RANKL Attenuates Sepsis-Associated Acute Lung Injury Through the OPG/RANKL/RANK/TLR4 Pathway.

Abstract

BACKGROUND: Sepsis-associated acute lung injury (SA-ALI) is a critical disease marked by a dysregulated immune response to infection, causing organ dysfunction. OBJECTIVE: We explored the effect of receptor activator of nuclear factor-κB ligand (RANKL) on SA-ALI and the mechanism involving the osteoprotegerin (OPG)/RANKL/RANK (receptor activator of nuclear factor-κB)/TLR4 (Toll-like receptor 4) signaling pathway. METHODS: The SA-ALI model was established in C57BL/6 mice. Recombinant RANKL or anti-RANKL antibodies were administered intraperitoneally as pretreatment 2 h before modeling. After 24 h of modeling, ELISA measured the cytokine concentrations in the serum and bronchoalveolar lavage fluid. The TLR4, RANK, RANKL, and OPG levels in the lung tissues were analyzed using Western blot and real-time quantitative PCR. HE staining assessed the pathological alterations in lung tissue. RESULTS: Recombinant RANKL pretreatment had a protective effect on SA-ALI mice and lowered the serum and bronchoalveolar lavage fluid concentrations of IL-1β, TNF-α, and IL-6. It also reduced TLR4, RANK, and OPG levels in lung tissue while increasing RANKL levels. Moreover, lung tissue pathological changes were alleviated by recombinant RANKL. Conversely, treatment with anti-RANKL antibodies reversed the changes in the above indicators and aggravated lung tissue pathological damage in mice. CONCLUSION: Pretreatment with recombinant RANKL can reduce lung damage in SA-ALI mice by inhibiting inflammation, with the underlying mechanism potentially associated with the OPG/RANKL/RANK/TLR4 pathway.