Cepharanthine alleviates lipopolysaccharide-induced acute lung injury through modulating macrophage polarization

Sep 30, 2026

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Acute lung injury (ALI) is driven by dysregulated inflammation in which macrophage functional states shape disease severity and recovery. This study evaluates whether cepharanthine (CEP), a natural bisbenzylisoquinoline alkaloid, alleviates LPS-induced ALI by regulating macrophage polarization. Using H&E staining, ELISA, immunofluorescence, and western blot, CEP improved mouse lung pathology, reduced IL-6 and TNF-α while increasing IL-10, suppressed M1 polarization and enhanced M2 polarization, inhibited TLR4/MAPK signaling, and activated the AMPK/Nrf2 pathway in vitro and in vivo.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Introduction

Background of acute lung injury and inflammation

Role of lipopolysaccharide and PRR/PAMP signaling

Macrophage polarization (M1/M2) in ALI

Cepharanthine and research rationale

Biological properties of CEP

Hypothesis and therapeutic strategy

[www. nature.com/scientificreports](www. nature.com/scientificreports) OPEN Cepharanthine alleviateslipopolysaccharide-induced acute lung injury through modulating macrophage polarization Longjiao Dang1, Biyao He1, Junjie Yang1, Jiayu Liu1, Yuexia Ding2􀀍 & Wenyu Xin1􀀍 Acute lung injury (ALI) is a common, severe respiratory disorder frequently related to acute lung inflammation. As crucial immunoregulatory cells, macrophages critically influence the pathological trajectory of ALI, with their functional states serving as predictive biomarkers for both lesion severity and patient recovery trajectories. Cepharanthine (CEP), a natural bisbenzylisoquinoline (BBIQ) alkaloid, was shown to have substantial anti-inflammatory properties. However, whether CEP can alleviate ALI by regulating macrophage polarization needs to be clarified. Therefore, the therapeutic effect ofCEP in ALI was explored via H&E staining, enzyme-linked immunosorbent assays (ELISAs), immunofluorescence, and western blot. In vivo, experimental data demonstrated that CEP intervention significantly ameliorated mouse pathological alterations. Specifically, the secretion levels of pro-inflammatory cytokines IL-6 and TNF-α were dose-dependently downregulated, while the expression of the anti-inflammatory mediator IL-10 exhibited a significant upregulation trend. Immunofluorescence staining revealed that CEP suppressed lipopolysaccharide (LPS)-induced M1 macrophage polarization and increased M2 macrophage polarization. Moreover, western blot results showed that CEP inhibited TLR4/MAPK signaling pathway activation but increasedAMPK phosphorylation and Nrf2/HO-1 expression. Experimental findings from in vitro studies aligned with observations corresponding to in vivo models. In summary, CEP can regulate macrophage polarization to protect against LPS-induced ALI by interfering with TLR4/MAPK signaling and activating the AMPK/ Nrf2 pathway. Keywords Acute lung injury, Lipopolysaccharide, Cepharanthine, Macrophage polarization Diffuse alveolar injury, which can result in excessive lung inflammation and alveolar epithelial cell death, is a characteristic of acute lung injury (ALI)1. Without timely treatment, patients can develop acute respiratory distress syndrome (ARDS), and the mortality rate can increase. Increased vascular permeability, pulmonary edema, intrapulmonary bleeding, and compromised gas exchange are some symptoms of ALI’s inflammatory and oxidative stress-related mechanisms2. Significant breakthroughs have been made with the increasing number of in-depth studies on ALI/ARDS. At present, the clinical treatment of ALI/ARDS mainly includes lung-protective ventilation and glucocorticoids3, but these treatments result in many side effects and poor prognoses. Therefore, effective therapeutic drugs against ALI are urgently needed. There is broad scientific consensus that lipopolysaccharide (LPS), functioning as a prototypical ligand in the study of pattern recognition receptor (PRR) systems, holds paramount importance within the research domain of Pathogen-Associated Molecular Patterns (PAMPs) . It is an essential component of the outer membrane of LPS and a vital pathogenic component of ALI4. Increased expression of many proinflammatory cytokines, such as TNF-α, IL-6, IL-1β, and NO, occurs via the ensuing cascades in response to LPS stimulation5. Moreover, appropriate inflammatory responses are crucial in inducing innate immunity and promoting pathogen clearance6. However, an excessive inflammatory response is vital in the pathogenesis of LPS-induced ALI7. Jin Li reported that Obacunone can reverse pathological damage in ALI by inhibiting excessive inflammatory response8. Based 1Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, School of Pharmacy, Binzhou Medical University, No.346 Guanhai Road, Laishan District, Yantai 264003, Shandong, China. 2Department of Pharmacy, the Aff

FAQs

What is the role of macrophage polarization in acute lung injury?

Macrophages are key immunoregulatory cells in ALI, and their polarization into M1 (pro-inflammatory) or M2 (immunomodulatory) states influences inflammatory progression and recovery.

How does cepharanthine (CEP) affect cytokine levels in LPS-induced ALI?

CEP downregulates pro-inflammatory cytokines IL-6 and TNF-α in a dose-dependent manner and increases the anti-inflammatory mediator IL-10.

Which signaling pathways are involved in CEP’s protective mechanism?

CEP inhibits activation of the TLR4/MAPK signaling pathway and promotes AMPK phosphorylation as well as Nrf2/HO-1 expression, supporting macrophage polarization changes and lung protection.

Sep 30, 2026

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