L6H9 attenuates LPS-induced acute lung injury in rats through targeting MD2

Acute lung injury (ALI) is a clinical syndrome characterized by respiratory failure and acute inflammatory response. Myeloid differentiation protein 2 (MD2) has been reported to play a pivotal role in the recognition of LPS and LPS-mediates inflammatory response. There have been no clinically effective therapeutic drugs for ALI. L6H9, an inhibitor of MD2, showed anti-inflammatory effects and cardiac protective activity. However, its effect on ALI has not been elucidated. In this study, intratracheal instillation of LPS was employed to induce ALI in rats. L6H9 pretreatment attenuates LPS-induced pathological variations in lung tissue and pulmonary edema. LPS instillation enhanced lung microvascular permeability, thereby causing inflammatory cells flow into bronchoalveolar lavage fluid (BALF). However, L6H9 inhibited the LPS-induced upregulation of total protein concentration and the number of inflammatory cells in BALF. In the meantime, macrophages infiltration in lung tissue induced by LPS was also mitigated by L6H9 treatment. Furthermore, L6H9 suppressed LPS-induced inflammatory cytokines expression in BALF, serum, and lung tissue. It is noteworthy that LPS-induced MD2/TLR4 complex formation was inhibited by L6H9 in lung tissue. On the whole, these results show that L6H9 can attenuate LPS-induced ALI in vivo by targeting MD2. Our study provide new candidate for the treatment of ALI.