Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 187, Issue 9, Pages 1984-1997Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2017.05.009
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Funding
- National Heart, Lung, and Blood Institute, NIH [P01 HL024136, R01 HL059157, R01 HL127402]
- Leducq Foundation Transatlantic Network of Excellence [11CVD03]
- Lymph Vessels in Obesity and Cardiovascular Disease [11CVD03]
- Angel-Works Foundation
- Swiss National Science Foundation [PBEZP3_145983, P300PB_164732]
- Swiss National Science Foundation (SNF) [PBEZP3_145983, P300PB_164732] Funding Source: Swiss National Science Foundation (SNF)
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Chylous pleural effusion (chylothorax) frequently accompanies lymphatic vessel malformations and other conditions with lymphatic defects. Although retrograde flow of chyle from the thoracic duct is considered a potential mechanism underlying chylothorax in patients and mouse models, the path chyle takes to reach the thoracic cavity is unclear. Herein, we use a novel transgenic mouse model, where doxycycline-induced overexpression of vascular endothelial growth factor (VEGF)-C was driven by the adipocyte-specific promoter adiponectin (ADN), to determine how chylothorax forms. Surprisingly, 100% of adult ADN-VEGF-C mice developed chylothorax within 7 days. Rapid, consistent appearance of chylothorax enabled us to examine the step-by-step development in otherwise normal adult mice. Dynamic imaging with a fluorescent tracer revealed that lymph in the thoracic duct of these mice could enter the thoracic cavity by retrograde flow into enlarged paravertebral Lymphatics and subpleural lymphatic plexuses that had incompetent Lymphatic valves. Pleural mesothelium overlying the lymphatic plexuses underwent exfoliation that increased during doxycycline exposure. Together, the findings indicate that chylothorax in ADN-VEGF-C mice results from retrograde flow of chyle from the thoracic duct into lymphatic tributaries with defective valves. Chyle extravasates from these plexuses and enters the thoracic cavity through exfoliated regions of the pleural mesothelium.
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