PULMONARY AND HEPATIC GENE-EXPRESSION FOLLOWING CECAL LIGATION AND PUNCTURE - MONOPHOSPHORYL LIPID-A PROPHYLAXIS ATTENUATES SEPSIS-INDUCED CYTOKINE AND CHEMOKINE EXPRESSION AND NEUTROPHIL INFILTRATION

Polymicrobial sepsis induced by cecal ligation and puncture (CLP) repr oduces many of the pathophysiologic features of septic shock In this s tudy, we demonstrate that mRNA for a broad range of pro- and anti-infl ammatory cytokine and chemokine genes are temporally regulated after C LP in the lung and liver. We also assessed whether prophylactic admini stration of monophosphoryl lipid A (MPL), a nontoxic derivative of lip opolysaccharide (LPS) that induces endotoxin tolerance and attenuates the sepsis syndrome in mice after CLP, would alter tissue-specific gen e expression post-CLP, Levels of pulmonary interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), granulocyte colony-stimulating fac tor (G-CSF), IL-1 receptor antagonist (IL-1ra), and IL-10 mRNA, as wel l as hepatic IL-1 beta, IL-6, gamma interferon (IFN-gamma), G-CSF, ind ucible nitric oxide synthase, and IL-10 mRNA, were reduced in MPL-pret reated mice after CLP compared to control mice. Chemokine mRNA express ion was also profoundly mitigated in MPL-pretreated mice after CLP. Sp ecifically, levels of pulmonary and hepatic macrophage inflammatory pr otein 1 alpha (MIP-1 alpha), MIP-1 beta, MIP-2, and monocyte chemoattr actant protein-1 (MCP-1) mRNA, as well as hepatic IFN-gamma-inducible protein 10 and KC mRNA, were attenuated in MPC-pretreated mice after C LP, Attenuated levels of IL-6, TNF-alpha, MCP-1, MIP-1 alpha, and MIP- 2 in serum also were observed in MPG-pretreated mice after CLP. Dimini shed pulmonary chemokine mRNA production was associated with reduced n eutrophil margination and pulmonary myeloperoxidase activity. These da ta suggest that prophylactic administration of MPL mitigates the sepsi s syndrome by reducing chemokine production and the recruitment of inf lammatory cells into tissues, thereby attenuating the production of pr oinflammatory cytokines.