EC dysfunction is a key event of the process of atheroge-nesis. EC can release nitric oxide (NO) in response to shear stress, and the loss of NO production leads to abnormal control of vascular tone. The EC-dependent dilation of vascular diameter is reduced in the coronary artery of KD patients with aneurysms. Furthermore, Dhillon et al. demonstrate that flow-mediated dilation of brachial artery is markedly reduced in KD patients without CAL compared with control subjects, and that abnormalities of systemic EC function are present many years after resolution of acute KD.
Table I Structural, Immunological and Functional Abnormalities of EC in KD Vasculitis.
I. Pathological findings
EC degeneration and necrosis
Intimal proliferation and neoangiogenesis
II. Immunological findings
1) Increased expression of adhesion molecules on EC Endothelial-leukocyte adhesion molecule-1 (ELAM-1) Intercellular adhesion molecule-1 (ICAM-1)
Matrix metalloproteinases 2 and 9 (MMP-2 and -9) Vascular endothelial growth factor (VEGF) and its receptor (fms-like tyrosine kinase-1 receptor, flt-1)
2) Increased production of serum soluble molecules derived from EC von Willbrand factor
Intercellular adhesion molecule-1 (ICAM-1) E-selectin (CD62E) III. Functional findings
Impaired EC-dependent dilation in systemic vessels including the coronary artery
Recently, circulating endothelial cells (CECs) are reported to be observed in several diseases with vascular injury. Nakatani et al. reveal that the number of CEC also increases during the acute phase of KD. Furthermore, the number of endothelial progenitor cells (EPCs), which were derived from the bone marrow, increases during the subacute phase in KD patients with CAL. Therefore, the increased numbers of CECs and EPCs are suggested to reflect the EC damage of this disease. Although the main origin of CECs may be mature ECs that have detached from the vessel walls, CECs also contain a small population of EPCs that might be involved in both the repair of EC damage and the potential vasculogenesis.
EC injury mediated by activated neutrophils has been seen in systemic inflammatory response syndrome, acute respiratory distress syndrome, and multiple organ failure. In the acute phase of KD, circulating leukocytes, especially neutrophils, increase in number, and the neutrophil function is also activated. Pathological studies reveal that neutrophils infiltrate the CAL in the early phase of KD. The activated neutrophils also secrete a large amount of such autotoxic mediators as proteases, toxic oxygen radicals, and arachi-donic metabolites, which are believed to induce EC injury. It is thus suggested that activated neutrophil-mediated EC injury may be involved in the pathogenesis of KD vasculitis.
Although treatment with a combination of aspirin and intravenous immunoglobulin (IVIG) is generally effective for KD patients, 5 to 15 percent of the patients develop CAL. Aspirin has possible antiplatelet activity and anti-thrombotic effect. Although mechanisms of action for IVIG have still not been elucidated fully, this preparation exhibits a broad spectrum of immunomodulatory activities. However, the therapeutic efficacy of both aspirin and IVIG is not specific for EC injury in KD vasculitis. Additional therapy focused on EC for KD vasculitis will be needed in future.
Circulating endothelial cells (CECs): Endotheliums mobilized in the circulation.
Coronary artery lesions (CAL): Dilatation, aneurysm and stenosis of coronary artery.
Endothelial cells (ECs): Please erase this term in Glossary, because this definition was provided in "CECs".
Kawasaki disease (KD): Mucocutaneous Lymph Node Syndrome.
Dhillon, R., Clarkson, P., Donald, A. E., Powe, A. J., Nash, M., Novelli, V., Dillon, M. J., and Deanfield, J. E. (1996). Endothelial dysfunction late after Kawasaki disease. Circulation 94, 2103-2106. This article provides an important evidence that abnormalities of systemic endothelial function are present many years after resolution of acute KD. Gavin, P. J., Crawford, S. E., Shulman, S. T., Garcia, F. L., and Rowley, A. H. (2003). Systemic arterial expression of matrix metalloproteinases 2 and 9 in acute Kawasaki disease. Arterioscler. Thromb. Vasc. Biol. 23, 576-581.
Leung, D. Y., Cotran, R. S., Kurt-Jones, E., Burns, J. C., Newburger, J. W., and Pober, J. S. (1989). Endothelial cell activation and high interleukin-1 secretion in the pathogenesis of acute Kawasaki disease. Lancet 2, 1298-1302. This article represents convincing evidence that endothe-lial cell activation plays an important role in the pathogenesis of acute KD.
Nakatani, K., Takeshita, S., Tsujimoto, T., Kawamura, Y., Tokutomi, T., and Sekine, I. (2003). Circulating endothelial cells in Kawasaki disease. Clin. Exp. Immunol. 131, 536-540. This article represents conclusive evidence that the number of CECs increases during the acute phase of KD.
Praprotnik, S., Rozman, B., Blank, M., and Shoenfeld, Y. (2000). Pathogenic role of anti-endothelial cell antibodies in systemic vasculitis. Wien. Klin. Wochenschr. 112, 660-664. This article provides a detailed review of pathogenic role of anti-endothelial cell antibodies in systemic vasculitis including Kawasaki disease. Takahashi, K., Oharaski, T., and Naoe, S. (2001). Pathological study of postcoronary arteritis in adolescents and young adults: With reference to the relationship between sequelae of Kawasaki disease and atherosclerosis. Pediatr. Cardiol. 22, 138-142. Takeshita, S., Dobashi, H., Nakatani, K., Koike, Y., Tsujimoto, H., Hirayama, K., Kawamura, Y., Mori, K., Sekine, I., and Yoshioka, S. (1997). Circulating soluble selectins in Kawasaki disease. Clin. Exp. Immunol. 108, 446-450. Takeshita, S., Tokutomi, T., Kawase, H., Nakatani, K., Tsujimoto, H., Kawamura, Y., and Sekine, I. (2001). Elevated serum levels of matrix metalloproteinase-9 (MMP-9) in Kawasaki disease. Clin. Exp. Immunol. 125, 340-344. Yasukawa, K., Terai, M., Shulman, S. T., Toyozaki, T., Yajima, S., Kohno, Y., and Rowley, A. H. (2002). Systemic production of vascular endothelial growth factor and fms-like tyrosine kinase-1 receptor in acute Kawasaki disease. Circulation 105, 766-769.
Dr. Takeshita worked at the National Defense Medical College from 1993 to 2002, and he became a professor of Ibaraki University, Faculty of Education in 2005. He focuses on the pathogenesis and etiology of
Kawasaki disease. His work is supported by a grant for Research on Specific Diseases from the Ministry of Health, Labor and Welfare, Japan.
Dr. Nakatani worked at the National Defense Medical College from 1996 to 2000 and at Kobayashi city hospital in 2003-2004. He focuses on the pathogenesis and etiology of Kawasaki disease.
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