Thromboxane prostanoid signaling in macrophages attenuates lymphedema and facilitates lymphangiogenesis in mice

Abstract

Background Accumulating evidence suggests that prostaglandin E2, an arachidonic acid (AA) metabolite, enhances lymphangiogenesis in response to inflammation. However, thromboxane A2 (TXA2), another AA metabolite, is not well known. Thus, this study aimed to determine the role of thromboxane prostanoid (TP) signaling in lymphangiogenesis in secondary lymphedema. Methods and results Lymphedema was induced by the ablation of lymphatic vessels in mouse tails. Compared with wild-type mice, tail lymphedema in Tp-deficient mice was enhanced, which was associated with suppressed lymphangiogenesis as indicated by decreased lymphatic vessel area and pro-lymphangiogenesis-stimulating factors. Numerous macrophages were found in the tail tissues of Tp-deficient mice. Furthermore, the deletion of TP in macrophages increased tail edema and decreased lymphangiogenesis and pro-lymphangiogenic cytokines, which was accompanied by increased numbers of macrophages and gene expression related to a pro-inflammatory macrophage phenotype in tail tissues. In vivo microscopic studies revealed fluorescent dye leakage in the lymphatic vessels in the wounded tissues. Conclusions The results suggest that TP signaling in macrophages promotes lymphangiogenesis and prevents tail lymphedema. TP signaling may be a therapeutic target for improving lymphedema-related symptoms by enhancing lymphangiogenesis.

Deletion of TP signaling in macrophages delays liver repair following APAP-induced liver injury by reducing accumulation of reparative macrophage and production of HGF

“…These results suggest that TP signaling in macrophages is involved in macrophage differentiation to repair damaged liver tissues exposed to APAP overdoses. Additionally, TP signaling in macrophages appears to be involved in macrophage polarization [15]; however, further studies are required to elucidate the mechanism underlying macrophage polarization via TP signaling.…”

“…However, recent evidence indicates that TP signaling promotes tissue repair by stimulating angiogenesis in gastric ulcers [13] and ischemic hind limbs [14]. TP signaling is also involved in the resolution of in ammation by enhancing lymphatic drainage through newly formed lymphatic vessels in the mouse tail during secondary lymphedema [15] and in the diaphragm during chronic peritonitis [16]. Furthermore, TP signaling plays a role in liver repair after carbon tetrachloride-induced liver injury [17,18].…”