Abstract
Background and Aims: Postoperative peritoneal adhesion formation frequently occurs and remains a major problem after abdominal surgery. Daikenchuto (TU-100), a traditional Japanese oral medicine, prevents peritoneal adhesion after abdominal surgery. However, the precise mechanism of action is still unclear. We recently reported that 6-shogaol (6SG) and hydroxy α-sanshool (HAS), the main ingredients in TU-100, are absorbed in humans and can enhance the endogenous anti-fibrotic and anti-inflammatory peptide, adrenomedullin (ADM). The peritoneal fibrinolytic system is crucial for peritoneal adhesion formation. The present study assessed the mechanism of ADM production and the fibrinolytic responses of mesothelial cells to inflammatory factors to determine the anti-adhesion mechanism of TU-100. Methods: Test samples were added to cultures of the rat mesothelial cell line 4/ 4RM-4. After 6 to 24 h, the levels of ADM, tissue plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) in the culture supernatants were measured by EIA and RT-PCR. The active ingredients of TU-100 in the blood of rats that were orally administered TU-100 were measured by LC-Ms/Ms. Results: ADM production by 4/4RM-4 cells was significantly increased upon the addition of 6SG and HAS, which were efficiently absorbed into the circulation within 30 minutes after oral administration. Because these compounds activate the transient receptor potential (TRP) V1 and A1 channels, the TRPA1 agonist allyl isothiocyanate (AITC) and TRPV1 agonist capsaicin (CAP) were evaluated in the ADM production test. AITC, but not CAP, was active and increased ADM production. This activity of 6SG, HAS and AITC was significantly abolished by also adding the TRPA1 antagonist HC-030031. RT-PCR analysis demonstrated that 4/4RM-4 cells expressed messenger RNA for TRPA1 but not TRPV1. Inflammatory mediators IL-6, TNFα, and lipopolysaccharide (LPS) upregulated PAI-1, but not tPA, production by 4/4RM-4 cells. Conversely, ADM downregulated PAI-1 without affecting tPA, and moreover inhibited IL-6 and TNFα production by immune cells. Conclusions: ADM can restore the imbalance in the fibrinolytic
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