Emerging Therapeutic Targets for Portal Hypertension.

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

Mechanobiology of portal hypertension.

The interplay between mechanical stimuli and cellular mechanobiology orchestrates the physiology of tissues and organs in a dynamic balance characterized by constant remodelling and adaptative processes. Environmental mechanical properties can be interpreted as a complex set of information and instructions that cells read continuously, and to which they respond. In cirrhosis, chronic inflammation and injury drive liver cells dysfunction, leading to excessive extracellular matrix deposition, sinusoidal pseudocapillarization, vascular occlusion and parenchymal extinction. These pathological events result in marked remodelling of the liver microarchitecture, which is cause and result of abnormal environmental mechanical forces, triggering and sustaining the long-standing and progressive process of liver fibrosis. Multiple mechanical forces such as strain, shear stress, and hydrostatic pressure can converge at different stages of the disease until reaching a point of no return where the fibrosis is considered non-reversible. Thereafter, reciprocal communication between cells and their niches becomes the driving force for disease progression. Accumulating evidence supports the idea that, rather than being a passive consequence of fibrosis and portal hypertension (PH), mechanical force-mediated pathways could themselves represent strategic targets for novel therapeutic approaches. In this manuscript, we aim to provide a comprehensive review of the mechanobiology of PH, by furnishing an introduction on the most important mechanisms, integrating these concepts into a discussion on the pathogenesis of PH, and exploring potential therapeutic strategies

Polyenylphosphatidylcholines as bioactive excipient in tablets for the treatment of liver fibrosis.

Liver fibrosis is a condition characterized by the accumulation of extracellular matrix (ECM) arising from the myofibroblastic transdifferentiation of hepatic stellate cells (HSCs) occurring as the natural response to liver damage. To date, no pharmacological treatments have been specifically approved for liver fibrosis. We recently reported a beneficial effect of polyenylphosphatidylcholines (PPCs)-rich formulations in reverting fibrogenic features of HSCs. However, unsaturated phospholipids' properties pose a constant challenge to the development of tablets as preferred patient-centric dosage form. Profiting from the advantageous physical properties of the PPCs-rich Soluthin® S 80 M, we developed a tablet formulation incorporating 70% w/w of this bioactive lipid. Tablets were characterized via X-ray powder diffraction, thermogravimetry, and Raman confocal imaging, and passed the major compendial requirements. To mimic physiological absorption after oral intake, phospholipids extracted from tablets were reconstituted as protein-free chylomicron (PFC)-like emulsions and tested on the fibrogenic human HSC line LX-2 and on primary cirrhotic rat hepatic stellate cells (PRHSC). Lipids extracted from tablets and reconstituted in buffer or as PFC-like emulsions exerted the same antifibrotic effect on both activated LX-2 and PRHSCs as observed with plain S 80 M liposomes, showing that the manufacturing process did not interfere with the bioactivity of PPCs

Transforming growth factor β-mediated micromechanics modulates disease progression in primary myelofibrosis.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadPrimary myelofibrosis (PMF) is a Ph-negative myeloproliferative neoplasm (MPN), characterized by advanced bone marrow fibrosis and extramedullary haematopoiesis. The bone marrow fibrosis results from excessive proliferation of fibroblasts that are influenced by several cytokines in the microenvironment, of which transforming growth factor-β (TGF-β) is the most important. Micromechanics related to the niche has not yet been elucidated. In this study, we hypothesized that mechanical stress modulates TGF-β signalling leading to further activation and subsequent proliferation and invasion of bone marrow fibroblasts, thus showing the important role of micromechanics in the development and progression of PMF, both in the bone marrow and in extramedullary sites. Using three PMF-derived fibroblast cell lines and transforming growth factor-β receptor (TGFBR) 1 and 2 knock-down PMF-derived fibroblasts, we showed that mechanical stress does stimulate the collagen synthesis by the fibroblasts in patients with myelofibrosis, through the TGFBR1, which however seems to be activated through alternative pathways, other than TGFBR2. Keywords: TGF-β; fibroblast activation; invasion; micromechanics; myelofibrosis; proliferation.School of Doctoral Studies-Iuliu Hatieganu University Romanian Government Ion Chiricuta Oncology Institute Cluj Napoca international collaborative grant of the European Economic Space between Romania and Iceland 2020-2022 1

Regression of portal hypertension: underlying mechanisms and therapeutic strategies.

Portal hypertension is the main non-neoplastic complication of chronic liver disease, being the cause of important life-threatening events including the development of ascites or variceal bleeding. The primary factor in the development of portal hypertension is a pathological increase in the intrahepatic vascular resistance, due to liver microcirculatory dysfunction, which is subsequently aggravated by extra-hepatic vascular disturbances including elevation of portal blood inflow. Evidence from pre-clinical models of cirrhosis has demonstrated that portal hypertension and chronic liver disease can be reversible if the injurious etiological agent is removed and can be further promoted using pharmacological therapy. These important observations have been partially demonstrated in clinical studies. This paper aims at providing an updated review of the currently available data regarding spontaneous and drug-promoted regression of portal hypertension, paying special attention to the clinical evidence. It also considers pathophysiological caveats that highlight the need for caution in establishing a new dogma that human chronic liver disease and portal hypertension is reversible

Role of calcium integrin-binding protein 1 in the mechanobiology of the liver endothelium.

Liver sinusoidal endothelial cells (LSECs) dysfunction is a key process in the development of chronic liver disease (CLD). Progressive scarring increases liver stiffness in a winch-like loop stimulating a dysfunctional liver cell phenotype. Cellular stretching is supported by biomechanically modulated molecular factors (BMMFs) that can translocate into the cytoplasm to support mechanotransduction through cytoskeleton remodeling and gene transcription. Currently, the molecular mechanisms of stiffness-induced LSECs dysfunction remain largely unclear. Here we propose calcium- and integrin-binding protein 1 (CIB1) as BMMF with crucial role in LSECs mechanobiology in CLD. CIB1 expression and translocation was characterized in healthy and cirrhotic human livers and in LSECs cultured on polyacrylamide gels with healthy and cirrhotic-like stiffnesses. Following the modulation of CIB1 with siRNA, the transcriptome was scrutinized to understand downstream effects of CIB1 downregulation. CIB1 expression is increased in LSECs in human cirrhosis. In vitro, CIB1 emerges as an endothelial BMMF. In human umbilical vein endothelial cells and LSECs, CIB1 expression and localization are modulated by stiffness-induced trafficking across the nuclear membrane. LSECs from cirrhotic liver tissue both in animal model and human disease exhibit an increased amount of CIB1 in cytoplasm. Knockdown of CIB1 in LSECs exposed to high stiffness improves LSECs phenotype by regulating the intracellular tension as well as the inflammatory response. Our results demonstrate that CIB1 is a key factor in sustaining cellular tension and stretching in response to high stiffness. CIB1 downregulation ameliorates LSECs dysfunction, enhancing their redifferentiation, and reducing the inflammatory response