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Originally published online as doi:10.2353/ajpath.2009.090133 on September 17, 2009

Published online before print September 17, 2009
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(American Journal of Pathology. 2009;175:1733-1745.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.090133

Role of CD11b+ Macrophages in Intraperitoneal Lipopolysaccharide-Induced Aberrant Lymphangiogenesis and Lymphatic Function in the Diaphragm

Kyung Eun Kim*, Young-Jun Koh*, Bong-Hyun Jeon*, Cholsoon Jang*, Jinah Han*, Raghu P. Kataru*, Reto A. Schwendener{dagger}, Jin-Man Kim{ddagger} and Gou Young Koh*

From the National Research Laboratory of Vascular Biology and Department of Biological Sciences and Graduate School of Nanoscience and Technology (World Class University),* Korea Advanced Institute of Science and Technology, Daejeon, Korea; the Laboratory of Liposome Research,{dagger} Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland; and the Department of Pathology,{ddagger} Chungnam National University School of Medicine, Daejeon, Korea

Lymphatic vessels in the diaphragm are essential for draining peritoneal fluid, but little is known about their pathological changes during inflammation. Here we characterized diaphragmatic lymphatic vessels in a peritonitis model generated by daily i.p. administration of lipopolysaccharide (LPS) in mice. Intraperitoneal LPS increased lymphatic density, branching, sprouts, connections, and network formation in the diaphragm in time- and dose-dependent manners. These changes were reversible on discontinuation of LPS administration. The LPS-induced lymphatic density and remodeling occur mainly through proliferation of lymphatic endothelial cells. CD11b+ macrophages were massively accumulated and closely associated with the lymphatic vessels changed by i.p. LPS. Both RT-PCR assays and experiments with vascular endothelial growth factor-C/D blockade and macrophage-depletion indicated that the CD11b+ macrophage-derived lymphangiogenic factors vascular endothelial growth factor-C/D could be major mediators of LPS-induced lymphangiogenesis and lymphatic remodeling through paracrine activity. Functional assays with India ink and fluorescein isothiocyanate-microspheres indicated that impaired peritoneal fluid drainage in diaphragm of LPS-induced peritonitis mice was due to inflammatory fibrosis and massive attachment of CD11b+ macrophages on the peritoneal side of the diaphragmatic lymphatic vessels. These findings reveal that CD11b+ macrophages play an important role in i.p. LPS-induced aberrant lymphangiogenesis and lymphatic dysfunction in the diaphragm.


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