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 8

CLEC2 deficiency results in reduced lung function associated with emphysematous changes.

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CLEC2 deficiency results in reduced lung function associated with emphys...
(A and B) H&E-stained images of lung tissue from 6- to 8-month-old plt-Clec2–KO and control mice. (C) Quantification of alveolar enlargement in 6- to 8-month-old plt-Clec2–KO and control mice by mean linear intercept (MLI). (D) Oxygen saturation in 6- to 8-month-old plt-Clec2–KO and control mice. (E and F) Van Gieson staining for elastin (black, arrows) in lung tissue from control and plt-Clec2–KO mice. (G) Western blot of whole lung tissue from 6- to 8-month-old plt-Clec2–KO and control mice for detection of the 25-kDa elastin fragment (EF). (H) Quantification of the 25-kDa elastin fragment in Western blots by fluorescence intensity (AU). Comparisons were made between matched littermates. (I) qPCR for MMP-12 expression in lung tissue from plt-Clec2–KO and control mice. Comparisons were made between matched littermates. (J and K) Immunohistochemical analysis of MMP-12 (red) in lung tissue from plt-Clec2–KO and control mice. Data are representative of at least 4 mice in each group. Scale bars: 25 μm. All values represent the mean ± SEM. *P < 0.05 and **P < 0.01, by Student’s t test.