Abstract
BackgroundMicrocirculatory disturbance is closely associated with multiple diseases such as ischemic and septic stroke. Luteolin (3,4,5,7-tetrahydroxyflavone) is a vascular protective flavonoid present in several dietary foods. However, how luteolin plays a role in microcirculatory disturbance is still unknown. The purpose of this study was to find out the influence of luteolin on the lipopolysaccharide (LPS)-induced microcirculatory disturbance, focusing on its effect on leukocyte adhesion and the underlying mechanism of this effect.MethodsAfter injecting LPS into rats, we used an inverted intravital microscope to observe the velocity of red blood cells in venules, numbers of leukocytes adherent to and emigrated across the venular wall, hydrogen peroxide production in venular walls and mast cell degranulation. Intestinal microcirculation blood flow was measured by High-resolution Laser Doppler Perfusion Imaging. Histological changes of small intestine and mesenteric arteries were evaluated. Additionally, cell adhesion stimulated by LPS was tested on EA.hy926 and THP-1 cells. The production of pro-inflammatory cytokines, adhesion molecules and the activation of TLR4/Myd88/NF-κB signaling pathway were determined.ResultsThe results showed luteolin significantly inhibited LPS-induced leukocyte adhesion, hydrogen peroxide production and mast cell degranulation, and increased intestinal microcirculation blood flow and ameliorated pathological changes in the mesenteric artery and the small intestine. Furthermore, luteolin inhibited the release of pro-inflammatory cytokines, the expression of TLR4, Myd88, ICAM-1, and VCAM-1, the phosphorylation of IκB-α and NF-κB/p65 in LPS stimulated EA.hy926.ConclusionsOur findings revealed that it is likely that luteolin can ameliorate microcirculatory disturbance. The inhibitory effects of luteolin on the leukocyte adhesion stimulated by LPS, which participates in the development of microcirculatory disturbance, are mediated through the regulation of the TLR4/Myd88/NF-κB signaling pathway.
Highlights
Microcirculatory disturbance is closely associated with multiple diseases such as ischemic and septic stroke
No adherent leukocyte was observed at 10 min after LPS injection in Luteolin enriched extracts (TLUT) 75 mg/kg group, while still some adherent leukocytes remained at 10 min in TLUT 45 mg/kg group
In order to explore the antiadhesion mechanisms of luteolin, we examined the expression of related factors of LPS/toll-like receptor 4 (TLR4)/Nuclear factor-kappa B (NF-κB) signaling pathway in EA.hy926 stimulated with LPS by western blot, including TLR4, Myd88, intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and activation of Inhibitor of Nuclear factorkappa B (IκB)-α and NF-κB/p65
Summary
Microcirculatory disturbance is closely associated with multiple diseases such as ischemic and septic stroke. Microcirculation is composed of arterioles, capillaries, and venules, functioning essentially as oxygen and source supply depending on the unique physiological need of the supplied organs [1]. It is composed of endothelial cells (ECs), basement membranes, pericytes, and smooth muscle cells. Microcirculatory disturbance, which can cause multiple organ damage, is a complex pathological process involving abnormal leukocyte-EC interactions, excessive production of peroxide, degranulated mast cells, and hyperpermeability of microvessel wall [2, 3]. Venules have been found to be closely related to some diseases [10] such as ischemic stroke [11]. In the process of treating related diseases, improving the disturbance of microcirculation is an important measure to achieve a good prognosis
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