PMID- 27789455 OWN - NLM STAT- MEDLINE DCOM- 20170615 LR - 20180920 IS - 1522-1547 (Electronic) IS - 0193-1857 (Linking) VI - 311 IP - 6 DP - 2016 Dec 1 TI - Catalpol restores LPS-elicited rat microcirculation disorder by regulation of a network of signaling involving inhibition of TLR-4 and SRC. PG - G1091-G1104 LID - 10.1152/ajpgi.00159.2016 [doi] AB - 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-kappaB 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. CI - Copyright (c) 2016 the American Physiological Society. FAU - Zhang, Yun-Pei AU - Zhang YP AD - Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China. AD - Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China. AD - Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China. AD - Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China. AD - Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, China; and. FAU - Pan, Chun-Shui AU - Pan CS AD - Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China. AD - Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China. AD - Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China. AD - Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, China; and. FAU - Yan, Li AU - Yan L AD - Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China. AD - Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China. AD - Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China. AD - Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, China; and. FAU - Liu, Yu-Ying AU - Liu YY AD - Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China. AD - Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China. AD - Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China. AD - Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, China; and. FAU - Hu, Bai-He AU - Hu BH AD - Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China. AD - Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China. AD - Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China. AD - Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, China; and. FAU - Chang, Xin AU - Chang X AD - Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China. AD - Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China. AD - Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China. AD - Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, China; and. FAU - Li, Quan AU - Li Q AD - Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China. AD - Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China. AD - Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China. AD - Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, China; and. FAU - Huang, Dan-Dan AU - Huang DD AD - Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China. AD - Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China. AD - Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China. AD - Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China. AD - Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, China; and. FAU - Sun, Hao-Yu AU - Sun HY AD - Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China. AD - Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China. AD - Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China. AD - Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China. AD - Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, China; and. FAU - Fu, Ge AU - Fu G AD - State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China. FAU - Sun, Kai AU - Sun K AD - Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China. AD - Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China. AD - Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China. AD - Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, China; and. FAU - Fan, Jing-Yu AU - Fan JY AD - Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China. FAU - Han, Jing-Yan AU - Han JY AD - Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China; hanjingyan@bjmu.edu.cn. AD - Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China. AD - Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China. AD - Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China. AD - Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, China; and. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20161027 PL - United States TA - Am J Physiol Gastrointest Liver Physiol JT - American journal of physiology. Gastrointestinal and liver physiology JID - 100901227 RN - 0 (Claudin-5) RN - 0 (Iridoid Glucosides) RN - 0 (Lipopolysaccharides) RN - 0 (Toll-Like Receptor 4) RN - 2415-24-9 (catalpol) RN - EC 2.7.10.2 (src-Family Kinases) RN - EC 3.4.22.1 (Cathepsin B) SB - IM MH - Animals MH - Capillary Permeability/*drug effects MH - Cathepsin B/metabolism MH - Claudin-5/metabolism MH - Hemorrhage/*metabolism MH - Human Umbilical Vein Endothelial Cells/drug effects/metabolism MH - Humans MH - Iridoid Glucosides/*pharmacology MH - Lipopolysaccharides/toxicity MH - Male MH - Mesentery/blood supply MH - Microcirculation/drug effects MH - Protein Binding MH - Rats MH - Rats, Wistar MH - Signal Transduction MH - Toll-Like Receptor 4/antagonists & inhibitors/*metabolism MH - src-Family Kinases/antagonists & inhibitors/*metabolism OTO - NOTNLM OT - cathepsin B OT - extracellular matrix OT - focal adhesion kinase OT - hemorrhage OT - tight junctions EDAT- 2016/10/30 06:00 MHDA- 2017/06/16 06:00 CRDT- 2016/10/30 06:00 PHST- 2016/04/21 00:00 [received] PHST- 2016/10/24 00:00 [accepted] PHST- 2016/10/30 06:00 [pubmed] PHST- 2017/06/16 06:00 [medline] PHST- 2016/10/30 06:00 [entrez] AID - ajpgi.00159.2016 [pii] AID - 10.1152/ajpgi.00159.2016 [doi] PST - ppublish SO - Am J Physiol Gastrointest Liver Physiol. 2016 Dec 1;311(6):G1091-G1104. doi: 10.1152/ajpgi.00159.2016. Epub 2016 Oct 27.