Extracellular nucleotides are released from injured cells and act as immunomodulators in various inflammatory conditions through diverse purinergic receptors. Recently, P2Y₆ receptor gene knockout was reported to suppress pathogenesis in a mouse model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). In this study, we investigated effects of a novel inhibitor of P2Y₆ receptor TIM-38 on LPS-induced ALI model mice.
In ALI model mice generated by intratracheal administration of LPS, UDP concentration was increased in bronchoalveolar lavage fluid (BALF). In addition, mRNA levels of inflammatory mediators such as TNFα, IL-6, and CXCL-2 were increased in lung tissues and the associated protrin secretions in BALF were observed in ALI model mice. Administration of TIM-38 significantly inhibited the elevation of inflammatory mediator mRNA expression and associated protein secretions induced by LPS. In addition, TIM-38 suppressed LPS-induced increase in infiltrated neutrophils in BALF. In the experiment using mice macrophage cell line RAW264.7, TIM-38 inhibited LPS-induced TNFα and IL-6 production, accompanied by inhibiting ERK and Akt, and NF-κB pathway. 
These results suggest that TIM-38 may be a potential therapeutic agent for  the lung tissue inflammatory responses induced by LPS in vivo through suppression of neutrophil migration and production of various inflammatory mediators.