Plasticity of airway lymphatics in development and disease

Abstract

The dynamic nature of lymphatic vessels is reflected by structural and functional modifications that coincide with changes in their environment. Lymphatics in the respiratory tract undergo rapid changes around birth, during adaptation to air breathing, when lymphatic endothelial cells develop button-like intercellular junctions specialized for efficient fluid uptake and transport. In inflammatory conditions, lymphatic vessels proliferate and undergo remodeling to accommodate greater plasma leakage and immune cell trafficking. However, the newly formed lymphatics are abnormal, and resolution of inflammation is not accompanied by complete reversal of the lymphatic vessel changes back to the baseline. As the understanding of lymphatic plasticity advances, approaches for eliminating the abnormal vessels and improving the functionality of those that remain move closer to reality. This chapter provides an overview of what is known about lymphatic vessel growth, remodeling, and other forms of plasticity that occur during development or inflammation, with an emphasis on the respiratory tract. Also addressed is the limited reversibility of changes in lymphatics during the resolution of inflammation.

Fig. 4.1

Plasticity of tracheal lymphatics in development. Buttons in initial lymphatics and zippers in collecting lymphatics of a normal mouse trachea. (a) Low magnification of VE-cadherin (red) stained button-like junctions in initial lymphatics (LV) and zipper-like junctions in blood vessels (BV). (b) The box in (a) is enlarged here to show discontinuous segments of VE-cadherin immunoreactivity (red) at buttons and segments of LYVE-1 staining (green) between buttons in an initial lymphatic. (c) VE-cadherin immunoreactivity (red) at zippers in the endothelium of a collecting lymphatic with little or no LYVE-1 staining. LYVE-1-positive leukocytes (green) are present outside the lymphatic. (d) Schematic diagram showing buttons and zipper in lymphatics revealed by VE-cadherin immunoreactivity. Middle panel shows the oak leaf-shaped endothelial cells marked by dashed lines. The right panel shows the enlarged diagram of buttons (red) at the sides of cell border flaps (green). Fluid is believed to flow through the junction-free flaps. (e) Development of button-like junctions from E16.5–P70 is shown as inverted gray scale images (upper panel, VE-cadherin) and in color (lower panel, VE-cadherin, red; LYVE-1, green). Scale bar: 100 μm (a); 20 μm (b, c); 10 μm (e). ((b, c, and e) reproduced from (Yao et al. 2012); (d) reproduced from (Baluk et al. 2007))

Fig. 4.2

Plasticity of lymphatics in airway inflammation. Changes in tracheal lymphatics after M. pulmonis infection. Confocal micrographs of mouse tracheal whole mounts stained for lymphatics (red, LYVE-1) and blood vessels (green, PECAM-1). (a) Few or no lymphatics are located over the cartilage rings (asterisks) in the pathogen-free mouse. (b) Tracheal lymphatics are present over cartilage rings in a mouse infected for 14 days. (c) Tracheal lymphatics are abundant and disorganized in a mouse infected for 42 days. H&E stained sections of mouse left lung. (d) No BALT is present in the pathogen-free lung. (e) BALT is abundant around the large bronchus and blood vessel in the lung of a mouse infected for 42 days. (f, g) Zipper-like junctions (“zippers,” arrows) are present in the endothelium of tracheal lymphatics after infection for 28 days. (h, i) Button-like junctions (“buttons,” arrows) are present in the endothelium of tracheal lymphatics when dexamethasone was given during the final 14 days of a 28-day infection. Scale bar: 200 μm (a–c); 400 μm (d, e); 20 μm (f, i). ((a–c) reproduced from (Yao et al. 2010); (f) reproduced from (Yao et al. 2012))