Inhibition of matrix metalloproteinase-9 activity improves coronary outcome in an animal model of Kawasaki disease

Kawasaki disease (KD) is the leading cause of acquired heart disease of children in North America. It is characterized by a massive immune activation and multi-system vasculitis, which evolves into a site-specific inflammatory response focused at the coronary arteries. Coronary artery (CA) inflammat...

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Bibliographic Details
Published in:Clinical and experimental immunology 2009-08, Vol.157 (2), p.300-309
Main Authors: Lau, A.C, Duong, T.T, Ito, S, Wilson, G.J, Yeung, R.S.M
Format: Article
Language:English
Subjects:
Analytical, structural and metabolic biochemistry
Aneurysm
Animal models
Animals
Animals, Newborn
Anti-Bacterial Agents - therapeutic use
Antibiotics
Arteritis
Biological and medical sciences
Cardiology. Vascular system
Cell activation
Cell Line
Cell walls
Chi-Square Distribution
Children
coronary artery
Coronary heart disease
Coronary Vessels - immunology
Disease Models, Animal
Doxycycline
Doxycycline - therapeutic use
Elastin
Enzymatic activity
Fundamental and applied biological sciences. Psychology
Gelatinase B
Heart
Heart diseases
Immune response
Inflammation
Kawasaki disease
Lactobacillus casei
Lymphocyte Activation - drug effects
Lymphocytes T
Matrix metalloproteinase
Matrix Metalloproteinase 9 - metabolism
Matrix Metalloproteinase Inhibitors
Medical sciences
Mice
Mice, Inbred C57BL
MMP-9
Mucocutaneous lymph node syndrome
Mucocutaneous Lymph Node Syndrome - drug therapy
Mucocutaneous Lymph Node Syndrome - immunology
Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis
Smooth muscle
Thymidine
TNF
Translational Studies
Tumor necrosis factor-a
Tumor Necrosis Factor-alpha - antagonists & inhibitors
Tumor Necrosis Factor-alpha - metabolism
Vascular system
Vasculitis
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Summary:Kawasaki disease (KD) is the leading cause of acquired heart disease of children in North America. It is characterized by a massive immune activation and multi-system vasculitis, which evolves into a site-specific inflammatory response focused at the coronary arteries. Coronary artery (CA) inflammation leads to elastin breakdown, destruction of the vessel wall and aneurysm formation. We have demonstrated recently the pivotal role of tumour necrosis factor (TNF)-α-mediated matrix metalloproteinase (MMP)-9 activity in the pathogenesis of elastin breakdown in a murine model of KD, Lactobacillus casei cell wall extract-induced coronary arteritis. Using this model, we evaluated the in vitro effects of doxycycline, an antibiotic with MMP inhibitory function, in modulating key pathogenic stages of disease leading to CA damage. Doxycycline inhibits T cell activation and TNF-α production in peripheral immune cells, as assessed by thymidine incorporation and a TNF bioassay respectively. Additionally, doxycycline inhibits directly MMP-9 enzymatic activity derived from TNF-α-stimulated vascular smooth muscle cells as assayed by zymography. More importantly, in vivo treatment of Lactobacillus casei cell wall extract (LCWE)-injected mice with doxycycline reduces significantly the incidence of CA elastin breakdown and reduces loss of elastin. Therefore, doxycycline can mitigate TNF-α-induced MMP-9-mediated coronary elastin breakdown and improve coronary outcome. Agents with the ability to inhibit both inflammation and the downstream effects of inflammation, such as MMP-9 activity, offer a promising therapeutic strategy for the management of children with KD.
ISSN:0009-9104
1365-2249
DOI:10.1111/j.1365-2249.2009.03949.x