Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation

Abstract

Edema occurs in asthma and other inflammatory diseases when the rate of plasma leakage from blood vessels exceeds the drainage through lymphatic vessels and other routes. It is unclear to what extent lymphatic vessels grow to compensate for increased leakage during inflammation and what drives the lymphangiogenesis that does occur. We addressed these issues in mouse models of (a) chronic respiratory tract infection with Mycoplasma pulmonis and (b) adenoviral transduction of airway epithelium with VEGF family growth factors. Blood vessel remodeling and lymphangiogenesis were both robust in infected airways. Inhibition of VEGFR-3 signaling completely prevented the growth of lymphatic vessels but not blood vessels. Lack of lymphatic growth exaggerated mucosal edema and reduced the hypertrophy of draining lymph nodes.

Resolvin D3 and Aspirin-Triggered Resolvin D3 Are Protective for Injured Epithelia

“…23,38,39 Lung lymphatic vessels increase in size and number in various pathological states. 23,38,39 The discovery of markers (LYVE1, VEGFR3) for lymphatic endothelial cells has facilitated identification of lymphatic vessels via immunostaining. 40,41 Herein, AT-RvD3 led to increased numbers of detectable lymphatic vessels at 72 hours after injury.…”

Interaction of tumor cells and lymphatic vessels in cancer progression

“…Lymphatic vessels may provide more resistance to regression than blood vessels, as shown after adenoviral delivery of VEGF-A, 42 and in an inflammation model where spontaneous regression of blood vessels, but not lymphatic vessels, was observed after resolution of tracheal Mycoplasma pulmonis infection. 48 Lymphatic endothelial cells may also sustain commonly used doses of radiation therapy. 114 Therefore, anti-lymphangiogenic and radiotherapy might be combined to inhibit lymphatic metastasis of potentially remaining tumor cells postoperatively in cases not complicated by postoperative lymphedema (Figure 3).…”

Role of Lymphatic Vessels in Tumor Immunity: Passive Conduits or Active Participants?

“…Inflammatory lymphangiogenesis can be driven by immune cell-released VEGF-C, and inflammatory stimuli promote lymphatic endothelial cell susceptibility to VEGF-C through the upregulation of VEGFR3 and Prox-1 [102]. Tissue necrosis factor α, as well as newly recruited macrophages and granulocytes, can enhance the local expression of VEGF-C within inflamed tissue to promote lymphangiogenesis [103]. Another pro-inflammatory cytokine, interleukin (IL)-1β, promotes lymphangiogenesis by stimulating VEGF-A, VEGF-C, and VEGF-D [104].…”

“…Inflammation-associated lymphangiogenesis may be important for the clearance of immune infiltrates; for example, inhibiting lymphangiogenesis by VEGFR-3 blockage exacerbated pulmonary edema caused by chronic myocplasma pulmonis infection and prevented the resolution of inflammation [103]. On the other hand, in cases of chronic inflammation, the extensive lymphatic remodeling that occurs can have detrimental affects on normal immune function [1,105,106].…”

“…For these conditions, treatment with anti-VEGF antibodies can, in some cases, promote disease resolution [106][107][108][109]. Furthermore, while vascular angiogenesis can be reversed in chronic inflammation, lymphangiogenic structures seem to persist [103,110]. This implies that while the blood vasculature requires both growth and maintenance cues the lymphatic vasculature may not.…”