Netrin-1 mitigates acute lung injury by preventing the activation of the Toll-like receptor 4/nuclear factor-KB (TLR4/NF-KB) signaling

Acute lung injury (ALI) is one of the most common high -risk diseases associated with a high mortality rate and is still a challenge to treat effectively. Netrin-1 (NT -1) is a novel peptide with a wide range of biological functions, however, its effects on ALI have not been reported before. In this study, an ALI model was constructed using lipopolysaccharide (LPS) and treated with NT -1. Pulmonary function and lung wet to dry weight ratio (W/D) were detected. The expressions of pro -inflammatory cytokines and chemokines interleukin-8 (IL -8), interleukin1 beta (IL-1 beta), and chemokine (C -X-C motif) ligand 2 (CXCL2) were measured using real-time polymerase chain reaction (RT-PCR) and enzyme -linked immunosorbent assay (ELISA). We found that the levels of NT -1 were reduced in the LPS-induced ALI mice model. Administration of NT -1 improved histopathological changes of lung tissues and lung function in LPS-challenged ALI mice. We also report that NT -1 decreased Myeloperoxidase (MPO) activity and ameliorated pulmonary edema. Additionally, treatment with NT -1 reduced the levels of proinflammatory cytokines and chemokines such as IL -8, IL-1 beta, and CXCL2 in lung tissues of LPS-challenged ALI mice. Importantly, NT -1 reduced cell count in BALF and mitigated oxidative stress (OS) by reducing the levels of MDA and increasing the levels of GSH. Mechanistically, it is shown that NT -1 reduced the levels of Toll -like receptor 4 (TLR4) and prevented nuclear translocation of nuclear factor -KB (NF -KB) p65. Our findings indicate that NT -1 is a promising agent for the treatment of ALI through inhibiting TLR4/NF-KB signaling.