Published online before print September 17, 2009

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Copyright © 2009 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2009.090133

Accepted for publication June 22, 2009.

Article

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

Kyung Eun Kim^*, Young-Jun Koh^*, Bong-Hyun Jeon^*, Cholsoon Jang^*, Jinah Han^*, Raghu P. Kataru^*, Reto A. Schwendener, Jin-Man Kim, 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, Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland; and the Department of Pathology, Chungnam National University School of Medicine, Daejeon, Korea

^@ To whom correspondence should be addressed. E-mail: gykoh{at}kaist.ac.kr.

	Abstract

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.