Hsu C.-C.Chuang W.-J.Chang C.-H.Tseng Y.-L.Peng H.-C.TUR-FU HUANG2021-05-312021-05-31201115387933https://scholars.lib.ntu.edu.tw/handle/123456789/564126Background and objectives:Septic shock is a major cause of morbidity and mortality in intensive care units, but there is still no effective therapy for the patients. We evaluated the effects of rhodostomin (Rn), an Arg-Gly-Asp-containing snake venom disintegrin, on lipopolysaccharide (LPS)-activated phagocytes in vitro and LPS-induced endotoxemia in vivo. Methods and results:Rn inhibited adhesion, migration, cytokine production and mitogen-activated protein kinase (MAPK) activation of macrophage induced by LPS. Flow cytometric analysis revealed that Rn specifically blocked anti-αv mAb binding to RAW264.7. Besides inhibiting MAPK activation of THP-1, Rn bound to LPS-activated THP-1 and specifically blocked anti-αvβ3 mAb binding to THP-1. Binding assays proved that integrin αvβ3 was the binding site for rhodostomin on phagocytes. Rn reversed the enhancement of fibronectin and vitronectin on LPS-induced monocyte adhesion and cytokine release. Transfection of integrin αv siRNA also inhibited LPS-induced activation of monocyte, and Rn exerted no further inhibitory effect. Furthermore, Rn significantly decreased the production of tumor necrosis factor-α (TNF-a), interleukin (IL)-6, -1β and -10 and attenuated cardiovascular dysfunction, including blood pressure and heart pulse, and thrombocytopenia in LPS-induced endotoxemic mice. Rn also protected against tissue inflammation as evidenced by histological examination. Conclusions:Rn may interact with αvβ3 integrin of monocytes/macrophages leading to interfere with the activation of phagocytes triggered by LPS. These results suggest that the protective function of Rn in LPS-induced endotoxemia may be attributed to its anti-inflammation activities in vivo. ? 2011 International Society on Thrombosis and Haemostasis.[SDGs]SDG3cytokine; disintegrin; fibronectin; interleukin 10; interleukin 1beta; interleukin 6; lipopolysaccharide; mitogen activated protein kinase; rhodostomin; small interfering RNA; tumor necrosis factor alpha; unclassified drug; vitronectin; vitronectin receptor; animal cell; animal experiment; animal model; animal tissue; antiinflammatory activity; article; binding site; blood pressure; cardiovascular disease; cell adhesion; cell migration; cytokine production; cytokine release; drug effect; endotoxemia; enzyme activation; heart rate; histopathology; human; human cell; immunohistochemistry; in vitro study; macrophage; male; mortality; mouse; nonhuman; phagocyte; priority journal; signal transduction; thrombocytopenia; tissue injury; Animals; Binding Sites; Cell Adhesion; Cell Line; Cell Movement; Cytokines; Disintegrins; Endotoxemia; Humans; Integrin alphaVbeta3; Lipopolysaccharides; Macrophage Activation; Male; MAP Kinase Signaling System; Mice; Mice, Inbred ICR; Peptides; Phagocytes; RNA Interference; RNA, Small Interfering; Thrombocytopeniajournal article10.1111/j.1538-7836.2010.04163.x211433762-s2.0-79952062165