title: Improvements in endotoxemic syndromes using a disintegrin, rhodostomin, through integrin αvβ3-dependent pathway.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: C-C
authors.initials: CC
authors.lastname: Hsu
authors.forename: W-J
authors.initials: WJ
authors.lastname: Chuang
authors.forename: C-H
authors.initials: CH
authors.lastname: Chang
authors.forename: Y-L
authors.initials: YL
authors.lastname: Tseng
authors.forename: H-C
authors.initials: HC
authors.lastname: Peng
authors.forename: T-F
authors.initials: TF
authors.lastname: Huang
mesh_terms: D000818:Animals; D001665:Binding Sites; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D019483:Disintegrins / Q000494:pharmacology; D019446:Endotoxemia / Q000188:drug therapy* / Q000503:physiopathology*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D008070:Lipopolysaccharides / Q000633:toxicity; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010455:Peptides / Q000494:pharmacology*; D010586:Phagocytes / Q000187:drug effects / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D013921:Thrombocytopenia / Q000097:blood / Q000188:drug therapy
chemical_list: D016207:Cytokines; D019483:Disintegrins; D039302:Integrin alphaVbeta3; D008070:Lipopolysaccharides; D010455:Peptides; D034741:RNA, Small Interfering; C072026:rhodostomin