Lymphatic impairment leads to pulmonary tertiary lymphoid organ formation and alveolar damage
Hasina Outtz Reed, … , Wayne W. Hancock, Mark L. Kahn
Hasina Outtz Reed, … , Wayne W. Hancock, Mark L. Kahn
Published June 3, 2019; First published April 4, 2019
Citation Information: J Clin Invest. 2019;129(6):2514-2526. https://doi.org/10.1172/JCI125044.
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Categories: Research Article Pulmonology Vascular biology

Lymphatic impairment leads to pulmonary tertiary lymphoid organ formation and alveolar damage

Abstract

The lung is a specialized barrier organ that must tightly regulate interstitial fluid clearance and prevent infection in order to maintain effective gas exchange. Lymphatic vessels are important for these functions in other organs, but their roles in the lung have not been fully defined. In the present study, we evaluated how the lymphatic vasculature participates in lung homeostasis. Studies using mice carrying a lymphatic reporter allele revealed that, in contrast to other organs, lung lymphatic collecting vessels lack smooth muscle cells entirely, suggesting that forward lymph flow is highly dependent on movement and changes in pressure associated with respiration. Functional studies using C-type lectin domain family 2–deficient (CLEC2-deficient) mice in which lymph flow is impaired because of loss of lympho-venous hemostasis, or using inducible lung-specific ablation of lymphatic endothelial cells in a lung transplant model revealed that loss of lymphatic function leads to an inflammatory state characterized by the formation of tertiary lymphoid organs (TLOs). In addition, impaired lymphatic flow in mice resulted in hypoxia and features of lung injury that resembled emphysema. These findings reveal both a lung-specific mechanism of lymphatic physiology and a lung-specific consequence of lymphatic dysfunction that may contribute to chronic lung diseases that arise in association with TLO formation.

Authors

Hasina Outtz Reed, Liqing Wang, Jarrod Sonett, Mei Chen, Jisheng Yang, Larry Li, Petra Aradi, Zoltan Jakus, Jeanine D’Armiento, Wayne W. Hancock, Mark L. Kahn

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Figure 6

Lung-specific LEC ablation leads to TLO formation.

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Lung-specific LEC ablation leads to TLO formation. (A) Schematic of the ...
(A) Schematic of the experimental approach used for lung-specific deletion of pulmonary lymphatics. iDTR expression was induced in LECs using LEC-specific Cre (VEGFR3CreERT2). Lungs from iDTR VEGFR3CreERT2 mice were used as donors for single lung transplantation into littermate recipients, and administration of DT to transplanted mice led to LEC death specifically in the transplanted lung, whereas control transplanted lungs had intact lymphatics. Timeline shows lung-specific lymphatic ablation in the lung transplants. (B and C) Immunohistochemical analysis of Prox1+Lyve1+ LEC nuclei in control lungs (B, arrows) and lungs with DT-mediated lymphatic ablation (C). (D) Quantification of Prox1+Lyve1+ nuclei in DT-treated iDTR VEGFR3CreERT2 transplanted lungs compared with control transplanted lungs. (E) Quantification of TLOs in DT-treated iDTR VEGFR3CreERT2 transplanted lungs compared with control transplants per ×4 (1.1 × 1.3 mm) microscopic field. (F) Correlation of TLOs to the number of Prox1+Lyve+ LEC nuclei in DT-treated iDTR VEGFR3CreERT2 transplanted lungs. Data are representative of 4 mice in each group. Scale bars: 25 μm. All values represent the mean ± SEM. *P < 0.05, by Student’s t test.