The role of receptor tyrosine kinase activation in cholangiocytes and pulmonary vascular endothelium in experimental hepatopulmonary syndrome

Abstract

Pulmonary vascular dilation and angiogenesis underlie experimental hepatopulmonary syndrome (HPS) induced by common bile duct ligation (CBDL) and may respond to receptor tyrosine kinase (RTK) inhibition. Vascular endothelial growth factor-A (VEGF-A) expression occurs in proliferating cholangiocytes and pulmonary intravascular monocytes after CBDL, the latter contributing to angiogenesis. CBDL cholangiocytes also produce endothelin-1 (ET-1), which triggers lung vascular endothelin B receptor-mediated endothelial nitric oxide synthase (eNOS) activation and pulmonary intravascular monocyte accumulation. However, whether RTK pathway activation directly regulates cholangiocyte and pulmonary microvascular alterations in experimental HPS is not defined. We assessed RTK pathway activation in cholangiocytes and lung after CBDL and the effects of the type II RTK inhibitor sorafenib in experimental HPS. Cholangiocyte VEGF-A expression and ERK activation accompanied proliferation and increased hepatic and circulating ET-1 levels after CBDL. Sorafenib decreased each of these events and led to a reduction in lung eNOS activation and intravascular monocyte accumulation. Lung monocyte VEGF-A expression and microvascular Akt and ERK activation were also found in vivo after CBDL, and VEGF-A activated Akt and ERK and angiogenesis in rat pulmonary microvascular endothelial cells in vitro. Sorafenib inhibited VEGF-A-mediated signaling and angiogenesis in vivo and in vitro and improved arterial gas exchange and intrapulmonary shunting. RTK activation in experimental HPS upregulates cholangiocyte proliferation and ET-1 production, leading to pulmonary microvascular eNOS activation, intravascular monocyte accumulation, and VEGF-A-mediated angiogenic signaling pathways. These findings identify a novel mechanism in cholangiocytes through which RTK inhibition ameliorates experimental HPS.

Sorafenib in Hepatopulmonary Syndrome: A Randomized, Double‐Blind, Placebo‐Controlled Trial

“…We have also shown that overexpression of endogenous inhibitors of angiogenesis implicated in our human studies (angiostatin and endostatin) reduced lung microvessel counts and normalized alveolar‐arterial oxygen gradient (AaPO 2 ) in the experimental model, supporting the key role of lung neovascularization in HPS . Finally, we have shown that the multispecific tyrosine kinase inhibitor sorafenib reversed vascular proliferation in the lungs and improved gas exchange in the rodent model when administered after the establishment of HPS …”

“…Historical studies and pathologic specimens from patients demonstrate increased vascularity in the lung . Administration of sorafenib to rats after common bile duct ligation (which recapitulates HPS) reverses abnormal oxygenation, reduces intrapulmonary vascular dilations and shunting, and decreases circulating monocytes and progenitor cells …”

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

“…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.…”

Potential Clinical Targets in Hepatopulmonary Syndrome: Lessons From Experimental Models

“…The beneficial effect of sorafenib may be attributed to at least three mechanisms. First, sorafenib might indirectly mitigate HPS by improving underlying liver injury, fibrosis, and PH . Second, sorafenib directly targets the VEGF/VEGFR‐2/Akt pathway and pulmonary angiogenesis in the pulmonary microvasculature in vivo and in rat pulmonary microvascular endothelial cells in vitro .…”