Am. J. Respir. Cell Mol. Biol., Volume 20, Number 6, June, 1999 1125-1135

High Levels of Peroxynitrite Are Generated in the Lungs of Irradiated Mice Given Cyclophosphamide and Allogeneic T Cells
A Potential Mechanism of Injury after Marrow Transplantation

Imad Y. Haddad, Angela Panoskaltsis-Mortari, David H. Ingbar, Shuxia Yang, Carlos E. Milla, and Bruce R. Blazar

Departments of Pediatrics and Pulmonary Medicine, University of Minnesota, Minneapolis, Minnesota

In a murine bone-marrow transplant (BMT) model designed to determine risk factors for lung dysfunction in irradiated mice, we reported that cyclophosphamide (Cy)-induced injury and lethality depended on the infusion of donor spleen T cells. In the study reported here, we hypothesized that alveolar macrophage (AM)-derived reactive oxygen/nitrogen species are associated with lung dysfunction caused by allogeneic T cells, which stimulate nitric oxide (·NO) production, and by Cy, which stimulates superoxide production. ·NO reacts with superoxide to form peroxynitrite, a tissue-damaging oxidant. On Day 7 after allogeneic BMT, bronchoalveolar lavage fluid (BALF) obtained from mice injected with T cells contained increased levels of nitrite, which was associated with increased lactate dehydrogenase and protein levels, both of which are indices of lung injury. The injury was most severe in mice receiving both T cells and Cy. Messenger RNA (mRNA) for inducible nitric oxide synthase was detected only in murine lungs injected with T cells ± Cy. AMs obtained on Day 7 after BMT from mice receiving T cells ± Cy spontaneously generated between 20 and 40 µM nitrite in culture, versus < 2 µM generated by macrophages obtained from mice undergoing BMT but not receiving T cells. The level of 3-nitrotyrosine, the stable byproduct of the reaction of peroxynitrite with tyrosine residues, was increased in the BALF proteins of mice injected with both T cells and Cy. We conclude that allogeneic T cells stimulate macrophage-derived ·NO, and that the addition of Cy favors peroxynitrite formation. Peroxynitrite generation clarifies the dependence of Cy-induced lung injury and lethality on the presence of allogeneic T cells.

This article has been cited by other articles:

				M. Shukla, S. Yang, C. Milla, A. Panoskaltsis-Mortari, B. R. Blazar, and I. Y. Haddad Absence of host tumor necrosis factor receptor 1 attenuates manifestations of idiopathic pneumonia syndrome Am J Physiol Lung Cell Mol Physiol, May 1, 2005; 288(5): L942 - L949. [Abstract] [Full Text] [PDF]

				C. Milla, S. Yang, D. N. Cornfield, M.-L. Brennan, S. L. Hazen, A. Panoskaltsis-Mortari, B. R. Blazar, and I. Y. Haddad Myeloperoxidase deficiency enhances inflammation after allogeneic marrow transplantation Am J Physiol Lung Cell Mol Physiol, October 1, 2004; 287(4): L706 - L714. [Abstract] [Full Text] [PDF]

				G. C. Hildebrandt, L. A. Corrion, K. M. Olkiewicz, B. Lu, K. Lowler, U. A. Duffner, B. B. Moore, W. A. Kuziel, C. Liu, and K. R. Cooke Blockade of CXCR3 Receptor:Ligand Interactions Reduces Leukocyte Recruitment to the Lung and the Severity of Experimental Idiopathic Pneumonia Syndrome J. Immunol., August 1, 2004; 173(3): 2050 - 2059. [Abstract] [Full Text] [PDF]

				A. Panoskaltsis-Mortari, J. R. Hermanson, E. Taras, O. D. Wangensteen, I. F. Charo, B. J. Rollins, and B. R. Blazar Post-BMT lung injury occurs independently of the expression of CCL2 or its receptor, CCR2, on host cells Am J Physiol Lung Cell Mol Physiol, February 1, 2004; 286(2): L284 - L292. [Abstract] [Full Text] [PDF]

				M. A. Qureshi, R. E. Girgis, H. K. Dandapantula, J. Abrams, and A. O. Soubani Increased Exhaled Nitric Oxide Following Autologous Peripheral Hematopoietic Stem-Cell Transplantation: A Potential Marker of Idiopathic Pneumonia Syndrome Chest, January 1, 2004; 125(1): 281 - 287. [Abstract] [Full Text] [PDF]

				I. Y. Haddad, C. Milla, S. Yang, A. Panoskaltsis-Mortari, S. Hawgood, D. L. Lacey, and B. R. Blazar Surfactant protein A is a required mediator of keratinocyte growth factor after experimental marrow transplantation Am J Physiol Lung Cell Mol Physiol, September 1, 2003; 285(3): L602 - L610. [Abstract] [Full Text] [PDF]

				A. Panoskaltsis-Mortari, J. R. Hermanson, E. Taras, O. D. Wangensteen, J. S. Serody, and B. R. Blazar Acceleration of idiopathic pneumonia syndrome (IPS) in the absence of donor MIP-1alpha (CCL3) after allogeneic BMT in mice Blood, May 1, 2003; 101(9): 3714 - 3721. [Abstract] [Full Text] [PDF]

				I. Y. Haddad Idiopathic Pneumonia after Marrow Transplantation: When Are Antioxidants Effective? Am. J. Respir. Crit. Care Med., December 15, 2002; 166(12): 1532 - 1534. [Full Text] [PDF]

