Altered lymphatics in an ovine model of congenital heart disease with increased pulmonary blood flow.
Abnormalities of the lymphatic circulation are well recognized in patients with congenital heart defects. However, it is not known how the associated abnormal blood flow patterns, such as increased pulmonary blood flow (PBF), might affect pulmonary lymphatic function and structure. Using well-established ovine models of acute and chronic increases in PBF, we cannulated the efferent lymphatic duct of the caudal mediastinal node and collected and analyzed lymph effluent from the lungs of lambs with acutely increased PBF (n = 6), chronically increased PBF (n = 6), and age-matched normal lambs (n = 8). When normalized to PBF, we found that lymph flow was unchanged following acute increases in PBF but decreased following chronic increases in PBF. The lymph:plasma protein ratio decreased with both acute and chronic increases in PBF. Lymph bioavailable nitric oxide increased following acute increases in PBF but decreased following chronic increases in PBF. In addition, we found perturbations in the transit kinetics of contrast material through the pleural lymphatics of lambs with chronic increases in PBF. Finally, there were structural changes in the pulmonary lymphatic system in lambs with chronic increases in PBF: lymphatics from these lambs were larger and more dilated, and there were alterations in the expression of vascular endothelial growth factor-C, lymphatic vessel endothelial hyaluronan receptor-1, and Angiopoietin-2, proteins known to be important for lymphatic growth, development, and remodeling. Taken together these data suggest that chronic increases in PBF lead to both functional and structural aberrations of lung lymphatics. These findings have important therapeutic implications that warrant further study.
Department of Pediatrics, University of California, San Francisco, 94143-0106, USA.
Sanjeev A
SA
Datar
Eric G
EG
Johnson
Peter E
PE
Oishi
Michael
M
Johengen
Eric
E
Tang
Angela
A
Aramburo
Jubilee
J
Barton
Hsuan-Chang
HC
Kuo
Stephen
S
Bennett
Konstantine
K
Xoinis
Bhupinder
B
Reel
Gokhan
G
Kalkan
Eniko
E
Sajti
Oscar
O
Osorio
Gary W
GW
Raff
Michael A
MA
Matthay
Jeffrey R
JR
Fineman
D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D006439:Hemodynamics / Q000502:physiology; D008168:Lung / Q000098:blood supply* / Q000378:metabolism / Q000503:physiopathology*; D008208:Lymphatic System / Q000378:metabolism / Q000503:physiopathology*; D042601:Lymphatic Vessels / Q000378:metabolism / Q000503:physiopathology*; D009569:Nitric Oxide / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism / Q000503:physiopathology; D011652:Pulmonary Circulation / Q000235:genetics / Q000502:physiology*; D012039:Regional Blood Flow / Q000235:genetics / Q000502:physiology; D012756:Sheep; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism
D042702:Angiopoietin-2; D042582:Vascular Endothelial Growth Factor C; D009569:Nitric Oxide