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Inhibition of transforming growth factor β worsens elastin degradation in a murine model of Kawasaki disease.
- Source :
-
The American journal of pathology [Am J Pathol] 2011 Mar; Vol. 178 (3), pp. 1210-20. - Publication Year :
- 2011
-
Abstract
- Kawasaki disease (KD) is an acute inflammatory illness marked by coronary arteritis. However, the factors increasing susceptibility to coronary artery lesions are unknown. Because transforming growth factor (TGF) β increases elastin synthesis and suppresses proteolysis, we hypothesized that, in contrast to the benefit observed in aneurysms forming in those with Marfan syndrome, inhibition of TGF-β would worsen inflammatory-induced coronary artery lesions. By using a murine model of KD in which injection of Lactobacillus casei wall extract (LCWE) induces coronary arteritis, we show that LCWE increased TGF-β signaling in the coronary smooth muscle cells beginning at 2 days and continuing through 14 days, the point of peak coronary inflammation. By 42 days, LCWE caused fragmentation of the internal and external elastic lamina. Blocking TGF-β by administration of a neutralizing antibody accentuated the LCWE-mediated fragmentation of elastin and induced an overall loss of medial elastin without increasing the inflammatory response. We attributed these increased pathological characteristics to a reduction in the proteolytic inhibitor, plasminogen activator inhibitor-1, and an associated threefold increase in matrix metalloproteinase 9 activity compared with LCWE alone. Therefore, our data demonstrate that in the coronary arteritis associated with KD, TGF-β suppresses elastin degradation by inhibiting plasmin-mediated matrix metalloproteinase 9 activation. Thus, strategies to block TGF-β, used in those with Marfan syndrome, are unlikely to be beneficial and could be detrimental.<br /> (Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Cell Wall chemistry
Collagen Type I metabolism
Complex Mixtures
Coronary Artery Disease metabolism
Coronary Artery Disease pathology
Coronary Vessels metabolism
Coronary Vessels pathology
Disease Models, Animal
Lacticaseibacillus casei chemistry
Matrix Metalloproteinase 9 metabolism
Mice
Plasminogen Activator Inhibitor 1 metabolism
Signal Transduction
Transforming Growth Factor beta metabolism
Tropoelastin metabolism
Elastin metabolism
Mucocutaneous Lymph Node Syndrome metabolism
Mucocutaneous Lymph Node Syndrome pathology
Protein Processing, Post-Translational
Transforming Growth Factor beta antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1525-2191
- Volume :
- 178
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The American journal of pathology
- Publication Type :
- Academic Journal
- Accession number :
- 21356372
- Full Text :
- https://doi.org/10.1016/j.ajpath.2010.11.054