Article

Soluble MD-2 activity in plasma from patients with severe sepsis and septic shock

Laboratory of the Division of Intensive Care, Department of Internal Medicine, University Hospital of Geneva, 24, rue Micheli-du-Crest, 1211 Geneva 14, Switzerland.
Blood (Impact Factor: 10.45). 01/2005; 104(13):4071-9. DOI: 10.1182/blood-2003-04-1290
Source: PubMed

ABSTRACT

In this paper, we show that plasma from patients with severe sepsis and septic shock but not normal plasma supports lipopolysaccharide (LPS) activation of epithelial cells expressing Toll-like receptor 4 (TLR4). Recombinant soluble myeloid differentiation protein-2 (MD-2) complemented normal plasma and allowed LPS activation of epithelial cells to levels measured with "septic" plasma, whereas soluble MD-2-depleted plasma lost its effects. The same "MD-2 activity" was found in urine from a patient with septic shock and in lung edema fluids from patients with adult respiratory distress syndrome (ARDS). Recombinant soluble MD-2 enabled LPS-dependent activation of epithelial cells bearing TLR4. LPS-binding protein (LBP) and soluble CD14 increased the sensitivity of TLR4-expressing epithelial cells to LPS but were not able to mediate LPS activation of these cells in the absence of soluble MD-2. An anti-MD-2 monoclonal antibody blocked LPS activation of TLR4-expressing cells only in the presence of septic plasma or septic urine. These results suggest that septic plasma containing soluble MD-2 leaking into the extravascular space supports LPS activation of TLR4-expressing epithelial cells. We therefore propose that soluble MD-2 is an important mediator of organ inflammation during sepsis.

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Available from: Greg Elson, May 23, 2014
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    • "In addition, fluorescent microscopy in the rat kidney showed that colocalization of TLR4 and CD14 in renal tubular cells and their expression patterns were markedly affected in response to sepsis.46 LPS injection in pretreated rats with an antagonist of renal beta2-adrenoreceptor (modulator of LPS transport in the kidney), decreased creatinine clearance combined with a significant increase in the expression of TLR4, CD14, and tumor necrosis factor alpha.59 Concurrently, soluble MD2 was found to be increased in the serum and urine of septic patients, and this molecule has been shown to increase TLR4 activation of the receptor in human embryonic kidney epithelial cells in response to LPS.60 "
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    ABSTRACT: The innate immune system plays an important role as a first response to tissue injury. This first response is carried out via germline-encoded receptors. Toll-like receptors (TLRs) are the first identified and best studied family of pattern recognition receptors. TLRs are expressed on a variety of cell types, including epithelial cells, endothelia, dendritic cells, monocytes/macrophages, and B- and T-cells. TLRs initiate innate immune responses and concurrently shape the subsequent adaptive immune response. They are sensors of both pathogens, through the exogenous pathogen-associated molecular patterns (PAMPs), and tissue injury, through the endogenous danger-associated molecular patterns (DAMPs). TLR signaling is critical in defending against invading microorganisms; however, sustained receptor activation is also implicated in the pathogenesis of inflammatory diseases. Ischemic kidney injury involves early TLR-driven immunopathology, and the resolution of inflammation is needed for rapid regeneration of injured tubule cells. Notably, the activation of TLRs also has been implicated in epithelial repair. This review focuses on the role of TLRs and their endogenous ligands within the inflammatory response of acute kidney injury.
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    • "Here, we show for the first time a strongly enhanced expression of MD-2 by pulmonary endothelial cells during sepsis. This increased MD-2 expression could be responsible for enhanced sensitivity to LPS, resulting in the production of chemokines and adhesion molecules and could explain the extreme susceptibility of lung tissue during endotoxemia and sepsis (Pugin et al., 2004). This is supported by a murine endotoxemia study, showing that the pulmonary endothelium is the dominant regulator of neutrophil accumulation and concomitant pulmonary failure (Andonegui et al., 2003). "

    Full-text · Dataset · May 2014
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    • "Here, we show for the first time a strongly enhanced expression of MD-2 by pulmonary endothelial cells during sepsis. This increased MD-2 expression could be responsible for enhanced sensitivity to LPS, resulting in the production of chemokines and adhesion molecules and could explain the extreme susceptibility of lung tissue during endotoxemia and sepsis (Pugin et al., 2004). This is supported by a murine endotoxemia study, showing that the pulmonary endothelium is the dominant regulator of neutrophil accumulation and concomitant pulmonary failure (Andonegui et al., 2003). "

    Full-text · Dataset · May 2014
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