Roles of Thromboxane Receptor Signaling in Enhancement of Lipopolysaccharide-Induced Lymphangiogenesis and Lymphatic Drainage Function in Diaphragm

Abstract

Objective: Thromboxane is an arachidonic acid metabolite that exerts its actions through a G-protein–coupled receptor with 7 transmembrane domains. Although an arachidonic acid metabolite, prostaglandin E 2 was reported to enhance lymphangiogenesis, little is known on other arachidonic acid metabolites. In the present study, we investigated the roles of TP (thromboxane prostanoid) signaling in facilitating lymphangiogenesis during inflammation. Approach and Results: Inflammation was induced by repeated intraperitoneal injections of lipopolysaccharide, and lymphangiogenesis essential for draining peritoneal fluids was estimated in the diaphragm. Lipopolysaccharide induced lymphangiogenesis in the diaphragm in a time-dependent manner in wild-type mice. Compared with wild-type mice, lipopolysaccharide-induced lymphangiogenesis in Tp -deficient ( Tp −/− ) mouse diaphragm tissues was suppressed, and this was accompanied by reduced drainage function from the peritoneal cavity. TP-positive macrophages and T cells were accumulated in the diaphragm and produced VEGF (vascular endothelial growth factor)-C and VEGF-D in a TP-dependent manner. Removal of macrophages and T cells resulted in reduced lymphangiogenesis and lowered expressions of VEGF-C and VEGF-D. Furthermore, Tp −/− bone marrow chimeric mice exhibited reduced lymphangiogenesis. Tp knockout specific to macrophages and T cells also led to reduced lymphangiogenesis and drainage function in mice with lipopolysaccharide injections. Conclusions: The present results suggest that TP signaling exerts prolymphangiogenic activity by acting on macrophages and T cells accumulated during inflammation and that TP signaling represents a novel target for controlling lymphangiogenesis.