Retrograde Lymph Flow Leads to Chylothorax in Transgenic Mice with Lymphatic Malformations

Maximilian Nitschké, Alexander Bell, Sinem Karaman, Meelad Amouzgar, Joseph M. Rutkowski, Philipp E. Scherer, Kari Alitalo, Donald M. McDonald

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1984-1997
Number of pages14
JournalAmerican Journal of Pathology
Volume187
Issue number9
DOIs
StatePublished - Sep 1 2017

Fingerprint

Chylothorax
Lymph
Chyle
Transgenic Mice
Thoracic Cavity
Thoracic Duct
Doxycycline
Epithelium
Vascular Endothelial Growth Factor C
Lymphatic Vessels
Adiponectin
Pleural Effusion
Adipocytes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Nitschké, M., Bell, A., Karaman, S., Amouzgar, M., Rutkowski, J. M., Scherer, P. E., ... McDonald, D. M. (2017). Retrograde Lymph Flow Leads to Chylothorax in Transgenic Mice with Lymphatic Malformations. American Journal of Pathology, 187(9), 1984-1997. https://doi.org/10.1016/j.ajpath.2017.05.009

Retrograde Lymph Flow Leads to Chylothorax in Transgenic Mice with Lymphatic Malformations. / Nitschké, Maximilian; Bell, Alexander; Karaman, Sinem; Amouzgar, Meelad; Rutkowski, Joseph M.; Scherer, Philipp E.; Alitalo, Kari; McDonald, Donald M.

In: American Journal of Pathology, Vol. 187, No. 9, 01.09.2017, p. 1984-1997.

Research output: Contribution to journalArticle

Nitschké, M, Bell, A, Karaman, S, Amouzgar, M, Rutkowski, JM, Scherer, PE, Alitalo, K & McDonald, DM 2017, 'Retrograde Lymph Flow Leads to Chylothorax in Transgenic Mice with Lymphatic Malformations', American Journal of Pathology, vol. 187, no. 9, pp. 1984-1997. https://doi.org/10.1016/j.ajpath.2017.05.009
Nitschké, Maximilian ; Bell, Alexander ; Karaman, Sinem ; Amouzgar, Meelad ; Rutkowski, Joseph M. ; Scherer, Philipp E. ; Alitalo, Kari ; McDonald, Donald M. / Retrograde Lymph Flow Leads to Chylothorax in Transgenic Mice with Lymphatic Malformations. In: American Journal of Pathology. 2017 ; Vol. 187, No. 9. pp. 1984-1997.
@article{af4116233e3445fc84a378b2bffb1ba5,
title = "Retrograde Lymph Flow Leads to Chylothorax in Transgenic Mice with Lymphatic Malformations",
abstract = "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.",
author = "Maximilian Nitschk{\'e} and Alexander Bell and Sinem Karaman and Meelad Amouzgar and Rutkowski, {Joseph M.} and Scherer, {Philipp E.} and Kari Alitalo and McDonald, {Donald M.}",
year = "2017",
month = "9",
day = "1",
doi = "10.1016/j.ajpath.2017.05.009",
language = "English (US)",
volume = "187",
pages = "1984--1997",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "9",

}

TY - JOUR

T1 - Retrograde Lymph Flow Leads to Chylothorax in Transgenic Mice with Lymphatic Malformations

AU - Nitschké, Maximilian

AU - Bell, Alexander

AU - Karaman, Sinem

AU - Amouzgar, Meelad

AU - Rutkowski, Joseph M.

AU - Scherer, Philipp E.

AU - Alitalo, Kari

AU - McDonald, Donald M.

PY - 2017/9/1

Y1 - 2017/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85027543573&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85027543573&partnerID=8YFLogxK

U2 - 10.1016/j.ajpath.2017.05.009

DO - 10.1016/j.ajpath.2017.05.009

M3 - Article

C2 - 28683257

AN - SCOPUS:85027543573

VL - 187

SP - 1984

EP - 1997

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 9

ER -