NKCC1 inhibition as a breakthrough in combating coagulopathy and boosting survival in LPS-induced DIC rat model

Sepsis presents a critical challenge, frequently escalating into a cascade characterized by uncontrolled inflammation, oxidative stress, and coagulopathy. This progression often leads to disseminated intravascular coagulation (DIC) and multiple organ dysfunction syndrome (MODS), both of which are life-threatening conditions. This study focuses on furosemide, a diuretic traditionally known for inhibiting the Na⁺-K⁺-2Cl^- cotransporter 1 (NKCC1), which has been recently identified for its anti-inflammatory and antioxidant properties. We investigated furosemide's therapeutic potential in a lipopolysaccharide (LPS)-induced DIC-like rat model. Male Wistar rats were assigned to four groups: a control group, a control group treated with furosemide (3 mg/kg, intravenously at 1 h), an LPS group (10 mg/kg, infused over 40 min), and an LPS group treated with furosemide. Coagulopathy progression was monitored using a refined scoring system based on the International Society on Thrombosis and Haemostasis (ISTH) criteria. LPS led to hemodynamic abnormalities, pronounced coagulopathy (meeting the overt stage criteria in our scoring system), multiple organ dysfunction (as evidenced by biochemical markers and blood flow analysis), and a high mortality rate. These effects were further exacerbated by increases in inflammatory cytokines, superoxide, nitric oxide, and NKCC1 expression. Notably, furosemide significantly mitigated these effects by limiting coagulopathy to the non-overt stage in our scoring system, alleviating multiple organ dysfunctions, and improving survival rates. The underlying therapeutic mechanisms are attributed to furosemide's anti-inflammatory and antioxidative properties, potentially mediated through NKCC1 inhibition. Our study not only underscores furosemide's potential in treating LPS-induced DIC, but also suggests its repurposing for managing sepsis and complex sepsis-related complications.