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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

Evaluation of Dose-Dependent Efficacy and Mechanisms of Aspirin Combined with Intravenous Immunoglobulin in a Murine Model of Kawasaki Disease Vasculitis

  • Kuang-Jen Chien1
  • Shih-Hui Huang2
  • Wei-De Wang1,3
  • Chun-Kuei Huang1
  • Ho-Chang Kuo4,5,6
  • Yao-Tsung Yeh7
  • Chu-Chuan Lin1
  • Kai-Sheng Hsieh8
  • Ken-Pen Weng1,9
9 affiliations
  1. 1Congenital Structural Heart Disease Center, Department of Pediatrics, Kaohsiung Veterans General Hospital, 386 Ta-Chung 1st Road, Kaohsiung 813, Taiwan
  2. 2Department of Nursing, Fooyin University, Kaohsiung 831, Taiwan
  3. 3Zuoying Armed Forces General Hospital, Kaohsiung 813, Taiwan
  4. 4Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
  5. 5Department of Pediatrics and Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
  6. 6College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
  7. 7Aging and Diseases Prevention Research Center, Department of Medical Laboratory Science and Biotechnology, Fooyin University, Kaohsiung 831, Taiwan
  8. 8Department of Pediatrics, China Medical University Children’s Hospital, Taichung 404, Taiwan
  9. 9School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
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Abstract

The requirement and molecular contribution of acute high-dose aspirin (ASA) in the treatment of Kawasaki disease (KD) remain clinically controversial. This study aimed to investigate the dose-dependent mechanism and pharmacodynamics of adjunctive ASA in an experimental KD mouse model. Male C57BL/6 mice were injected with Lactobacillus casei cell wall extract (LCWE; 100 µg/day, Days 1–7) to induce systemic coronary arteritis. On Day 14, mice received intravenous immunoglobulin (IVIG) (2 g/kg, i.p.) monotherapy (G3) or IVIG combined with High-dose (100 mg/kg; G4), Medium-dose (50 mg/kg; G5), or Low-dose ASA (5 mg/kg; G6) daily via oral gavage for 3 days (Days 14–16), followed by a 5-day drug washout until sacrifice on Day 21. Coronary vasculitis and internal elastic lamina integrity were quantified using H&E and Verhoeff–Van Gieson (VVG) staining. Heart tissue activation of p-nuclear factor kappa-B (NF-κB) and downstream matrix metalloproteinance-9 (MMP-9) expression were evaluated by Western blot. High-dose ASA combined with IVIG (G4) achieved statistically superior suppression of upstream NF-κB phosphorylation (p-NF-κB/NF-κB ratio) and perivascular leukocyte infiltration compared to IVIG monotherapy (G3) (p < 0.05). This acute upstream blockade directly preserved arterial wall architecture, with G4 demonstrating near-baseline structural restoration of the internal elastic lamina on VVG scoring (G4 vs. G3, p < 0.05). Following the 5-day drug washout, downstream MMP-9 expression in G4 converged with G3 levels due to pharmacodynamic waning, whereas suboptimal mid/low-dose ASA regimens (G5/G6) displayed lingering MMP-9 elevation, indicating persistent low-grade matrix remodeling. Acute high-dose ASA provides a non-redundant, synergistic anti-inflammatory effect alongside IVIG to prevent early elastolysis. Maintaining adequate acute ASA dose followed by careful post-withdrawal tapering is vital to prevent delayed arterial wall remodeling and coronary aneurysm progression.

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Cite

BibTeXRIS
BibTeX
@article{chien2026evaluation,
  title = {{Evaluation of Dose-Dependent Efficacy and Mechanisms of Aspirin Combined with Intravenous Immunoglobulin in a Murine Model of Kawasaki Disease Vasculitis}},
  author = {Kuang-Jen Chien and Shih-Hui Huang and Wei-De Wang and Chun-Kuei Huang and Ho-Chang Kuo and Yao-Tsung Yeh and Chu-Chuan Lin and Kai-Sheng Hsieh and Ken-Pen Weng},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = oct,
  doi = {10.3390/ijms27219783},
  url = {https://www.mdpi.com/1422-0067/27/21/9783},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Evaluation of Dose-Dependent Efficacy and Mechanisms of Aspirin Combined with Intravenous Immunoglobulin in a Murine Model of Kawasaki Disease Vasculitis
AU  - Kuang-Jen Chien
AU  - Shih-Hui Huang
AU  - Wei-De Wang
AU  - Chun-Kuei Huang
AU  - Ho-Chang Kuo
AU  - Yao-Tsung Yeh
AU  - Chu-Chuan Lin
AU  - Kai-Sheng Hsieh
AU  - Ken-Pen Weng
PY  - 2026
DA  - 2026/10/30
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27219783
UR  - https://www.mdpi.com/1422-0067/27/21/9783
AB  - The requirement and molecular contribution of acute high-dose aspirin (ASA) in the treatment of Kawasaki disease (KD) remain clinically controversial. This study aimed to investigate the dose-dependent mechanism and pharmacodynamics of adjunctive ASA in an experimental KD mouse model. Male C57BL/6 mice were injected with Lactobacillus casei cell wall extract (LCWE; 100 µg/day, Days 1–7) to induce systemic coronary arteritis. On Day 14, mice received intravenous immunoglobulin (IVIG) (2 g/kg, i.p.) monotherapy (G3) or IVIG combined with High-dose (100 mg/kg; G4), Medium-dose (50 mg/kg; G5), or Low-dose ASA (5 mg/kg; G6) daily via oral gavage for 3 days (Days 14–16), followed by a 5-day drug washout until sacrifice on Day 21. Coronary vasculitis and internal elastic lamina integrity were quantified using H&E and Verhoeff–Van Gieson (VVG) staining. Heart tissue activation of p-nuclear factor kappa-B (NF-κB) and downstream matrix metalloproteinance-9 (MMP-9) expression were evaluated by Western blot. High-dose ASA combined with IVIG (G4) achieved statistically superior suppression of upstream NF-κB phosphorylation (p-NF-κB/NF-κB ratio) and perivascular leukocyte infiltration compared to IVIG monotherapy (G3) (p < 0.05). This acute upstream blockade directly preserved arterial wall architecture, with G4 demonstrating near-baseline structural restoration of the internal elastic lamina on VVG scoring (G4 vs. G3, p < 0.05). Following the 5-day drug washout, downstream MMP-9 expression in G4 converged with G3 levels due to pharmacodynamic waning, whereas suboptimal mid/low-dose ASA regimens (G5/G6) displayed lingering MMP-9 elevation, indicating persistent low-grade matrix remodeling. Acute high-dose ASA provides a non-redundant, synergistic anti-inflammatory effect alongside IVIG to prevent early elastolysis. Maintaining adequate acute ASA dose followed by careful post-withdrawal tapering is vital to prevent delayed arterial wall remodeling and coronary aneurysm progression.
SN  - 1422-0067
ER  -