Role of extracellular matrix metalloproteases in sickle cell anemia

Abstract

Sickle cell anemia (SCD) results from a single point mutation, substituting valine for glutamic acid at the sixth position in the b-globin chain, producing hemoglobin S (HbS). Polymerization of deoxy HbS causes deformation, rigidification and fragilization of the red cells resulting in hemolytic anemia, vasoocclusive events and progressive functional asplenia (Costa 2000). The mechanisms involved in the vasoocclusive events of sickle cell disease are complex and remain to be elucidated. The inflammatory responses play an important role in the SCD and increased leukocyte counts, cytokine production and adhesion molecule expression are observed in sickle cell patients. With the development of the sickle transgenic mouse model the SCD inflammatory process could be further investigated (Trudel et al., 1994; Paszty et al., 1997). Studies have shown that nitric oxide (NO) plays an important role in the pathophysiology of SCD and sickle transgenic mouse model research has demonstrated that iNOS and eNOS expression are elevated in these animals, showing that NO production is altered (Bank e cols, 1996; Kaul et al., 2000). The matrix metalloproteinases (MMPs) are endopeptidases capable of cleaving one or more extracellular matrix components. MMPs are important in normal development, wound healing, and a wide variety of pathological process, including tumor growth and migration, arthritis, aortic aneurism and pulmonary diseases (Parks & Mecham, 1998; Woessner & Nagase, 2000). The aim of this study is to determine the role of MMP, as well as the relationship between NO and MMP in SCD, using sickle transgenic mouse models and blood cells of sickle cell patients.