Pulmonary and Hepatic Gene Expression following Cecal Ligation and Puncture: Monophosphoryl Lipid A Prophylaxis Attenuates Sepsis-Induced Cytokine and Chemokine Expression and Neutrophil Infiltration

Abstract

Polymicrobial sepsis induced by cecal ligation and puncture (CLP) reproduces many of the pathophysiologic features of septic shock. In this study, we demonstrate that mRNA for a broad range of pro- and anti-inflammatory cytokine and chemokine genes are temporally regulated after CLP in the lung and liver. We also assessed whether prophylactic administration of monophosphoryl lipid A (MPL), a nontoxic derivative of lipopolysaccharide (LPS) that induces endotoxin tolerance and attenuates the sepsis syndrome in mice after CLP, would alter tissue-specific gene expression post-CLP. Levels of pulmonary interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), granulocyte colony-stimulating factor (G-CSF), IL-1 receptor antagonist (IL-1ra), and IL-10 mRNA, as well as hepatic IL-1β, IL-6, gamma interferon (IFN-γ), G-CSF, inducible nitric oxide synthase, and IL-10 mRNA, were reduced in MPL-pretreated mice after CLP compared to control mice. Chemokine mRNA expression was also profoundly mitigated in MPL-pretreated mice after CLP. Specifically, levels of pulmonary and hepatic macrophage inflammatory protein 1α (MIP-1α), MIP-1β, MIP-2, and monocyte chemoattractant protein-1 (MCP-1) mRNA, as well as hepatic IFN-γ-inducible protein 10 and KC mRNA, were attenuated in MPL-pretreated mice after CLP. Attenuated levels of IL-6, TNF-α, MCP-1, MIP-1α, and MIP-2 in serum also were observed in MPL-pretreated mice after CLP. Diminished pulmonary chemokine mRNA production was associated with reduced neutrophil margination and pulmonary myeloperoxidase activity. These data suggest that prophylactic administration of MPL mitigates the sepsis syndrome by reducing chemokine production and the recruitment of inflammatory cells into tissues, thereby attenuating the production of proinflammatory cytokines.

Neurokinin-1 receptor antagonist treatment protects mice against lung injury in polymicrobial sepsis

“…Recruitment of various inflammatory cells including neutrophils is mediated by chemokines [32], MCP-1 and MIP-2, which are known to orchestrate migration of leukocytes during sepsis and lead to tissue injury. We have shown that MCP-1 and MIP-2 level in lung correlates with neutrophil infiltration in the lung [15].…”

Microvascular Dysfunction in Sepsis

“…Circulating PMN accumulate in a variety of organ systems of animals rendered septic (or endotoxemic), including the heart (6,55,56,128), intestinal muscularis (130), skeletal muscle (69), mesentery (28), lung (1,69,112,142,144,185), and liver (69,118,151,189). However, there are reports that circulating PMN do not accumulate in the intestinal mucosa (130) or skeletal muscle (141) during normotensive polymicrobial sepsis.…”

The role of chemokines in the immunopathology of the liver

“…After their migration into the hepatic parenchyma, activated neutrophils can produce oxygen-derived radicals that induce lipid peroxidation of cell membranes and eventual hepatic necrosis. In a sepsis model induced by cecal ligation and puncture (CLP), CC chemokine expression is dramatically upregulated in the liver, and examples include MIP-1a, MIP-1b, and MCP-1 (33). Furthermore, although sources of MCP-1 are not known, other studies have shown that MCP-1 levels are elevated in the serum (34) and in the liver (35), due partly to its exaggerated release from the Kupffer cells of the liver.…”

“…The ELR-CXC chemokines also play a role in sepsis. KC, MIP-2, and IP-10 are expressed in the liver during sepsis (33,36,37). While neutralization of KC did not decrease neutrophil influx, it did decrease liver injury (36).…”