Abstract
Introduction: The angiotensin II type 1 receptor (AT1R) blockers play a crucial role in mediating inflammatory responses, and their blockade has emerged as a potential therapeutic strategy for mitigating sepsis-related organ damage, especially the liver. Fimasartan, a novel AT1R antagonist, has shown promise in preclinical studies for its anti-inflammatory properties and ability to improve survival in murine models of sepsis.
Objectives: This study aimed to explore the therapeutic potential of fimasartan in mitigating liver injury within a murine sepsis model.
Materials and Methods: This experimental study investigated the effects of fimasartan on sepsis-induced liver injury in 24 male albino Swiss mice, divided into four groups: Sham (laparotomy without cecal ligation and puncture [CLP]), CLP (cecal ligation and puncture to induce sepsis), vehicle (received dimethyl sulfoxide [DMSO]), and fimasartan-treated (received 3 mg/kg fimasartan intraperitoneal one hour before CLP). After 24 hours, the mice were sacrificed, and blood samples were analyzed for aspartate aminotransferase (AST), alanine aminotransferase (ALT), and macrophage migration inhibitory factor (MIF) levels, while liver tissues were examined for biomarkers including intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6), caspase-11, microtubule-associated protein 1A/1B-light chain 3 (LC3), malondialdehyde (MDA), superoxide dismutase (SOD), and Wnt/β-catenin genes. Histopathological analysis of liver tissues was also performed. The results were compared across groups to assess the therapeutic potential of fimasartan in mitigating sepsis-induced liver injury.
Results: The results demonstrated that following the CLP procedure, liver indicators such as ALT, AST, IL-6, ICAM-1, MIF, MDA, caspase-11, and liver injury scores were significantly elevated compared to the sham group. In contrast, treatment with fimasartan resulted in a marked reduction of these elevated levels compared to the CLP group. Additionally, CLP induction led to a significant decrease in hepatic levels of LC3, SOD, and Wnt/β-catenin signaling activity relative to the sham-operated controls. However, administration of fimasartan significantly reversed these reductions, highlighting its potential protective effects on liver function in sepsis.
Conclusion: Fimasartan demonstrated significant hepatoprotective effects in sepsis-induced liver injury. These findings suggest that fimasartan, an established angiotensin II receptor blocker already approved for hypertension management, could potentially be repurposed as an adjunctive therapy for patients with sepsis to mitigate liver dysfunction, a major contributor to sepsis mortality. Given the current limited therapeutic options for sepsis-induced organ damage, fimasartan represents a promising candidate for clinical trials, particularly in septic patients with early signs of liver involvement.