Inhibitory effects of pentacyclic triterpenoids from Astilbe rivularis on TGFBIp-induced inflammatory responses in vitro and in vivo

• Transforming growth factor β induced protein (TGFBIp) is an important extracellular mediator of sepsis.
• Compounds 1–3 inhibited LPS-induced secretion of TGFBIp.
• Compounds 1–3 inhibited TGFBIp-mediated hyperpermeability.
• Compounds 1–3 inhibited TGFBIp-mediated septic response.
• Compounds 1–3 reduced TGFBIp-induced septic mortality.

Transforming growth factor β induced protein (TGFBIp) is an extracellular matrix protein which expression in several cell types is greatly increased by TGF-β. TGFBIp is released by human umbilical vein endothelial cells (HUVECs), and functions as a mediator of experimental sepsis. Pentacyclic triterpenoids bearing a carboxyl group at C-27 position, 3β,6α-dihydroxyolup-20(29)-ene (1), 3β,6β-dihydroxyolean-12-en-27-oic acid (2) and 3β,24-dihydroxyolean-12-en-27-oic acid (3), are representative bioactive molecules in the genus Astilbe that possess cytotoxic, anti-inflammatory and wounds healing activities. Based on the biological effects of C-27 carboxylated pentacyclic triterpenoids, we investigated the anti-inflammatory effects of compounds 1–3 against TGFBIp-mediated vascular inflammatory responses. The anti-inflammatory activities of compounds 1–3 were determined by measuring permeability, leukocytes adhesion and migration, and activation of pro-inflammatory proteins in TGFBIp-activated human HUVECs and mice. We found that compounds 1–3 inhibited TGFBIp-induced barrier disruption, expression of cell adhesion molecules (CAMs) and adhesion/transendothelial migration of neutrophils to human endothelial cells. Each compound also suppressed TGFBIp-induced hyperpermeability and leukocyte migration in vivo. These results suggest that compounds 1–3 possess anti-inflammatory functions by inhibiting hyperpermeability, expression of CAMs, and adhesion and migration of leukocytes, thereby endorsing its usefulness as a therapy for vascular inflammatory diseases.