Efficient pulmonary lymphatic drainage is necessary for inflammation resolution in ARDS
Pu-hong Zhang, Wen-wu Zhang, Shun-shun Wang, Cheng-hua Wu, Yang-dong Ding, Xin-yi Wu, Fang Gao Smith, Yu Hao, Sheng-wei Jin
Pu-hong Zhang, Wen-wu Zhang, Shun-shun Wang, Cheng-hua Wu, Yang-dong Ding, Xin-yi Wu, Fang Gao Smith, Yu Hao, Sheng-wei Jin
View: Text | PDF
Research Article Pulmonology Vascular biology

Efficient pulmonary lymphatic drainage is necessary for inflammation resolution in ARDS

Abstract

The lymphatic vasculature is the natural pathway for the resolution of inflammation, yet the role of pulmonary lymphatic drainage function in sepsis-induced acute respiratory distress syndrome (ARDS) remains poorly characterized. In this study, indocyanine green–near infrared lymphatic living imaging was performed to examine pulmonary lymphatic drainage function in septic mouse models. We found that the pulmonary lymphatic drainage was impaired owing to the damaged lymphatic structure in sepsis-induced ARDS. Moreover, prior lymphatic defects by blocking vascular endothelial growth factor receptor-3 (VEGFR-3) worsened sepsis-induced lymphatic dysfunction and inflammation. Posttreatment with vascular endothelial growth factor-C (Cys156Ser) (VEGF-C156S), a ligand of VEGFR-3, ameliorated lymphatic drainage by rejuvenating lymphatics to reduce the pulmonary edema and promote draining of pulmonary macrophages and neutrophils to pretracheal lymph nodes. Meanwhile, VEGF-C156S posttreatment reversed sepsis-inhibited CC chemokine ligand 21 (CCL21), which colocalizes with pulmonary lymphatic vessels. Furthermore, the advantages of VEGF-C156S on the drainage of inflammatory cells and edema fluid were abolished by blocking VEGFR-3 or CCL21. These results suggest that efficient pulmonary lymphatic drainage is necessary for inflammation resolution in ARDS. Our findings offer a therapeutic approach to sepsis-induced ARDS by promoting lymphatic drainage function.

Authors

Pu-hong Zhang, Wen-wu Zhang, Shun-shun Wang, Cheng-hua Wu, Yang-dong Ding, Xin-yi Wu, Fang Gao Smith, Yu Hao, Sheng-wei Jin

×

Figure 8

Enhancement of lymphatic drainage by VEGF-C156S is dependent on the VEGFR-3/CCL21 pathway.

Options: View larger image (or click on image) Download as PowerPoint
Enhancement of lymphatic drainage by VEGF-C156S is dependent on the VEGF...
(A) Monitoring and treatment scheme. MAZ51 was intraperitoneally injected at 10 mg/kg of body weight for 30 days (5 days per week) for blocking VEGFR-3. CCL21 was blocked on days 2, 4, and 6 by CCL21-blocking antibody (αCCL21). VEGF-C156S was administrated to LPS-induced sepsis model following the administration of anti-CCL21 (αCCL21)/IgG (Iso) antibodies or MAZ51/Vector. (B–E) The lymphatic drainage function was determined by IVIS. The remaining ICG was quantified and presented as relative radiance at 0 hours, 24th hour, and 48th hour. The ICG clearance rate at the 24th hour and 48th hour (Vector Iso n = 6, MAZ51 n = 6; αCCL21 n = 6; representative data from 3 independent experiments). (F and G) Fluorescence intensities of ICG were determined in the pLNs at 30 minutes after the pour of ICG by IVIS and confocal microscopy at the 24th hour (Vector Iso n = 6, MAZ51 n = 6; αCCL21 n = 6; representative data from 3 independent experiments). All n values refer to the number of mice used, and the error bars depict mean ± SD. P values were calculated by a 1-way ANOVA with Tukey’s multiple-comparison test.