The Covert Side of Ascites in Cirrhosis: Cellular and Molecular Aspects

Ascites, a common complication of portal hypertension in cirrhosis, is characterized by the accumulation of fluid within the peritoneal cavity. While traditional theories focus on hemodynamic alterations and renin-angiotensin-aldosterone system (RAAS) activation, recent research highlights the intricate interplay of molecular and cellular mechanisms. Inflammation, mediated by cytokines (interleukin-1, interleukin-4, interleukin-6, tumor necrosis factor-α), chemokines (chemokine ligand 21, C-X-C motif chemokine ligand 12), and reactive oxygen species (ROS), plays a pivotal role. Besides pro-inflammatory cytokines, hepatic stellate cells (HSCs), sinusoidal endothelial cells (SECs), and smooth muscle cells (SMCs) contribute to the process through their activation and altered functions. Once activated, these cell types can worsen ascites accumulationthrough extracellular matrix (ECM) deposition and paracrine signals. Besides this, macrophages, both resident and infiltrating, through their plasticity, participate in this complex crosstalk by promoting inflammation and dysregulating lymphatic system reabsorption. Indeed, the lymphatic system and lymphangiogenesis, essential for fluid reabsorption, is dysregulated in cirrhosis, exacerbating ascites. The gut microbiota and intestinal barrier alterations which occur in cirrhosis and portal hypertension also play a role by inducing inflammation, creating a vicious circle which worsens portal hypertension and fluid accumulation. This review aims to gather these aspects of ascites pathophysiology which are usually less considered and to date have not been addressed using specific therapy. Nonetheless, it emphasizes the need for further research to understand the complex interactions among these mechanisms, ultimately leading to targeted interventions in specific molecular pathways, aiming towards the development of new therapeutic strategies.