Mechanistic insights into mitigation of sepsis-induced acute lung injury by quercitrin via TLR4/MAPK pathway inhibition.

Abstract

OBJECTIVES: Sepsis-induced acute lung injury (ALI) lacks effective treatments. Quercitrin, a natural flavonoid with anti-inflammatory and antioxidant properties, shows therapeutic potential, but its mechanisms, particularly regarding TLR4/MAPK pathway inhibition, require clarification. METHODS: A lipopolysaccharide (LPS)-induced murine ALI model was utilized. Mice were divided into: control, LPS + vehicle, and LPS + Quercitrin (7.5, 15, 30 mg/kg) groups. We evaluated lung histopathology, wet/dry ratio, bronchoalveolar lavage fluid cell counts, myeloperoxidase activity, inflammatory cytokines (by ELISA), oxidative markers (malondialdehyde, superoxide dismutase), and TLR4/MAPK pathway proteins (by Western blot). Rescue studies involved co-treatment with the TLR4/MAPK agonist. KEY FINDINGS: Quercitrin administration, in a dose-dependent manner, improved survival, ameliorated lung injury scores, reduced pulmonary oedema (wet-to-dry ratio), and suppressed inflammatory cell infiltration and myeloperoxidase activity. It significantly decreased pro-inflammatory cytokine levels and mitigated oxidative stress by lowering malondialdehyde and elevating superoxide dismutase. Mechanistically, quercitrin inhibited TLR4 expression and the phosphorylation of p38, JNK, and ERK MAPKs. The protective effects were substantially reversed by TLR4/MAPK agonist co-administration. CONCLUSIONS: Quercitrin protects against LPS-induced ALI by mitigating inflammatory responses and oxidative stress. This protection is mechanistically linked to the inhibition of the TLR4/MAPK signaling pathway, underscoring its therapeutic potential for sepsis-associated ALI.