Optimised murine model of influenza-induced respiratory sepsis for studying acute kidney injury

Abstract

Abstract Background Viral respiratory sepsis, driven by influenza and COVID-19, is increasingly prominent clinically. However, there is a lack of preclinical models that reliably replicate its associated acute kidney injury (AKI), a major contributor to morbidity and mortality. Methods We refined an established model of influenza-induced respiratory sepsis by administering graded intranasal H1N1 A/PR/8/34 doses (3.7 × 10¹, 3.7 × 10³, and 3.7 × 10⁴ TCID₅₀) in male BALB/c mice. We defined humane endpoints to ≥ 30% body weight loss, monitored clinical severity, weight, and glycaemia daily for 14 days, and assessed multi-organ dysfunction via serum biochemistry, histopathology, renal qPCR, and longitudinal serum neutrophil gelatinase-associated lipocalin (NGAL) ELISA. Results The 3.7 × 10⁴ TCID₅₀ dose yielded 66.7% mortality by day 8, with a peak clinical score (MSS) of 10, > 30% weight loss, and hypoglycaemia (blood glucose < 70 mg/dL). Infected mice exhibited dose-dependent multi-organ dysfunction, with substantial elevations in serum creatinine (median: 204 [IQR: 142–600] µmol/L), bilirubin (40.62 [29.3–124.9] µmol/L), and creatine phosphokinase (CPK) (9822 [1272–11352] U/L). Renal NGAL expression increased 7-fold, aligning with rising serum creatinine levels and histopathological glomerular enlargement. Serum NGAL rose sharply by day 2 (4990 ng/mL) and sustained 5.7–7.6-fold elevation versus sham controls through days 4–8. Conclusion This optimised model simulates influenza-induced respiratory sepsis with AKI, highlighting serum NGAL as an early, dynamic biomarker. It provides a valuable preclinical tool for mechanistic and therapeutic studies in respiratory sepsis-associated AKI.