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Background Haemolysis occurs in a number of haematologic and non-haematologic diseases, including sickle cell disease, malaria and sepsis. Elevated extracellular haemoglobin (Hb) can trigger specific events that are associated with adverse clinical outcomes. For example, in sickle cell disease, cell-free haemoglobin has been proposed to reduce nitric oxide (NO) bioavailability and induce vascular oxidative stress and, possibly, inflammation [1]. Hydroxyurea, a drug used commonly as a therapy for sickle cell disease, may exert some of its effects by acting as a NO donor, in vivo [2]. This study aimed to compare the effects of haemolytic and inflammatory stimuli on blood vessel leukocyte recruitment in vivo. The effects of the acute administration of hydroxyurea (HU) or an NO donor on these alterations were also investigated. Methods Inflammatory or hemolytic processes were induced in C57BL/6 mice (2-4 months old) and cremaster muscles of mice were prepared for intravital microscopy (IVM), according to protocols described in figure 1. Plasma-free Hb was measured with Drabkin’s solution. Results C57BL/6 mice that received water i.v. (H2O mice) presented marked vascular haemolysis after 15 min; levels of plasma Hb were more than doubled in H2O mice, compared to mice that receiving PBS i.v. (2.57±0.43g/dL, 1.08 ±0.08g/dL Hb, respectively, p<0.01, n=3-5), and resembled those of SCD mice (data not shown). In contrast, C57BL/6 mice (n=3) that received an inflammatory stimulus (TNFa) showed no alteration in plasma free Hb levels (1.29 ±0.43 g/dL, 1.23±0.09 g/dL; PBS and TNF-a, respectively). IVM demonstrated that both the inflammatory and haemolytic stimuli induced leukocyte adhesion to vessel walls (3.57±0.84; 11.07±0.92; 7.25±1.20 [100µm -1 ]f or PBS, TNF-a and H2O, respectively, p<0.05, N=15-30 venules), as well as leukocyte extravasation (1.07±0.17; 4.02±0.39; 2.97±0.49 [per 100 µm x 50 µm] for PBS, TNF-a and H2O, respectively, p<0.05, N=15-30 venules). Surprisingly, when HU was given simultaneously with TNF-a or following H2O, this drug was able to prevent leukocyte recruitment in both models, reducing both leukocyte adhesion (7.40±0.47; 2.79±0.34 [100 µm -1 ] for TNF-a+PBS and TNF-a+HU, respectively, p<0.0001, n=30-60 venules; and 7.84±0.73; 2.41±0.37 for H2O+PBS and H2O+HU, p<0.0001, n=20-30 venules) and leukocyte extravasation (3.88±0.26; 1.22±0.18 for TNF-a+PBS and TNF-a+HU, p<0.0001, n=30-60 venules and 2.98±0.32; 1.94±0.21 for H2O+PBS and H2O+HU, p<0.0001, n=20-30 venules) and increased leukocyte rolling (18.11±1.58; 25.48±5.01 for TNF-a+PBS and TNF-a+HU, respectively, p<0.05, n=30-60 venules and 11.56±1.47; 32.47±3.54 for H2O+PBS and H2O+HU, p<0.0001, n=20-30 venules). Additionally, DEANO was also able to reverse the inflammatory process installed by TNF-a, reducing leukocyte adhesion (10.24 ±1.49; 11.45±1.40 for TNF-a before and after vehicle control, n=21-22 venules; 7.63±0.63; 3.76±0.41 for TNF-a, before and after DEANO, p<0.01; n=29-35 venules) and extravasation (1.95±0.29; 3.23±0.44 before and after vehicle control, p<0.05, n=21-22 venules; 2.49±0.25; 2.24±0.24 before and after DEANO, n=29-35 venules).

Hydroxyurea reduces leukocyte interactions with the vessel wall in a haemolytic mouse model via a possible NO/cGMP-mediated effect