Modulation of the CEACAM1/TIM3 pathway by traditional Chinese medicine Xuebijing alleviates sepsis-induced lung injury through inhibition of NETs formation

Shuai Zhang; Ming Jiang; Chao Wu; Huali Wang; Fei He

doi:10.1016/j.jep.2025.120280

Modulation of the CEACAM1/TIM3 pathway by traditional Chinese medicine Xuebijing alleviates sepsis-induced lung injury through inhibition of NETs formation

J Ethnopharmacol. 2025 Jul 10:120280. doi: 10.1016/j.jep.2025.120280. Online ahead of print.

Authors

Shuai Zhang¹, Ming Jiang², Chao Wu³, Huali Wang⁴, Fei He⁵

Affiliations

¹ Department of General Practice,Nanjing Second Hospital,Nanjing University of Chinese Medicine,Nanjing,210003.
² Department of Emergency Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing 210008, China.
³ Department of Infectious Disease, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, 210008, China.
⁴ Department of General Practice,Nanjing Second Hospital,Nanjing University of Chinese Medicine,Nanjing,210003. Electronic address: wanghuali78@126.com.
⁵ Department of Emergency Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing 210008, China. Electronic address: hefei1201@njglyy.com.

PMID: 40651727
DOI: 10.1016/j.jep.2025.120280

Abstract

Ethnopharmacological relevance: Xuebijing (XBJ), a traditional Chinese medicine formulation approved for the adjunctive treatment of sepsis, is derived from the classic Xuefu Zhuyu decoction. The formulation comprises key ingredients such as Carthamus tinctorius L., Paeonia lactiflora Pall., Ligusticum chuanxiong Hort., Salvia miltiorrhiza Bge., and Angelica sinensis (Oliv.) Diels, which are known for their anti-inflammatory and microcirculatory-regulating properties.

Aim of the study: To investigate whether XBJ alleviates sepsis-induced acute lung injury (S-ALI) by suppressing neutrophil extracellular traps (NETs) formation through the carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1)/T-cell immunoglobulin domain and mucin domain-3 (TIM3) pathway.

Materials and methods: S-ALI was induced in mice by cecal ligation and puncture and treated with XBJ at doses of 5, 10, or 20 mg/kg to assess the effects of XBJ on lung inflammation, oxidative stress, and pulmonary function. In the in vitro experiment, phorbol 12-myristate 13-acetate-stimulated neutrophils were treated with XBJ at 5%, 10%, or 20% concentrations to evaluate cytokine production, oxidative stress, NETs formation, and expression of CEACAM1 and TIM3 proteins. Additionally, a CEACAM1-overexpressing model in differentiated HL-60 neutrophil-like cells was used to investigate whether the CEACAM1/TIM3 pathway modulates the protective effects of XBJ.

Results: XBJ significantly reduced lung inflammation, oxidative stress, and NETs formation; enhanced lung function; and downregulated CEACAM1/TIM3 expression in vivo. In the in vitro study, XBJ attenuated inflammation, oxidative stress, and NETs formation and suppressed CEACAM1/TIM3 expression. However, CEACAM1 overexpression reversed these protective effects.

Conclusions: XBJ alleviates S-ALI by inhibiting NETs formation and mitigating inflammation and oxidative stress, likely through modulation of the CEACAM1/TIM3 pathway.

Keywords: CEACAM1/TIM3 pathway; Inflammation; Neutrophil extracellular traps; Sepsis-associated acute lung injury; Traditional Chinese medicine; Xuebijing.