Journal article
A Central Role for CD68(+) Macrophages in Hepatopulmonary Syndrome: Reversal by Macrophage Depletion
American journal of respiratory and critical care medicine, Vol.183(8), pp.1080-1091
04/15/2011
DOI: 10.1164/rccm.201008-1303OC
PMCID: PMC3086745
PMID: 21148721
Abstract
Rationale
: 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.
Objectives
: 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).
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 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.
Details
- Title: Subtitle
- A Central Role for CD68(+) Macrophages in Hepatopulmonary Syndrome: Reversal by Macrophage Depletion
- Creators
- Thenappan Thenappan - University of ChicagoAnkush Goel - University of ChicagoGlenn Marsboom - University of ChicagoYong-Hu Fang - University of ChicagoPeter T. Toth - University of ChicagoHannah J. Zhang - University of ChicagoHidemi Kajimoto - Kurume UniversityZhigang Hong - University of ChicagoJonathan Paul - University of ChicagoChristian Wietholt - University of ChicagoJennifer Pogoriler - University of ChicagoLin Piao - University of ChicagoJalees Rehman - University of ChicagoStephen L. Archer - University of Chicago
- Resource Type
- Journal article
- Publication Details
- American journal of respiratory and critical care medicine, Vol.183(8), pp.1080-1091
- DOI
- 10.1164/rccm.201008-1303OC
- PMID
- 21148721
- PMCID
- PMC3086745
- NLM abbreviation
- Am J Respir Crit Care Med
- ISSN
- 1073-449X
- eISSN
- 1535-4970
- Publisher
- American Thoracic Society
- Number of pages
- 12
- Language
- English
- Date published
- 04/15/2011
- Academic Unit
- Cardiology; Stead Family Department of Pediatrics
- Record Identifier
- 9984961113602771
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