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 April 4, 2019
Citation Information: J Clin Invest. 2019;129(6):2514-2526. https://doi.org/10.1172/JCI125044.
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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 5

Loss of CLEC2 results in impaired drainage of fluid and cells from the lungs.

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Loss of CLEC2 results in impaired drainage of fluid and cells from the l...
(A) Wet-to-dry ratios for control and plt-Clec2–KO lungs at baseline and in response to acid-induced lung injury (ALI). (B) Schematic of cell-tracing experiment for assessment of lymphatic leukocyte trafficking from the lungs to draining LNs. Intratracheal administration of CTV-labeled leukocytes was followed by harvesting of mLNs for flow cytometric analysis. (C) Identification of CD45+CTV+ leukocytes in the lungs and mLNs of WT mice 48 hours after intratracheal administration. (D) Flow cytometric analysis of CD45+CTV+ leukocytes in mLNs from iClec2-KO and control mice, 48 hours after intratracheal administration. (E) Quantification of CTV+ leukocytes in mLNs from control and iClec2-KO mice after intratracheal administration, as a percentage of total CD45+ leukocytes. (F) Quantification of CTV+ leukocytes in mLNs from control and iClec2-KO mice after intravenous administration, as a percentage of total CD45+ leukocytes. Data are representative of at least 4 mice in each group. All values represent the mean ± SEM. *P < 0.05, by Student’s t test.