title: A central role for CD68(+) macrophages in hepatopulmonary syndrome. Reversal by macrophage depletion.
abstract: BACKGROUND
  The etiology of hepatopulmonary syndrome (HPS), a common complication of cirrhosis, is unknown. Inflammation and macrophage accumulation occur in HPS; however, their importance is unclear. Common bile duct ligation (CBDL) creates an accepted model of HPS, allowing us to investigate the cause of HPS.
  
  
  OBJECTIVE
  We hypothesized that macrophages are central to HPS and investigated the therapeutic potential of macrophage depletion.
  
  
  METHODS
  Hemodynamics, alveolar-arterial gradient, vascular reactivity, and histology were assessed in 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).
  
  
  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 elevated levels of plasma 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.
authors.affiliation: Section of Cardiology, Department of Medicine, The University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
authors.forename: Thenappan
authors.initials: T
authors.lastname: Thenappan
authors.forename: Ankush
authors.initials: A
authors.lastname: Goel
authors.forename: Glenn
authors.initials: G
authors.lastname: Marsboom
authors.forename: Yong-Hu
authors.initials: YH
authors.lastname: Fang
authors.forename: Peter T
authors.initials: PT
authors.lastname: Toth
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Zhang
authors.forename: Hidemi
authors.initials: H
authors.lastname: Kajimoto
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Hong
authors.forename: Jonathan
authors.initials: J
authors.lastname: Paul
authors.forename: Christian
authors.initials: C
authors.lastname: Wietholt
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pogoriler
authors.forename: Lin
authors.initials: L
authors.lastname: Piao
authors.forename: Jalees
authors.initials: J
authors.lastname: Rehman
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology* / Q000502:physiology; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology* / Q000502:physiology; D001165:Arteriovenous Malformations / Q000209:etiology / Q000503:physiopathology; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020065:Hepatopulmonary Syndrome / Q000209:etiology / Q000276:immunology*; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000166:cytology / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000502:physiology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000502:physiology; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D048049:Extracellular Signal-Regulated MAP Kinases; D052247:Nitric Oxide Synthase Type II; D010982:Platelet-Derived Growth Factor; D042461:Vascular Endothelial Growth Factor A; C539355:CD68 protein, rat; D000097382:CD68 Molecule; C467498:vascular endothelial growth factor A, rat; C496318:Nos2 protein, rat