Role of CD11b+ macrophages in intraperitoneal lipopolysaccharide-induced aberrant lymphangiogenesis and lymphatic function in the diaphragm

Am J Pathol. 2009 Oct;175(4):1733-45. doi: 10.2353/ajpath.2009.090133. Epub 2009 Sep 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Vessels / drug effects
  • Blood Vessels / pathology
  • CD11b Antigen / metabolism*
  • Cell Adhesion / drug effects
  • Cell Proliferation / drug effects
  • Clodronic Acid / pharmacology
  • Diaphragm / drug effects
  • Diaphragm / pathology
  • Diaphragm / physiopathology*
  • Endothelial Cells / drug effects
  • Endothelial Cells / pathology
  • Injections, Intraperitoneal
  • Ligands
  • Lipopolysaccharides / administration & dosage*
  • Lipopolysaccharides / pharmacology*
  • Liposomes
  • Lymph Nodes / drug effects
  • Lymph Nodes / pathology
  • Lymphangiogenesis / drug effects*
  • Lymphatic Vessels / drug effects
  • Lymphatic Vessels / pathology
  • Lymphatic Vessels / physiopathology*
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Mice
  • Organ Size / drug effects
  • Peritonitis / chemically induced
  • Peritonitis / physiopathology
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism


  • CD11b Antigen
  • Ligands
  • Lipopolysaccharides
  • Liposomes
  • Clodronic Acid
  • Vascular Endothelial Growth Factor Receptor-3