Neonatal sepsis is a life-threatening inflammatory condition. Extracellular 
cold-inducible RNA-binding protein (CIRP), a proinflammatory mediator, plays a 
critical role in the pathogenesis of sepsis-induced lung injury in neonates. 
Luteolin, a polyphenolic flavonoid, has potent anti-inflammatory properties. 
However, the effects of luteolin on CIRP production and neonatal sepsis-induced 
lung injury remained unknown. We therefore hypothesize that treatment with 
luteolin suppresses CIRP production and attenuates lung injury in neonatal 
sepsis. To study this, sepsis was induced in C57BL/6J mouse pups (5-7 days) by 
intraperitoneal cecal slurry injection (CSI). One hour after CSI, luteolin 
(10 mg/kg body weight) or vehicle (normal saline) was administered through 
intraperitoneal injection. CIRP mRNA and protein were determined and lung injury 
was assessed at 10 h after CSI. Our results showed that administration of 
luteolin decreased CIRP mRNA and protein, improved lung architecture, reduced 
lung edema, and apoptosis after CSI. To examine the direct effect of luteolin on 
CIRP production, peritoneal macrophages were isolated from neonatal mice and 
stimulated with 100 ng/mL LPS with or without the presence of luteolin. The 
result indicates that luteolin directly inhibited LPS-induced CIRP production in 
neonatal macrophages. In addition, luteolin also downregulated hypoxia-inducible 
factor-1α (HIF-1α) and NOD-like receptor 3 (NLRP3) expression in septic neonates 
and in LPS-stimulated neonatal macrophages. In conclusion, administration of 
luteolin suppresses CIRP production and attenuates lung injury in neonatal 
sepsis. The beneficial effect of luteolin may be related to downregulation of 
HIF-1α and NLRP3 expression in neonatal macrophages. Luteolin may be developed 
as an adjunctive therapy for neonatal sepsis.