Oxidative Stress-Induced Liver Damage and Remodeling of the Liver Vasculature.

As an organ critically important for targeting and clearing viruses, bacteria, and other foreign material, the liver operates via immune-tolerant, anti-inflammatory mechanisms indispensable to the immune response. Stress and stress-induced factors disrupt the homeostatic balance in the liver, inflicting tissue damage, injury, and remodeling. These factors include oxidative stress (OS) induced by viral infections, environmental toxins, drugs, alcohol, and diet. A recurrent theme seen among stressors common to multiple liver diseases is the induction of mitochondrial dysfunction, increased reactive oxygen species expression, and depletion of ATP. Inflammatory signaling additionally exacerbates the condition, generating a proinflammatory, immunosuppressive microenvironment and activation of apoptotic and necrotic mechanisms that disrupt the integrity of liver morphology. These pathways initiate signaling pathways that significantly contribute to the development of liver steatosis, inflammation, fibrosis, cirrhosis, and liver cancers. In addition, hypoxia and OS directly enhance angiogenesis and lymphangiogenesis in chronic liver diseases. Late-stage consequences of these conditions often narrow the outcomes for liver transplantation or result in death. This review provides a detailed perspective on various stress-induced factors and the specific focus on role of OS in different liver diseases with special emphasis on different molecular mechanisms. It also highlights how resultant changes in the liver vasculature correlate with pathogenesis.

Conjugated Bile Acids Promote Lymphangiogenesis by Modulation of the Reactive Oxygen Species-p90RSK-Vascular Endothelial Growth Factor Receptor 3 Pathway.

Conjugated bile acids (BA) are significantly elevated in several liver pathologies and in the metastatic lymph node (LN). However, the effects of BAs on pathological lymphangiogenesis remains unknown. The current study explores the effects of BAs on lymphangiogenesis. BA levels were elevated in the LN and serum of Mdr2-/- mice (model of sclerosing cholangitis) compared to control mice. Liver and LN tissue sections showed a clear expansion of the lymphatic network in Mdr2-/- mice, indicating activated lymphangiogenic pathways. Human lymphatic endothelial cells (LECs) expressed BA receptors and a direct treatment with conjugated BAs enhanced invasion, migration, and tube formation. BAs also altered the LEC metabolism and upregulated key metabolic genes. Further, BAs induced the production of reactive oxygen species (ROS), that in turn phosphorylated the redox-sensitive kinase p90RSK, an essential regulator of endothelial cell dysfunction and oxidative stress. Activated p90RSK increased the SUMOylation of the Prox1 transcription factor and enhanced VEGFR3 expression and 3-D LEC invasion. BA-induced ROS in the LECs, which led to increased levels of Yes-associated protein (YAP), a lymphangiogenesis regulator. The suppression of cellular YAP inhibited BA-induced VEGFR3 upregulation and lymphangiogenic mechanism. Overall, our data shows the expansion of the lymphatic network in presclerotic liver disease and establishes a novel mechanism whereby BAs promote lymphangiogenesis.

Cellular Senescence as a Brake or Accelerator for Oncogenic Transformation and Role in Lymphatic Metastasis.

Cellular senescence-the irreversible cell cycle arrest driven by a variety of mechanisms and, more specifically, the senescence-associated secretory phenotype (SASP)-is an important area of research in the context of different age-related diseases, such as cardiovascular disease and cancer. SASP factors play both beneficial and detrimental roles in age-related disease progression depending on the source of the SASPs, the target cells, and the microenvironment. The impact of senescence and the SASP on different cell types, the immune system, and the vascular system has been widely discussed. However, the impact of replicative or stress-induced senescence on lymphatic biology and pathological lymphangiogenesis remains underexplored. The lymphatic system plays a crucial role in the maintenance of body fluid homeostasis and immune surveillance. The perturbation of lymphatic function can hamper normal physiological function. Natural aging or stress-induced premature aging influences the lymphatic vessel structure and function, which significantly affect the role of lymphatics in tumor dissemination and metastasis. In this review, we focus on the role of senescence on lymphatic pathobiology, its impact on cancer, and potential therapeutic interventions to manipulate the aged or senescent lymphatic system for disease management.