000150:complications* / Q000209:etiology / Q000276:immunology; D006146:Guanidines / Q000494:pharmacology; D008212:Lymphocyte Depletion; D016676:Macrophages, Alveolar / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D009573:Nitrites / Q000097:blood; D011014:Pneumonia / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D011828:Radiation Chimera; D013154:Spleen / Q000166:cytology; D013481:Superoxides / Q000378:metabolism; D013577:Syndrome; D013601:T-Lymphocytes / Q000637:transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D006146:Guanidines; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D009569:Nitric Oxide; C004479:pimagedine