Lymphatic Changes in Respiratory Diseases: More than Just Remodeling of the Lung?

Abstract

Advances in our ability to identify lymphatic endothelial cells and differentiate them from blood endothelial cells have led to important progress in the study of lymphatic biology. Over the past decade, preclinical and clinical studies have shown that there are changes to the lymphatic vasculature in nearly all lung diseases. Efforts to understand the contribution of lymphatics and their growth factors to disease initiation, progression, and resolution have led to seminal findings establishing critical roles for lymphatics in lung biology spanning from the first breath after birth to asthma, tuberculosis, and lung transplantation. However, in other diseases, it remains unclear if lymphatics are part of the overall lung remodeling process or real contributors to disease pathogenesis. The goal of this Translational Review is to highlight some of the advances in our understanding of the role(s) of lymphatics in lung disease and shed light on the critical needs and unanswered questions that might lead to novel translational applications.

Keywords: edema; hyaluronan; lung disease; lymphangiogenesis; lymphatics.

Figure 1.

Schematic of lymphatic distribution in the healthy human lung. Lymphatics in the lung accompany the major airways and respiratory bronchioles, and they are also present near the intralobular arterioles and small veins. In addition, there is a network of subpleural lymphatics, which are distributed beneath pulmonary pleura. Under physiological conditions, lymphatic vessels generally do not extend to the distal alveolar spaces.

Figure 2.

Schematic of an initial lymphatic. Hyaluronic acid is transported via lymphatic vessel hyaluronan receptor (LYVE)-1, whereas interstitial fluid, proteins, macromolecules, white blood cells, and antigens enter initial lymphatics through valve-like openings between lymphatic endothelial cells.