Protective Effects of No-Albumin and Albumin on Lung Injury Induced by Hypoxia/Reoxygenation in a Mouse Model of Sickle Cell Disease.

Abstract Clinical manifestations of sickle cell disease are related to vaso-occlusive (VOC) events, which are responsible for acute and chronic organ damages. We have recently shown the beneficial effects of inhaled nitric oxide (NO) in both transgenic sickle cell (SAD) mice exposed to hypoxia/reoxygenation (H/R) and in sickle cell children with acute painful crisis (Blood102: 1097, 2003; JAMA289: 1136,2003). Polynitroxyl-albumine (PNA), nitrosylated at position 34, may represent a new therapeutic tool in acute sickle cell VOCs. In SAD mice, PNA was intraperitoneally (ip) administrated and a dose-response curve was determined. Methemoglobin (MetHb) levels and blood pressure were measured under normoxia. PNA, 300 mg/Kg twice a day (equal to 4.5 mM/Kg twice a d.), induced a significant but transitory decrease in blood pressure 60 min after ip injection, while MetHb levels did not change. The effects of PNA and human serum albumine (hsAlb) on ischemia/reperfusion (H/R) lung injury related to sickle cell disease were then studied. SAD mice were divided into 4 groups of 6 animals each: one served as normoxia untreated control. The other groups were exposed to 46 hrs hypoxia (8% O2) followed by 2 hrs normoxia: one served as untreated hypoxic group, one was treated with hsAlb (300 mg/Kg twice a day) and one with PNA (300 mg/Kg twice a day). We evaluated lung histopathology, complete blood counts, bronchoalveolar (BAL) fluid neutrophil counts, cytokine levels, which are activated by H/R stimulus and are modulated by inhaled NO (Blood102:1087, 2003). In addition to histological lung damage, H/R induced an increase in blood neutrophils, a market increase in BAL total leukocyte and neutrophil counts, an increase in BAL IL-6 and IL-1β, with no significant changes in BAL IL-10 and TNF-α levels. PNA prevented the H/R lung injury, determined a reduction in H/R mediated increase in blood neutrophils, prevented the increase in BAL total leukocyte and neutrophil counts and in BAL IL-6 and IL-1β levels, while no change was observed in BAL IL-10, TNF-α and MetHb levels. hsAlb ameliorates the H/R lung injury but it did not affect either the H/R induced blood neutrophils, and BAL cells and cytokines. These results show that the beneficial effects of PNA are similar to those observed with inhaled NO and that PNA could be therapeutically efficacious in sickle cell disease.