title: Catalpol restores LPS-elicited rat microcirculation disorder by regulation of a network of signaling involving inhibition of TLR-4 and SRC.
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.
authors: Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China.|Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.|Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.|Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.|Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, China; and.
authors: Yun-Pei
authors: YP
authors: Zhang
authors: Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.|Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.|Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.|Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, China; and.
authors: Chun-Shui
authors: CS
authors: Pan
authors: Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.|Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.|Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.|Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, China; and.
authors: Li
authors: L
authors: Yan
authors: Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.|Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.|Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.|Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, China; and.
authors: Yu-Ying
authors: YY
authors: Liu
authors: Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.|Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.|Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.|Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, China; and.
authors: Bai-He
authors: BH
authors: Hu
authors: Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.|Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.|Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.|Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, China; and.
authors: Xin
authors: X
authors: Chang
authors: Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.|Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.|Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.|Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, China; and.
authors: Quan
authors: Q
authors: Li
authors: Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China.|Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.|Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.|Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.|Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, China; and.
authors: Dan-Dan
authors: DD
authors: Huang
authors: Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China.|Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.|Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.|Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.|Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, China; and.
authors: Hao-Yu
authors: HY
authors: Sun
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors: Ge
authors: G
authors: Fu
authors: Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.|Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.|Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.|Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, China; and.
authors: Kai
authors: K
authors: Sun
authors: Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.
authors: Jing-Yu
authors: JY
authors: Fan
authors: Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China; hanjingyan@bjmu.edu.cn.|Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.|Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.|Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.|Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, China; and.
authors: Jing-Yan
authors: JY
authors: Han
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D002401:Cathepsin B / Q000378:metabolism; D062507:Claudin-5 / Q000378:metabolism; D006470:Hemorrhage / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D057888:Iridoid Glucosides / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D008643:Mesentery / Q000098:blood supply; D008833:Microcirculation / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D062507:Claudin-5; D057888:Iridoid Glucosides; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4; C078040:catalpol; D019061:src-Family Kinases; D002401:Cathepsin B
keywords: cathepsin B; extracellular matrix; focal adhesion kinase; hemorrhage; tight junctions