Protective effects of S-nitrosoalbumin on lung injury induced by hypoxia-reoxygenation in mouse model of sickle cell disease.
Nitric oxide (NO) is a potential new therapeutic agent for sickle cell disease (SCD). We investigated the effects of NO donor on hypoxia-induced acute lung injury that occurs when transgenic sickle cell SAD mice are exposed to chronic hypoxia, a model for lung vasoocclusive sickle cell events. In wild-type and SAD mice, intraperitoneal injection of S-nitrosoalbumin (NO-Alb) produced no significant hematologic changes under room air conditions, whereas it induced mild temporary hypotension and inhibition of platelet aggregation. NO-Alb administration (300 mg/kg ip twice a day, equivalent to 7.5 microM NO) in wild-type and SAD mice exposed to 46 h of hypoxia (8% oxygen) followed by 2 h of normoxia resulted in 1) reduction of the hypoxia-induced increase in blood neutrophil count, 2) prevention of hypoxia-induced increased IL-6 and IL-1beta levels in bronchoalveolar lavage, 3) reduction of the lung injury induced by hypoxia-reoxygenation, 4) prevention of thrombus formation, and 5) 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.
de Franceschi
Lucia
L
Section of Internal Medicine, Department of Clinical and Experimental Medicine, University of Verona, Italy. lucia.defranceschi@univr.it
Malpeli
Giorgio
G
Scarpa
Aldo
A
Janin
Anne
A
Muchitsch
Eva Maria
EM
Roncada
Paola
P
Leboeuf
Christhope
C
Corrocher
Roberto
R
Beuzard
Yves
Y
Brugnara
Carlo
C
D000755:Anemia, Sickle Cell / Q000150:complications*; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D004341:Drug Evaluation; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D000860:Hypoxia / Q000150:complications*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009603:Nitroso Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D010974:Platelet Aggregation / Q000187:drug effects; D011668:Pulmonary Veno-Occlusive Disease / Q000517:prevention & control*; D015427:Reperfusion Injury / Q000150:complications*; D012710:Serum Albumin, Bovine / Q000494:pharmacology* / Q000627:therapeutic use
D009603:Nitroso Compounds; C091665:S-nitrosoalbumin; D012710:Serum Albumin, Bovine; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse