Role of MCP-1 in endotoxemia and sepsis.
Sepsis is a complex clinical syndrome resulting from a harmful host inflammatory response to infection. Similarly, lipopolysaccharide (LPS) induced endotoxemia is marked by the activation of inflammatory responses, which can lead to shock, multiple organ damage and even death. Inflammatory mediator, chemokines are known to play an important role in the pathogenesis of sepsis and endotoxemia. Monocyte chemoattractant protein (MCP)-1, a prototype of CC chemokines, is a potent chemoattractant and a regulatory mediator involved in a variety of inflammatory diseases. The objective of this study is to investigate the role of MCP-1, by using bindarit, a blocker of MCP-1 synthesis, in murine models of sepsis and endotoxemia. Treatment with bindarit both prophylactically and therapeutically significantly (P<0.05) reduced MCP-1 levels in the lungs and liver in both sepsis and endotoxemia. In addition, prophylactic and therapeutic treatment with bindarit significantly (P<0.05) protected mice against sepsis and endotoxemia, as evidenced by the attenuation in lung and liver myeloperoxidase (MPO) activity, an indicator of neutrophil recruitment. The protective effect of bindarit was further confirmed by histological examination of lung and liver sections. Treatment with bindarit reduced lung and liver injury as indicated by decreased thickening of alveolar and neutrophil infiltration in CLP-induced sepsis and LPS-induced endotoxemia. Considering these results, we propose that anti-MCP-1 strategies may be of potential therapeutic value in the treatment of sepsis and endotoxemia.
Ramnath
Raina Devi
RD
Department of Pharmacology, National University of Singapore, Singapore.
Ng
Siaw Wei
SW
Guglielmotti
Angelo
A
Bhatia
Madhav
M
D000818:Animals; D002147:Calmodulin / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000378:metabolism*; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D007191:Indazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008070:Lipopolysaccharides; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010538:Peritonitis / Q000188:drug therapy / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology* / Q000627:therapeutic use; D018805:Sepsis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*
D002147:Calmodulin; D018932:Chemokine CCL2; D007191:Indazoles; D008070:Lipopolysaccharides; D011422:Propionates; D009195:Peroxidase; C079489:bindarit