TY - JOUR
T1 - A central role for CD68(+) macrophages in hepatopulmonary syndrome
T2 - Reversal by macrophage depletion
AU - Thenappan, Thenappan
AU - Goel, Ankush
AU - Marsboom, Glenn
AU - Fang, Yong Hu
AU - Toth, Peter T.
AU - Zhang, Hannah J.
AU - Kajimoto, Hidemi
AU - Hong, Zhigang
AU - Paul, Jonathan
AU - Wietholt, Christian
AU - Pogoriler, Jennifer
AU - Piao, Lin
AU - Rehman, Jalees
AU - Archer, Stephen L.
PY - 2011/4/15
Y1 - 2011/4/15
N2 - Rationale: The etiology of hepatopulmonary syndrome (HPS), a common complication of cirrhosis, isunknown. Inflammation and macrophage accumulation occur in HPS; however, their importance is unclear. Common bile ductligation (CBDL) creates an accepted model of HPS, allowing us to investigate the cause of HPS. Objectives: We hypothesized that macrophages are centraltoHPS and investigated the therapeutic potential of macrophage depletion. Methods: Hemodynamics, alveolar-arterial gradient, vascular reactivity, and histology were assessedin CBDL versus sham rats (n = 21 per group). The effects of plasma on smooth muscle cell proliferation and endothelial tube formation were measured. Macrophage depletion was used to prevent (gadolinium) or regress (clodronate) HPS. CD68(+) macrophages and capillary density were measured in the lungs of patients with cirrhosis versus control patients (n = 10 per group). Measurements and Main Results: CBDL increased cardiac output and alveolar-arterial gradient by causing capillary dilatation and arteriovenous malformations. Activated CD68(+) macrophages (nuclear factor-κB+) accumulated in HPS pulmonary arteries, drawn by elevatedlevels of plasm a endotoxin and lung monocyte chemoattractant protein-1. These macrophages expressed inducible nitric oxide synthase, vascular endothelial growth factor, and platelet-derived growth factor. HPS plasma increased endothelial tube formation and pulmonary artery smooth muscle cell proliferation. Macrophage depletion prevented and reversed the histological and hemodynamic features of HPS. CBDL lungs demonstrated increased medial thickness and obstruction of small pulmonary arteries. Nitric oxide synthase inhibition unmasked exaggerated pulmonary vasoconstrictor responses in HPS. Patients with cirrhosis had increased pulmonary intravascular macrophage accumulation and capillary density. Conclusions: HPS results from intravascular accumulation of CD68(+) macrophages. An occult proliferative vasculopathy may explain the occasional transition to portopulmonary hypertension. Macrophage depletion may have therapeutic potential in HPS..
AB - Rationale: The etiology of hepatopulmonary syndrome (HPS), a common complication of cirrhosis, isunknown. Inflammation and macrophage accumulation occur in HPS; however, their importance is unclear. Common bile ductligation (CBDL) creates an accepted model of HPS, allowing us to investigate the cause of HPS. Objectives: We hypothesized that macrophages are centraltoHPS and investigated the therapeutic potential of macrophage depletion. Methods: Hemodynamics, alveolar-arterial gradient, vascular reactivity, and histology were assessedin CBDL versus sham rats (n = 21 per group). The effects of plasma on smooth muscle cell proliferation and endothelial tube formation were measured. Macrophage depletion was used to prevent (gadolinium) or regress (clodronate) HPS. CD68(+) macrophages and capillary density were measured in the lungs of patients with cirrhosis versus control patients (n = 10 per group). Measurements and Main Results: CBDL increased cardiac output and alveolar-arterial gradient by causing capillary dilatation and arteriovenous malformations. Activated CD68(+) macrophages (nuclear factor-κB+) accumulated in HPS pulmonary arteries, drawn by elevatedlevels of plasm a endotoxin and lung monocyte chemoattractant protein-1. These macrophages expressed inducible nitric oxide synthase, vascular endothelial growth factor, and platelet-derived growth factor. HPS plasma increased endothelial tube formation and pulmonary artery smooth muscle cell proliferation. Macrophage depletion prevented and reversed the histological and hemodynamic features of HPS. CBDL lungs demonstrated increased medial thickness and obstruction of small pulmonary arteries. Nitric oxide synthase inhibition unmasked exaggerated pulmonary vasoconstrictor responses in HPS. Patients with cirrhosis had increased pulmonary intravascular macrophage accumulation and capillary density. Conclusions: HPS results from intravascular accumulation of CD68(+) macrophages. An occult proliferative vasculopathy may explain the occasional transition to portopulmonary hypertension. Macrophage depletion may have therapeutic potential in HPS..
KW - Arteriovenous malformations
KW - Cirrhosis
KW - Clodronate
KW - Liver transplantation
KW - Portopulmonary hypertension
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U2 - 10.1164/rccm.201008-1303OC
DO - 10.1164/rccm.201008-1303OC
M3 - Article
C2 - 21148721
AN - SCOPUS:79954585526
SN - 1073-449X
VL - 183
SP - 1080
EP - 1091
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 8
ER -