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) 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)-alpha-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-alpha 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-alpha-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-alpha-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.
Lau
A C
AC
Cell Biology Program, Hospital for Sick Children Research Institute, University of Toronto, Toronto, Canada.
Duong
T T
TT
Ito
S
S
Wilson
G J
GJ
Yeung
R S M
RS
D000818:Animals; D000831:Animals, Newborn; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D002460:Cell Line; D016009:Chi-Square Distribution; D003331:Coronary Vessels / Q000276:immunology; D004195:Disease Models, Animal; D004318:Doxycycline / Q000627:therapeutic use*; D008213:Lymphocyte Activation / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D009080:Mucocutaneous Lymph Node Syndrome / Q000188:drug therapy* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
D000900:Anti-Bacterial Agents; D061965:Matrix Metalloproteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline