Submitted on November 2, 2005
Accepted on March 23, 2006
Protective Effects of S-Nitroso-Albumin on Lung Injury Induced by Hypoxia/Reoxygenation in a Mouse Model of Sickle Cell Disease
Lucia De Franceschi1*, Giorgio Malpeli2, Aldo Scarpa2, Annie Janin3, Eva M Muchitsch4, Paola Roncada5, Christhope Leboeuf3, Roberto Corrocher6, Yves Beuzard7, and Carlo Brugnara8
1 Clinical and Experimental Medicine, University of Verona, Verona, Italy
2 Pathology, University of Verona, Verona, Italy
3 Laboratorie de Pathologie, IUH/INSERM 02 20, Hopital S Louis, Paris, France
4 Experimental Pharmacology, Baxter Bioscience, Vienna, Austria
5 Istituto Italiano Spallanzani, Milan, Italy
6 Department of Clinical and Experimental Medicine, University of Verona, Verona, Italy
7 Laboratory of Hematopoietic Gene Therapy, INSERM U733, Centre Hayem, Hopital S Louis, Paris, France
8 Laboratory of Medicine and Pathology, Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
* To whom correspondence should be addressed. E-mail: lucia.defranceschi{at}univr.it.
Nitric oxide (NO) is a potential new therapeutic agent for sickle cell disease (SCD). We investigated the effects of the NO-donor on hypoxia-induced acute lung injury that occurs when transgenic sickle SAD mice are exposed to chronic hypoxia, a model for lung vaso-occlusive sickle-cell events. In wild-type and SAD mice, the intraperitoneal-injection (ip) of NO-Alb produce no significant hematologic changes under room-air condition, while it induced mild-temporary hypotension and inhibition of platelet aggregation. NO-Alb administration (300 mg/Kg twice a day ip, equivalent to 7.5 µM NO) in wild-type and SAD mice exposed to 46 hours hypoxia (8% oxygen) followed by 2 hours normoxia resulted in i) reduction of the hypoxia-induced-increase in blood neutrophil count; ii) prevention of hypoxia-induced increased IL-6 and IL-1
levels in bronchoalveolar-lavage; iii) reduction of the lung injury induced by hypoxia/reoxygenation; iv) prevention of thrombi formation; v) prevention of hypoxia-induced increase of lung matrix metalloproteinase 9 gene expression. These effects provide new insights into the possible use of NO-Alb in the treatment of acute lung injury in SCD.
