TaoHe ChengQi Decoction Inhibits PAD4-mediated Neutrophil Extracellular Traps and Mitigates Acute Lung Injury Induced By Sepsis

Acute lung injury (ALI) is a significant complication of sepsis, characterized by high morbidity, mortality, and poor prognosis. Neutrophils, as one of the most important intrinsic immune cells in the lung, play a crucial role in the development and progression of ALI. In ALI, neutrophils are able to produce neutrophil extracellular traps (NETs), and an excess of NETs can exacerbate inflammatory injury. Some studies have shown that TaoHe ChengQi Decoction (THCQD) can ameliorate sepsis-induced lung inflammation, modulate immune function. The aim of this study was to investigate how THCQD improves ALI and its relationship with NETs in sepsis patients, with a view to providing new perspectives and interventions for clinical treatment. The experimental results show that THCQD improved the survival rate and alleviated lung injury in the CLP-induced ALI mouse model. Additionally, THCQD attenuated neutrophil, macrophage infiltration and inflammatory responses, while also decreasing the production of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α. More importantly, further experiments confirmed that THCQD suppresses the formation of NETs both in vivo and in vitro. In addition, THCQD effectively reduced the expression of peptidyl arginine deiminase 4 (PAD4) protein, and molecular docking was used to predict that some of the active compounds in THCQD could bind tightly to PAD4. Overexpression of PAD4 partially counteracted THCQD's inhibitory effects on PAD4. Overall, these results above strongly suggest that THCQD mitigates CLP-induced acute lung injury by inhibiting PAD4-mediated NETs.