Vascular pathophysiology of Sickle Cell Disease: deciphering pathophysiological influence of red blood cells on leukocytes and the endothelium.
Sickle cell disease (SCD)-associated acute vaso-occlusive painful crises (VOC) have been shown to involve not only entrapment of sickled red blood cells but also abnormal vascular phenotype in animal models with a strong rational to move forward in clinical trials of vaso modulating drugs. Furthermore, chronic vasculopathy is a growing matter of concern because silent cerebral ischemia, leg ulcers, remodeling of the bones, lungs and heart, retinopathy and renal damage affect most sickle cell anemia patients.
We focus on the mechanisms that promote or aggravate VOC and chronic microvascular damage. This latter condition is becoming a most common feature in SCD, revealed by a glomerular damage, microalbuminuria or a macroalbuminuria with subsequent risk of severe renal insufficiency. Other damages such as retinopathy, vascular remodeling and cardiac and lung remodeling and ischemia are also involved.
This latter outcome increases mortality by 50% and reduces patient survival to 4 years after its onset. Chronic renal insufficiency is thus critical contributor to morbidity and mortality associated SCD. We can anticipate that the prevalence of chronic renal failure will increase as the life expectancy of the patients is increasing too. Albuminuria is a sensitive marker of microvascular (glomerular) damage in this population and precedes the development of renal insufficiency. Albuminuria is detected in children and at 40 year, 80% of patients with SS disease had albuminuria in a recent study. We speculate that insight into underlying mechanisms involved in the pathogenesis of albuminuria in SCD nephropathy would help understanding the general microvasculopathy. Albuminuria may indicate disturbance in renal hemodynamics and chronic dysfunction of the filtration barrier in the glomerulus that precedes its onset. Indeed, SCD is a condition with a high prevalence of unexplained glomerular hyperfiltration, with a strong correlation with chronic hemolysis and leukocyte count, suggesting a mechanism involving both an increased cardiac output, a hemolysis-mediated abnormal vascular tone and glomerular damage.
- Mouse models of sickle cell disease
- Models of sickle cell vaso-occlusive crises.
- Models of SCD associated nephropathy.
- Molecular signatures of tissue inflammation in SCD.
- Metabolic cages for urine collections.
- Assessment of vascular reactivity in vitro (myograph) and in vivo (ultrasound-Doppler imaging).
- Magnetic Resonance Imaging to evaluate tissue perfusion in mice (through our Research Centre and University Paris Descartes).
- Optical Fluorescence Molecular Tomography for quantification of protease activity, vascular leak and tissue perfusion.
- Evaluation of leukocyte activation markers (FACS, RT-qPCR), and functions.
- In development: intravital videomicroscopy to study cell to endothelium interaction (rolling, adhesion, diapedesis) in living mice.
- Erythrocyte microparticles can induce kidney vaso-occlusions in a murine model of sickle cell disease.
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- Epidermal growth factor receptor promotes glomerular injury and renal failure in rapidly progressive crescentic glomerulonephritis. Bollée G, Flamant M, Schordan S, Fligny C, Rumpel E, Milon M, Schordan E, Sabaa N, Vandermeersch S, Galaup A, Rodenas A, Casal I, Sunnarborg SW, Salant DJ, Kopp JB, Threadgill DW, Quaggin SE, Dussaule JC, Germain S, Mesnard L, Endlich K, Boucheix C, Belenfant X, Callard P, Endlich N, Tharaux PL. Nat Med. 2011;17(10):1242-50.
- Endothelin in renal injury due to sickle cell disease.
Tharaux PL. Contrib Nephrol. 2011;172:185-99. Epub 2011 Aug 30. Review.
- Sickling of red blood cells through rapid oxygen exchange in microfluidic drops. Abbyad P, Tharaux PL, Martin JL, Baroud CN, Alexandrou A. Lab Chip. 2010 ;10(19):2505-12.
- Glomerular hyperfiltration in adult sickle cell anemia: a frequent hemolysis associated feature. Haymann JP, Stankovic K, Levy P, Avellino V, Tharaux PL, Letavernier E, Grateau G, Baud L, Girot R, Lionnet F. Clin J Am Soc Nephrol. 2010;5(5):756-61.
- Single europium-doped nanoparticles measure temporal pattern of reactive oxygen species production inside cells. Casanova D, Bouzigues C, Nguyên TL, Ramodiharilafy RO, Bouzhir-Sima L, Gacoin T, Boilot JP, Tharaux PL, Alexandrou A. Nat Nanotechnol. 2009;4(9):581-5.
- Second harmonic microscopy to quantify renal interstitial fibrosis and arterial remodeling. Strupler M, Hernest M, Fligny C, Martin JL, Tharaux PL, Schanne-Klein MC. J Biomed Opt. 2008;13(5):054041.
- Endothelin receptor antagonism prevents hypoxia-induced mortality and morbidity in a mouse model of sickle cell disease. Sabaa N, de Franceschi L, Bonnin P, Castier Y, Malpeli G, Debbabi H, Galaup A, Maier-Redelsperger M, Vandermeersch S, Scarpa A, Janin A, Levy B, Girot R, Beuzard Y, Leboeuf C, Henri A, Germain S, Dussaule J-C, Tharaux P-L. J. Clin. Invest. 2008; 118(5):1924-33.
- Ultrasound imaging of renal vaso-occlusive events in transgenic sickle mice exposed to hypoxic stress. Bonnin P, Sabaa N, Flamant M, Debbabi H, Tharaux PL. Ultrasound Med Biol. 2008;34(7):1076-84.