				K. S. Bhalla and R. J. Folz Idiopathic Pneumonia Syndrome after Syngeneic Bone Marrow Transplant in Mice Am. J. Respir. Crit. Care Med., December 15, 2002; 166(12): 1579 - 1589. [Abstract] [Full Text] [PDF]

				D. M. Flanagan, C. D. Jennings, S. W. Goes, B. E. Caywood, R. Gross, A. M. Kaplan, and J. S. Bryson Nitric oxide participates in the intestinal pathology associated with murine syngeneic graft-versus-host disease J. Leukoc. Biol., October 1, 2002; 72(4): 762 - 768. [Abstract] [Full Text] [PDF]

				S. Yang, C. Milla, A. Panoskaltsis-Mortari, S. Hawgood, B. R. Blazar, and I. Y. Haddad Surfactant Protein A Decreases Lung Injury and Mortality after Murine Marrow Transplantation Am. J. Respir. Cell Mol. Biol., September 1, 2002; 27(3): 297 - 305. [Abstract] [Full Text] [PDF]

				S. Yang, A. Panoskaltsis-Mortari, M. Shukla, B. R. Blazar, and I. Y. Haddad Exuberant Inflammation in Nicotinamide Adenine Dinucleotide Phosphate-Oxidase-Deficient Mice After Allogeneic Marrow Transplantation J. Immunol., June 1, 2002; 168(11): 5840 - 5847. [Abstract] [Full Text] [PDF]

				A. DUGUET, H. IIJIMA, S.-Y. EUM, Q. HAMID, and D. H. EIDELMAN Eosinophil Peroxidase Mediates Protein Nitration in Allergic Airway Inflammation in Mice Am. J. Respir. Crit. Care Med., October 1, 2001; 164(7): 1119 - 1126. [Abstract] [Full Text] [PDF]

				S. Yang, V. A. Porter, D. N. Cornfield, C. Milla, A. Panoskaltsis-Mortari, B. R. Blazar, and I. Y. Haddad Effects of oxidant stress on inflammation and survival of iNOS knockout mice after marrow transplantation Am J Physiol Lung Cell Mol Physiol, October 1, 2001; 281(4): L922 - L930. [Abstract] [Full Text] [PDF]

				B. Pelaez, J. A. Campillo, J. A. Lopez-Asenjo, and J. L. Subiza Cyclophosphamide Induces the Development of Early Myeloid Cells Suppressing Tumor Cell Growth by a Nitric Oxide-Dependent Mechanism J. Immunol., June 1, 2001; 166(11): 6608 - 6615. [Abstract] [Full Text] [PDF]

				J. R. Wright, P. Borron, K. G. Brinker, and R. J. Folz Surfactant Protein A . Regulation of Innate and Adaptive Immune Responses in Lung Inflammation Am. J. Respir. Cell Mol. Biol., May 1, 2001; 24(5): 513 - 517. [Full Text]

				S. Yang, C. Milla, A. Panoskaltsis-Mortari, D. H. Ingbar, B. R. Blazar, and I. Y. Haddad Human Surfactant Protein A Suppresses T Cell-Dependent Inflammation and Attenuates the Manifestations of Idiopathic Pneumonia Syndrome in Mice Am. J. Respir. Cell Mol. Biol., May 1, 2001; 24(5): 527 - 536. [Abstract] [Full Text]

				K. R. Cooke, G. R. Hill, A. Gerbitz, L. Kobzik, T. R. Martin, J. M. Crawford, J. P. Brewer, and J. L. M. Ferrara Hyporesponsiveness of Donor Cells to Lipopolysaccharide Stimulation Reduces the Severity of Experimental Idiopathic Pneumonia Syndrome: Potential Role for a Gut-Lung Axis of Inflammation J. Immunol., December 1, 2000; 165(11): 6612 - 6619. [Abstract] [Full Text] [PDF]

				S. YANG, A. PANOSKALTSIS-MORTARI, D. H. INGBAR, S. MATALON, S. ZHU, E. R. RESNIK, C. L. FARRELL, D. L. LACEY, B. R. BLAZAR, and I. Y. HADDAD Cyclophosphamide Prevents Systemic Keratinocyte Growth Factor-induced Up-Regulation of Surfactant Protein A after Allogeneic Transplant in Mice Am. J. Respir. Crit. Care Med., November 1, 2000; 162(5): 1884 - 1890. [Abstract] [Full Text]

				A. Panoskaltsis-Mortari, R. M. Strieter, J. R. Hermanson, K. V. Fegeding, W. J. Murphy, C. L. Farrell, D. L. Lacey, and B. R. Blazar Induction of monocyte- and T-cell-attracting chemokines in the lung during the generation of idiopathic pneumonia syndrome following allogeneic murine bone marrow transplantation Blood, August 1, 2000; 96(3): 834 - 839. [Abstract] [Full Text] [PDF]

				I. Y. Haddad, A. Panoskaltsis-Mortari, D. H. Ingbar, E. R. Resnik, S. Yang, C. L. Farrell, D. L. Lacey, D. N. Cornfield, and B. R. Blazar Interactions of keratinocyte growth factor with a nitrating species after marrow transplantation in mice Am J Physiol Lung Cell Mol Physiol, August 1, 1999; 277(2): L391 - L400. [Abstract] [Full Text] [PDF]

				R. J. Folz Mechanisms of Lung Injury after Bone Marrow Transplantation Am. J. Respir. Cell Mol. Biol., June 1, 1999; 20(6): 1097 - 1099. [Full Text]