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Prepublished online as a Blood First Edition Paper on April 10, 2003; DOI 10.1182/blood-2002-07-2135. This Article Full Text (PDF) All Versions of this Article: 2002-07-2135v1 102/3/1087    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by De Franceschi, L. Articles by Beuzard, Y. Search for Related Content PubMed PubMed Citation Articles by De Franceschi, L. Articles by Beuzard, Y. Social Bookmarking                   What's this? Submitted July 18, 2002 Accepted March 20, 2003 Inhaled nitric oxide protects transgenic SAD mice from sickle cell disease-specific lung injury induced by hypoxia/reoxygenation Lucia De Franceschi*, Antonella Baron, Aldo Scarpa, Christophe Adrie, Anne Janin, Stefano Barbi, Jean Kister, Philippe Rouyer-Fessard, Roberto Corrocher, Philippe Leboulch, and Yves Beuzard Clinical and Experimental Medicine, University of Verona, Verona, Italy Pathology, University of Verona, Verona, Italy Laboratory of Gene Therapy, IUH, Hopital St. Louis, Paris, France Laboratory of Pathology, INSERM, ERM 02 20 IUH, Hopital St. Luis, Paris, France Laboratory of Hematology, INSERM, U 473 Bicetre Hopital, Le Kremlin Bicetre, France Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA; Harvard Medical School and Division of Genetics, Department of Medicine, Brigham & Women's Hospital, Boston, MA, USA * Corresponding author; email: lucia.defranceschi{at}univr.it. Central to the pathophysiology of sickle cell disease are the vaso-occlusive events which lead to tissue damages and life threatening complications. Lungs are particularly vulnerable to vaso-occlusion because of their specific vasculature. We developed a mouse model of hypoxia/reoxygenation lung injury closely mimicking the lung pathology of human sickle cell patients. This model involves the exposure of SAD transgenic sickle mice to hypoxia (8% oxygen) for 4, 10, 46 hours followed by 2 hours reoxygenation. Gene expression profiling of SAD lung tissue pointed to the specific induction of genes involved in the response to ischemic stress and microcirculation remodeling: Hspcb, Hsp86-1, Nfe2l2, Ace and Fgf7. Hypoxia/reoxygenation also induced a marked increase in bronchoalveolar (BAL) total leukocyte and neutrophil counts, BAL total protein content and BAL TNF- , IL-6, IL1 and MIP-2 levels, all indicators of enhanced inflammatory response as compared to control mice. Nitric oxide (NO) was administered to SAD mice. NO (40 ppm) inhalation protected SAD mice from the histopathological lesions of ischemic/reperfusion lung injury with corresponding normalization and/or modulation of tissue gene expression profiles. Inhaled NO: (i) significantly reduced the increase in BAL total protein content, BAL total leukocyte and neutrophil counts; (ii) modulated BAL cytokine network and (ii) did not affect hemoglobin and methemoglobin levels. The present study provides evidences for the beneficial effects of inhaled NO in pulmonary injury induced by hypoxia/reoxygenation in a mouse model of SCD and opens new avenues in drug design based upon tissue gene expression profiling. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. De Franceschi, O. S. Platt, G. Malpeli, A. Janin, A. Scarpa, C. Leboeuf, Y. Beuzard, E. Payen, and C. 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Doctor Extrapulmonary effects of inhaled nitric oxide: role of reversible s-nitrosylation of erythrocytic hemoglobin. Proceedings of the ATS, January 1, 2006; 3(2): 153 - 160. [Abstract] [Full Text] [PDF] L. De Franceschi, G. Malpeli, A. Janin, E. Muchitsch, A. Scarpa, P. Leboulch, C. Leboeuf, Y. Beuzard, and C. Brugnara Protective Effects of No-Albumin and Albumin on Lung Injury Induced by Hypoxia/Reoxygenation in a Mouse Model of Sickle Cell Disease. Blood (ASH Annual Meeting Abstracts), November 16, 2004; 104(11): 3580 - 3580. [Abstract] A. Solovey, R. Kollander, A. Shet, L. C. Milbauer, S. Choong, A. Panoskaltsis-Mortari, B. R. Blazar, R. J. Kelm Jr, and R. P. Hebbel Endothelial cell expression of tissue factor in sickle mice is augmented by hypoxia/reoxygenation and inhibited by lovastatin Blood, August 1, 2004; 104(3): 840 - 846. [Abstract] [Full Text] [PDF]

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