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An essential role of high-molecular-weight kininogen in endotoxemia
Yang, Aizhen Xie, Zhanli Colman, Robert W. Dai, Jihong
Yang, Aizhen
Xie, Zhanli
Colman, Robert W.
Dai, Jihong
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Journal article
Date
2017-08-09
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Pathology and Laboratory Medicine
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https://doi.org/10.1084/jem.20161900
Abstract
In this study, we show that mice lacking high-molecular-weight kininogen (HK) were resistant to lipopolysaccharide (LPS)-induced mortality and had significantly reduced circulating LPS levels. Replenishment of HK-deficient mice with human HK recovered the LPS levels and rendered the mice susceptible to LPS-induced mortality. Binding of HK to LPS occurred through the O-polysaccharide/core oligosaccharide, consistent with the ability to bind LPS from K. pneumoniae, P. aeruginosa, S. minnesota, and different E. coli strains. Binding of LPS induced plasma HK cleavage to the two-chain form (HKa, containing a heavy chain [HC] and a light chain [LC]) and bradykinin. Both HKa and the LC, but not the HC, could disaggregate LPS. The light chain bound LPS with high affinity (Kd = 1.52 × 10−9 M) through a binding site in domain 5 (DHG15). A monoclonal antibody against D5 significantly reduced LPS-induced mortality and circulating LPS levels in wild-type mice. Thus, HK, as a major LPS carrier in circulation, plays an essential role in endotoxemia.
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Citation
Aizhen Yang, Zhanli Xie, Bo Wang, Robert W. Colman, Jihong Dai, Yi Wu; An essential role of high-molecular-weight kininogen in endotoxemia. J Exp Med 4 September 2017; 214 (9): 2649–2670. doi: https://doi.org/10.1084/jem.20161900
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Rockefeller University Press
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Journal of Experimental Medicine, Vol. 214, Iss. 9
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