Emerging Therapeutic Targets for Portal Hypertension

Abstract

Purpose of Review Portal hypertension is responsible of the main complications of cirrhosis, which carries a high mortality. Recent treatments have improved prognosis, but this is still far from ideal. This paper reviews new potential therapeutic targets unveiled by advances of key pathophysiologic processes. Recent Findings Recent research highlighted the importance of suppressing etiologic factors and a safe lifestyle and outlined new mechanisms modulating portal pressure. These include intrahepatic abnormalities linked to inflammation, fibrogenesis, vascular occlusion, parenchymal extinction, and angiogenesis; impaired regeneration; increased hepatic vascular tone due to sinusoidal endothelial dysfunction with insufficient NO availability; and paracrine liver cell crosstalk. Moreover, pathways such as the gut-liver axis modulate splanchnic vasodilatation and systemic inflammation, exacerbate liver fibrosis, and are being targeted by therapy. We have summarized studies of new agents addressing these targets. Summary New agents, alone or in combination, allow acting in complementary mechanisms offering a more profound effect on portal hypertension while simultaneously limiting disease progression and favoring regression of fibrosis and of cirrhosis. Major changes in treatment paradigms are anticipated.

Semiconducting polymer dots for multifunctional integrated nanomedicine carriers

“…9 -Upper Part). Firstly, Pdots-based nano drugs can effortlessly penetrate the 100–150 nm opening in liver sinusoidal endothelial cells (LSECs), thereby accessing the Disse Space [ 473 ]. Subsequently, under the influence of liver parenchymal epithelial cells, NPs undergo biodegradation and are transported to intrahepatic bile ducts before being excreted from the gastrointestinal tract [ 474 , 475 ].…”

Review article: Recent advances in ascites and acute kidney injury management in cirrhosis

“…Portal hypertension is the key determinant of complications in cirrhosis such as varices with its risk for haemorrhage, formation of ascites with its complications such as spontaneous bacterial peritonitis (SBP), dilutional hyponatremia, hepatorenal syndrome (HRS) and hepatic encephalopathy (HE). 1,2 Ascites is the most common first decompensating event in cirrhosis and heralds the onset of the decompensation phase. Even the presence of only ultrasound detectable ascites is associated with a significant 1-year mortality or need for liver transplant in 17% of patients irrespective of the Model of Endstaged Liver Disease (MELD) score.…”

“…An important consequence of cirrhosis is the development of portal hypertension, which results from a combination of increased portal flow and increased intrahepatic vascular resistance. Portal hypertension is the key determinant of complications in cirrhosis such as varices with its risk for haemorrhage, formation of ascites with its complications such as spontaneous bacterial peritonitis (SBP), dilutional hyponatremia, hepatorenal syndrome (HRS) and hepatic encephalopathy (HE) 1,2 . Ascites is the most common first decompensating event in cirrhosis and heralds the onset of the decompensation phase.…”

Microvascular engineering for the development of a non-embedded liver sinusoid with a lumen: when endothelial cells do not lose their edge

“…Liver sinusoidal endothelial cells (LSECs), which compose these capillaries, feature microscopic fenestrae on their surface 10 , allowing for controlled passage of metabolites. They also express various mechanosensors which make them highly responsive to pressure, shear and changes in surrounding stiffness 11,12 which can in turn significantly impact the entire microenvironment in both homeostasis preservation and disease development 13,14 . Still, the mechanisms at play remain unclear, primarily due to the lack of an appropriate model.…”

“…Liver sinusoids are one such specialized capillaries, featuring highly porous microvessels with a discontinuous BM composed mainly of laminin and collagen IV, as well as microscopic fenestrae (8) . These unique attributes make liver sinusoidal endothelial cells (LSECs) highly permeable (9) but also extremely responsive to mechanics, and their response to changes in their surroundings can in turn significantly impact the entire microenvironment (10, 11). The mechanisms at play in liver sinusoidal capillarization (including the loss of fenestrae ) under mechanical stress are not elucidated, primarily due to the absence of an appropriate model.…”