These have all been shown to contribute to sickle crises.įollowing early ex vivo work ( 11), an important in vivo imaging study in the transgenic mouse ( 3) proposed a two stage model where vaso-occlusion could be caused by adhesion of deformable sickled cells in post capillary venules followed by selective trapping of dense sickle cells. As noted by Kalambur et al ( 10), transgenic mice exhibit the following useful properties (i) red blood cells change shape when they become deoxygenated, (ii) adhesion of red blood cells, (iii) rolling and adhesion of white blood cells, (iv) stasis in post capillary venules, and (v) an inflammatory response similar to human SCD. Transgenic mice expressing human α and β S globins have proved to be a more realistic model for investigating microvascular blood flow as they exhibit many properties similar to human microvasculature ( 10). This was first demonstrated in early in vitro studies ( 8, 9) using static assays where it was shown that there was abnormal adhesion of sickle red blood cells to cultured human endothelium. Much of this work has focused on adhesion of sickle red blood cells to vascular endothelial cells as an explanation for the occurrence of vaso-occlusive crises. ( 5), Kaul ( 6), and Hebbel ( 7) provide useful perspectives on current understanding and future challenges in SCD. IVM has been a crucial tool for researchers in understanding SCD and in the development of new treatments. The first section summarises some key papers in the use of IVM in animal models, the second section discusses a smaller body of work relating to measurements on human volunteers.
Although other optical techniques, such as laser Doppler flowmetry, have been applied to investigate the bulk properties of the microcirculation, the focus in this section is on IVM as it provides the capability to image at the cellular level and has the potential for in vivo flow cytometry.
The most widely used tool by researchers in the field of SCD is IVM. Finally, their potential uses in understanding SCD are discussed. New optical techniques for imaging the microcirculation are briefly reviewed in the optical techniques for imaging the microcirculation section. Some of the progress made to date in the understanding of SCD using IVM in both transgenic mice and human volunteers are highlighted in the following section. The main aim of this brief review article is to highlight some of the new techniques developed for in vivo imaging and cytometry of the microcirculation and suggest how they could benefit SCD research. These have been widely applied in fields, such as cancer research where it is important to monitor circulating white blood cells but they have not yet been adopted by the SCD research community. Many of these have been further developed to provide the capability for in vivo flow cytometry. However, in recent years there have been numerous and significant advances in the development of techniques for imaging the microcirculation and understanding the circulation of cells within the body. IVM is a valuable tool for research into SCD with studies being carried out on transgenic mice and human volunteers. Intravital microscopy (IVM) has helped to propose an explanation for sickle crises based on cell adhesion to the vascular endothelium followed by logjamming of rigid sickle cells ( 3) and has stimulated much research into new antiadhesion therapies ( 4). Cell adhesion, inflammation, change in vessel diameter, and coagulation all play roles and are better understood using in vivo models. This also guided research into new treatments and although gelation plays a significant role in SCD it is not the only factor. The condition is characterized by blockages of the microcirculation, which cause painful episodes (crises).Įarly work focused on the gelation of sickled red blood cells in vitro and is summarized by Eaton and Hofrichter ( 2). SCD is caused by the inheritance of the sickle β globin gene (β S) and is the homozygous state (SS) when this gene is inherited from both parents. Life expectancy is shortened, with studies reporting an average life expectancy of 42 and 48 years for males and females, respectively ( 1). Sickle cell disease (SCD) is the most common genetic condition worldwide and it is estimated that 300,000 babies are born with the condition every year and that 5% of the global population (∼340 million) carry the genetic trait.
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