A Central Role for CD68(+) Macrophages in Hepatopulmonary Syndrome

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 5 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(1) macrophages and capillary density were measured in the lungs of patients with cirrhosis versus control patients (n 5 10 per group). Measurements and Main Results: CBDL increased cardiac output and alveolar-arterial gradient by causing capillary dilatation and arteriovenous malformations. Activated CD68(1) macrophages (nuclear factor-kB1) 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 (1) macrophages. An occult proliferative vasculopathy may explain the occasional transition to portopulmonary hypertension. Macrophage depletion may have therapeutic potential in HPS.Keywords: liver transplantation; arteriovenous malformations; clodronate; cirrhosis; portopulmonary hypertension Hepatopulmonary syndrome (HPS), characterized by hypoxemia and intrapulmonary shunting, occurs in 5 to 32% of patients with liver disease (1). HPS significantly increases mortality and worsens functional status and quality of life in patients with cirrhosis (2). The major pathological abnormalities in HPS include alveolar capillary dilatation and pulmonary arteriovenous malformations (3). Clinically, patients with HPS present with hypoxemia and signs of a hyperdynamic circulatory state that include low systemic vascular resistance, low pulmonary vascular resistance (PVR), and high cardiac output (CO) (1). The pathogenesis of HPS is unclear, and currently there are no effective medical therapies. Orthotopic liver transplantation is the only available treatment (1). It is noteworthy that some patients with cirr...

Intrapulmonary vascular dilatations are common in portopulmonary hypertension and may be associated with decreased survival

“…[35][36][37] Data from animal models of HPS suggest a central role for pulmonary intravascular macrophages through generation of inducible nitric oxide synthase, vascular endothelial growth factor, and platelet-derived growth factor. 35,38,39 Inhibition of nitric oxide synthase, the endothelin-B receptor, and vascular endothelial growth factor has mitigated HPS in animal models. [40][41][42] Notably, these same mediators have also been implicated in POPH and endothelin receptor antagonists (dual and selective), and phosphodiesterase-5 inhibitors are mainstays of therapy for PAH and POPH.…”

“…14 Additionally, a substantial degree of overlap has been described in the histologic findings of each condition. Thenappan et al 38 identified a proliferative vasculopathy in the small pulmonary arteries of a rat model of HPS, alongside the characteristic changes of HPS such as vasodilatation and neoangiogenesis. Similarly, dilated arterial segments have been observed proximal to plexogenic vascular lesions in PAH with and without liver disease.…”

Portopulmonary hypertension and hepatopulmonary syndrome: a clinician-oriented overview

“…A local increase in pro-inflammatory mediators and pulmonary intravascular sequestration of macrophages leading to an increase in iNOS activity and NO production has also been described [70]. This may be caused by bacterial translocation and systemic endotoxaemia and, presumably, it is largely mediated by tumour necrosis factor-a [71,72]. Other mechanisms/associations identified to date through human or experimental studies include increased angiogenesis through upregulation of the vascular endothelial growth factor, increased carbon monoxide production through haem oxygenase, and increased levels of oestrogen and progesterone.…”

Hepatopulmonary Syndrome: A Brief Review

“…ET-1 levels were found to be elevated in cirrhosis and IPVD cases [9]. Macrophages could also induce vasodilatation due to heme oxygenase (HO-1) production that resulted in increased production of carbon monoxide (CO) [11]. Furthermore, gene polymorphisms also played a role in angiogenesis that had been linked with advanced HPS [12].…”