Abstract 19195: A Central Role for CD68(+) Pulmonary Intravascular Macrophages in the Etiology of Hepatopulmonary Syndrome: Syndrome Reversal by Macrophage Depletion
Introduction: Hepatopulmonary syndrome (HPS) is characterized by hypoxemia, pulmonary capillary dilatation, and cirrhosis of the liver. The pathogenesis of HPS is poorly understood and no treatment other than liver transplantation is effective. Common bile duct ligation (CBDL) is an accepted animal model of HPS. CD68(+) macrophages accumulate in CBDL lungs; however, their role in the pathogenesis of HPS is not well characterized. Aim: We hypothesized that macrophages are central to the etiology of HPS, serving as a source of angiogenic, vasodilatory and proliferative growth factors. We investigated whether macrophage depletion prevents and reverses HPS.
Methods: Ligation of the common bile duct (CBDL; n=15) versus sham (n=6) was performed in adult male Sprague-Dawley rats. CBDL rats received vehicle (n=6), GdCl3 (10 mg/kg, IV biweekly for 4 weeks; n=6) or clodronate (15mg/kg, IV bodyweight biweekly for 2 weeks; n=3). Hemodynamics and lung vascular structure (using micro CT angiography, confocal microscopy and histology) were assessed at week 4. The effects of CBDL plasma on smooth muscle cells (SMC) proliferation and endothelial tube formation were assessed.
Results: CBDL rats recapitulated human HPS. Plasma endotoxin level was increased in CBDL and pulmonary arteries had accumulation of NF-κB(+), CD68(+) macrophages expressing inducible nitric oxide synthase (iNOS), VEGF and PDGF. CBDL plasma PDGF level was increased, and plasma increased SMC proliferation and angiogenic tube-formation. Histology revealed the expected capillary dilatation and arteriovenous malformations (AVM). An unexpected proliferative, vasculopathy was noted and microCT angiography showed dropout of small arteries in CBDL. Macrophage depletion normalized (A-a) gradient, cardiac output, and pulmonary vascular resistance, reduced capillary dilatation, and decreased CBDL plasma's angiogenic potential.
Conclusions: HPS results from intravascular accumulation of CD68(+) macrophages, whcih release vasodilatory (iNOS), angiogenic (VEGF) and proliferative (PDGF) factors, accounting for the capillary dilatation, AVMs and a newly-recognized proliferative vasculopathy. Depletion of CD68(+) macrophages can prevent or reverse experimental HPS.
- © 2010 by American Heart Association, Inc.