NITRIC OXIDE CONTRIBUTES TO THE PROGRESSION OF CORONARY ARTERY LESIONS IN ACUTE KAWASAKI DISEASE
Yu Xianyi1, Ichida Fukiko1, Chen Rui1, Uese Kei-ichiro1, Hirono Kei-ich1, Hamamichi Yuji1, Hashimoto Ikuo1, Futatani Takeshi1, Tsubata Shinichi1, Kumada Tokimasa2, Okada Eikichi2, Terai Masaru3, and Miyawaki Toshio1
1Departments of Pediatrics and 2Departments of Pathology-1, Toyama Medical & Pharmaceutical University, Toyama ,
3Department of Pediatrics, Chiba University, Chiba, Japan
Objective: Although nitric oxide (NO) serves many vasoprotective roles including stimulation of endothelial cell growth following arterial injury, massive release of NO, particularly synthesized by nitric oxide synthase (iNOS), causes arterial wall degeneration conversely. We investigated whether enhanced NO production may contribute to the progression of coronary arterial lesions, often seen in acute Kawasaki disease (KD).
Methods: We studied 55 patients, aged 4 months to 7 years 3 months; those with (n=24) or those without (n=31) coronary artery lesions (CAL) in acute KD. We initially measured the serum levels of nitrate/nitrite, and then determined the cellular origin of NO by flow cytometric analysis of inducible NO synthase (iNOS) expressed in leukocytes, and in coronary aneurysm and in circulating endothelial cells by immunohistochemical analysis.
Results: The serum nitrate/nitrite levels and iNOS expression in neutrophils were maximal at pretreatment, particularly marked in patients with CAL (P<0.001 and P=0.001, respectively), and declined rapidly until 2 weeks post onset. While iNOS expression monocytes and the number of iNOS positive circulating endothelial cells were maximal at 2weeks post onset, when CAL generally develops, especially higher in patients with CAL (P=0.035 and P=0.012, respectively). The immunohistochemical study showed iNOS immunoreactivity in endothelial cells and monocytes/macroph ages in coronary aneurysm in acute KD.
Conclusions: The findings in our study suggest that a neutrophil-derived excessive amount of NO, synthesized by iNOS, may play a role in early arterial wall injury, whereas monocytes/macrophages- and endothelial cells-derived NO may contribute to the progression of CAL and later vascular remodeling in acute KD.