1. Academic Validation
  2. Catalpol restores LPS-elicited rat microcirculation disorder by regulation of a network of signaling involving inhibition of TLR-4 and SRC

Catalpol restores LPS-elicited rat microcirculation disorder by regulation of a network of signaling involving inhibition of TLR-4 and SRC

  • Am J Physiol Gastrointest Liver Physiol. 2016 Dec 1;311(6):G1091-G1104. doi: 10.1152/ajpgi.00159.2016.
Yun-Pei Zhang 1 2 3 4 5 Chun-Shui Pan 2 3 4 5 Li Yan 2 3 4 5 Yu-Ying Liu 2 3 4 5 Bai-He Hu 2 3 4 5 Xin Chang 2 3 4 5 Quan Li 2 3 4 5 Dan-Dan Huang 1 2 3 4 5 Hao-Yu Sun 1 2 3 4 5 Ge Fu 6 Kai Sun 2 3 4 5 Jing-Yu Fan 2 Jing-Yan Han 7 2 3 4 5
Affiliations

Affiliations

  • 1 Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China.
  • 2 Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.
  • 3 Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.
  • 4 Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.
  • 5 Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, China; and.
  • 6 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.
  • 7 Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China; hanjingyan@bjmu.edu.cn.
Abstract

LPS-induced microvascular hyperpermeability and hemorrhage play a key role in the development of sepsis, the attenuation of which might be an important strategy to prevent sepsis. However, the current clinical therapies have proven to be inefficient in improving the prognosis for patients with sepsis. Catalpol, an iridoid glycoside extracted from the roots of Rehmannia, has been reported to protect against LPS-induced acute lung injury through a Toll-like receptor-4 (TLR-4)-mediated NF-κB signaling pathway. However, it is still unknown whether catalpol can be an effective treatment to ameliorate the LPS-induced microvascular disorder. The present study aimed to investigate the impact of catalpol on LPS-induced mesenteric microvascular disorder and its underlying mechanism. Male Wistar rats were challenged by infusion of LPS (10 mg·kg-1·h-1) through the left femoral vein for 120 min. Post-treatment with catalpol (10 mg/kg) alleviated the LPS-induced microvascular hyperpermeability and hemorrhage; reduced mortality; ameliorated the alteration in the distribution of claudin-5 and the junctional adhesion molecule-1, as well as the degradation of collagen IV and laminin; and attenuated the increase of TLR-4 level, phosphorylations of Src tyrosine kinase, phosphatidyl inositol 3-kinase, focal adhesion kinase, and Cathepsin B activation. In vitro study in human umbilical vein endothelial cells verified these results and further revealed that inhibition of TLR-4 and Src each simulated some, but not all, of the effects that catalpol exerted. Besides, surface plasmon resonance showed that catalpol could directly bind to TLR-4 and Src. These results demonstrated that catalpol was able to ameliorate the LPS-induced microvascular barrier damage and hemorrhage by targeting both TLR-4 and Src, thus attenuating the phosphorylation of Src kinase, phosphatidyl inositol 3-kinase, and focal adhesion kinase, as well as Cathepsin B activation.

Keywords

cathepsin B; extracellular matrix; focal adhesion kinase; hemorrhage; tight junctions.

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