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ResearchIn-Press PreviewPulmonologyVascular biology Open Access | 10.1172/jci.insight.173440

Efficient pulmonary lymphatic drainage is necessary for inflammation resolution in ARDS

Pu-hong Zhang,1 Wen-wu Zhang,1 Shun-shun Wang,1 Cheng-hua Wu,1 Yang-dong Ding,1 Xin-yi Wu,1 Fang Gao Smith,1 Yu Hao,1 and Sheng-wei Jin2

1Department of Anaesthesia and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China

2the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China

Find articles by Zhang, P. in: JCI | PubMed | Google Scholar

1Department of Anaesthesia and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China

2the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China

Find articles by Zhang, W. in: JCI | PubMed | Google Scholar

1Department of Anaesthesia and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China

2the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China

Find articles by Wang, S. in: JCI | PubMed | Google Scholar

1Department of Anaesthesia and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China

2the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China

Find articles by Wu, C. in: JCI | PubMed | Google Scholar

1Department of Anaesthesia and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China

2the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China

Find articles by Ding, Y. in: JCI | PubMed | Google Scholar

1Department of Anaesthesia and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China

2the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China

Find articles by Wu, X. in: JCI | PubMed | Google Scholar

1Department of Anaesthesia and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China

2the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China

Find articles by Smith, F. in: JCI | PubMed | Google Scholar

1Department of Anaesthesia and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China

2the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China

Find articles by Hao, Y. in: JCI | PubMed | Google Scholar

1Department of Anaesthesia and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China

2the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China

Find articles by Jin, S. in: JCI | PubMed | Google Scholar

Published November 16, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.173440.
Copyright © 2023, Zhang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published November 16, 2023 - Version history
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Abstract

The lymphatic vasculature is the natural pathway for the resolution of inflammation, while the role of pulmonary lymphatic drainage function in sepsis-induced acute respiratory distress syndrome (ARDS) remains poorly characterized. In this study, Indocyanine green (ICG)-Near Infrared (NIR) lymphatic living imaging was performed to examine pulmonary lymphatic drainage function in septic mice 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 (VEGFR3), worsened sepsis-induced lymphatic dysfunction and inflammation. The post-treatment of vascular endothelial growth factor-C (Cys156Ser) (VEGF-C156S), a ligand of VEGFR3, ameliorated lymphatic drainage through rejuvenating lymphatics to reduce the pulmonary edema and promote pulmonary macrophages and neutrophils to drain to pretracheal lymph nodes (pLNs). Meanwhile, VEGF-C156S post-treatment reversed sepsis-inhibited C-C motif chemokine ligand 21 (CCL21), which co-localizes with the pulmonary lymphatic vessels. Furthermore, the advantages of VEGF-C156S on the drainage of inflammatory cells and edema fluid were abolished by blocking VEGFR3 or CCL21. These results suggest that efficient pulmonary lymphatic drainage is necessary for inflammation resolution in ARDS. Our findings offer a novel therapeutic approach to sepsis-induced ARDS by promoting lymphatic drainage function.

Graphical Abstract
graphical abstract
Supplemental material

View Supplementary Video 1. The consecutive lymphatic flow in control mice.

View Supplementary Video 2. The obstructed lymphatic flow in sepsis mice.

View Supplementary Video 3. ICG drains primarily via the pulmonary lymphatic vessels in control mice.

View Supplementary Video 4. ICG drains primarily via the pulmonary lymphatic vessels in sepsis mice.

Version history
  • Version 1 (November 16, 2023): In-Press Preview
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