Uridine-mediated Activation of the Keap1-Nrf2 Pathway for Alleviating Sepsis-induced Acute Lung Injury

ABSTRACT

Background: Sepsis-induced pulmonary injury poses a significant challenge in critical care due to its high morbidity and mortality rates. Objectives: This study explores the potential of uridine to mitigate sepsis-induced pulmonary damage, specifically targeting the activation of the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. Materials and Methods: Both in vitro and in vivo approaches were utilized, incorporating MH-S cell lines exposed to lipopolysaccharide (LPS) to simulate inflammatory conditions and cecal ligation and puncture (CLP)-induced sepsis model in mice. The effects of uridine were evaluated on survival rates, pulmonary damage, bacterial colonization, as well as the expression of NRF2, KEAP1, heme oxygenase-1 (HO-1), and inflammatory cytokines. Results: Uridine treatment led to elevated levels of Nrf2 and HO-1, reduced KEAP1 expression, improved survival rates, decreased pulmonary damage and bacterial presence, and modulation of the Keap1-Nrf2 pathway. adeno-associated virus-mediated Nrf2 overexpression alleviated lung injury. The NRF2 inhibitor ML385 counteracted the beneficial effects of uridine, underscoring the critical role of the Keap1-Nrf2 pathway in these outcomes. Conclusion: Activation of the Keap1-Nrf2 pathway by uridine holds promise as a therapeutic strategy to enhance outcomes in sepsis-induced pulmonary damage. Further investigation is warranted to assess the therapeutic potential of uridine in sepsis management and to elucidate the underlying mechanisms of its protective effects.

KEYWORDS

• Sepsis
• acute lung injury
• uridine
• Keap1-Nrf2 signaling
• therapeutic strategy

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• DOI10.1177/09731296241275755Copy

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