Pyrrolidine dithiocarbamate prevents I-kappaB degradation and reduces microvascular injury induced by lipopolysaccharide in multiple organs.
Lipopolysaccharide (LPS) is a key mediator of multiple organ injury observed in septic shock. The mechanisms responsible for LPS-induced multiple organ injury remain obscure. In the present study, we tested the hypothesis that the LPS-induced injury occurs through activation of the transcription factor, nuclear factor-kappaB (NF-kappaB). We examined the effects of inhibiting NF-kappaB activation in vivo in the rat on LPS-induced: 1) gene and protein expression of the cytokine-inducible neutrophil chemoattractant (CINC) and intercellular adhesion molecule-1 (ICAM-1); b) neutrophil influx into lungs, heart, and liver; and c) increase in microvascular permeability induced by LPS in these organs. LPS (8 mg/kg, i.v.) challenge of rats activated NF-kappaB and induced CINC and ICAM-1 mRNA and protein expression. Pretreatment of rats with pyrrolidine dithiocarbamate (50, 100, and 200 mg/kg, i.p.), an inhibitor of NF-kappaB activation, prevented LPS-induced I-kappaBalpha degradation and the resultant NF-kappaB activation and inhibited, in a dose-related manner, the LPS-induced CINC and ICAM-1 mRNA and protein expression. Pyrrolidine dithiocarbamate also markedly reduced the LPS-induced tissue myeloperoxidase activity (an indicator of tissue neutrophil retention) and the LPS-induced increase in microvascular permeability in these organs. These results demonstrate that NF-kappaB activation is an important in vivo mechanism mediating LPS-induced CINC and ICAM-1 expression, as well as neutrophil recruitment, and the subsequent organ injury. Thus, inhibition of NF-kappaB activation may be an important strategy for the treatment of sepsis-induced multiple organ injury.
Liu
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SF
Department of Pharmacology, The University of Illinois, College of Medicine, Chicago, Illinois, USA.
Ye
X
X
Malik
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AB
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D002196:Capillaries / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004794:Enzyme Repression; D006133:Growth Substances / Q000096:biosynthesis / Q000235:genetics; D020672:I-kappa B Proteins; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011759:Pyrrolidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000473:pathology*; D013859:Thiocarbamates / Q000627:therapeutic use*
D000975:Antioxidants; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D004268:DNA-Binding Proteins; D006133:Growth Substances; D020672:I-kappa B Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011759:Pyrrolidines; D012333:RNA, Messenger; D013859:Thiocarbamates; D018799:Intercellular Adhesion Molecule-1; C020972:pyrrolidine dithiocarbamic acid; D009195:Peroxidase