Abstract Objective: Shenfu injection (SFI), derived from traditional Chinese Medicine, is commonly used to treat septic shock. Although programmed cell death signaling between macrophages and lymphocytes is known to be activated in sepsis, its role in mediating SFI’s therapeutic effects remains a central unanswered question. This work seeks to delineate the impact of SFI on immune regulation during sepsis in a rat model, aiming to uncover the associated molecular mechanisms that involve programmed cell death. Materials and Methods: Cecal ligation and puncture were employed to establish a rat model of sepsis, followed by SFI administration. Serum lactate and cytokine levels were measured. Programmed death signaling in splenic macrophages and lymphocytes was assessed. A lipopolysaccharide (LPS)-induced macrophage model was used to investigate SFI’s effects on inflammatory responses and ferroptosis-related gene expression. Results: SFI reduced serum lactate levels, spleen index, and inflammation in Cecal ligation and puncture (CLP)-induced septic rats. It also decreased monocyte apoptosis and programmed death signaling of lymphocytes in the spleen, and suppressed the production of programmed death-ligand 1 (PD-L1). In LPS-treated macrophages, SFI suppressed the expression of inflammation-and ferroptosis-related genes as well as PD-L1. In vitro experiments with cells showed that SFI triggered the activation of nuclear factor erythroid 2-related factor 2 (NRF2). Conclusions: SFI attenuated acute lung injury and immunosuppression in CLP-induced septic rats by suppressing programmed cell death signaling between macrophages and lymphocytes. These therapeutic effects are partially mediated via NRF2-dependent regulation of ferroptosis-related genes, suggesting SFI as a promising adjuvant therapy for sepsis management.
Xu et al. (Mon,) studied this question.
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