Improvements in endotoxemic syndromes using a disintegrin, rhodostomin, through integrin αvβ3-dependent pathway

C. C. Hsu, Woei-Jer Chuang, C. H. Chang, Y. L. Tseng, H. C. Peng, T. F. Huang

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background 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.

Original languageEnglish
Pages (from-to)593-602
Number of pages10
JournalJournal of Thrombosis and Haemostasis
Volume9
Issue number3
DOIs
Publication statusPublished - 2011 Mar 1

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Disintegrins
Integrins
Lipopolysaccharides
Phagocytes
Monocytes
Endotoxemia
Mitogen-Activated Protein Kinases
rhodostomin
Cytokines
Inflammation
Vitronectin
Snake Venoms
Macrophage Activation
Septic Shock
Interleukin-1
Fibronectins
Thrombocytopenia
Small Interfering RNA
Transfection
Intensive Care Units

All Science Journal Classification (ASJC) codes

  • Hematology

Cite this

Hsu, C. C. ; Chuang, Woei-Jer ; Chang, C. H. ; Tseng, Y. L. ; Peng, H. C. ; Huang, T. F. / Improvements in endotoxemic syndromes using a disintegrin, rhodostomin, through integrin αvβ3-dependent pathway. In: Journal of Thrombosis and Haemostasis. 2011 ; Vol. 9, No. 3. pp. 593-602.
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Improvements in endotoxemic syndromes using a disintegrin, rhodostomin, through integrin αvβ3-dependent pathway. / Hsu, C. C.; Chuang, Woei-Jer; Chang, C. H.; Tseng, Y. L.; Peng, H. C.; Huang, T. F.

In: Journal of Thrombosis and Haemostasis, Vol. 9, No. 3, 01.03.2011, p. 593-602.

Research output: Contribution to journalArticle

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AB - Background 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.

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